| 1. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Kollhoff, A., et al.
(författare)
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The first widespread solar energetic particle event observed by Solar Orbiter on 2020 November 29
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 656
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Tidskriftsartikel (refereegranskat)abstract
- Context. On 2020 November 29, the first widespread solar energetic particle (SEP) event of solar cycle 25 was observed at four widely separated locations in the inner (≲1 AU) heliosphere. Relativistic electrons as well as protons with energies > 50 MeV were observed by Solar Orbiter (SolO), Parker Solar Probe, the Solar Terrestrial Relations Observatory (STEREO)-A and multiple near-Earth spacecraft. The SEP event was associated with an M4.4 class X-ray flare and accompanied by a coronal mass ejection and an extreme ultraviolet (EUV) wave as well as a type II radio burst and multiple type III radio bursts.Aims. We present multi-spacecraft particle observations and place them in context with source observations from remote sensing instruments and discuss how such observations may further our understanding of particle acceleration and transport in this widespread event.Methods. Velocity dispersion analysis (VDA) and time shift analysis (TSA) were used to infer the particle release times at the Sun. Solar wind plasma and magnetic field measurements were examined to identify structures that influence the properties of the energetic particles such as their intensity. Pitch angle distributions and first-order anisotropies were analyzed in order to characterize the particle propagation in the interplanetary medium.Results. We find that during the 2020 November 29 SEP event, particles spread over more than 230° in longitude close to 1 AU. The particle onset delays observed at the different spacecraft are larger as the flare–footpoint angle increases and are consistent with those from previous STEREO observations. Comparing the timing when the EUV wave intersects the estimated magnetic footpoints of each spacecraft with particle release times from TSA and VDA, we conclude that a simple scenario where the particle release is only determined by the EUV wave propagation is unlikely for this event. Observations of anisotropic particle distributions at SolO, Wind, and STEREO-A do not rule out that particles are injected over a wide longitudinal range close to the Sun. However, the low values of the first-order anisotropy observed by near-Earth spacecraft suggest that diffusive propagation processes are likely involved.
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| 3. |
- Wallen, K. E., et al.
(författare)
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Integrating team science into interdisciplinary graduate education : an exploration of the SESYNC Graduate Pursuit
- 2019
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Ingår i: Journal of Environmental Studies and Sciences. - : Springer Science and Business Media LLC. - 2190-6483 .- 2190-6491. ; 9:2, s. 218-233
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Tidskriftsartikel (refereegranskat)abstract
- Complex socio-environmental challenges require interdisciplinary, team-based research capacity. Graduate students are fundamental to building such capacity, yet formal opportunities for graduate students to develop these capacities and skills are uncommon. This paper presents an assessment of the Graduate Pursuit (GP) program, a formal interdisciplinary team science graduate research and training program administered by the National Socio-Environmental Synthesis Center (SESYNC). Quantitative and qualitative assessment of the program’s first cohort revealed that participants became significantly more comfortable with interdisciplinary research and team science approaches, increased their capacity to work across disciplines, and were enabled to produce tangible research outcomes. Qualitative analysis of four themes—(1) discipline, specialization, and shared purpose, (2) interpersonal skills and personality, (3) communication and teamwork, and (4) perceived costs and benefits—encompass participants’ positive and negative experiences and support findings from past assessments. The findings also identify challenges and benefits related to individual personality traits and team personality orientation, the importance of perceiving a sense of autonomy and independence, and the benefit of graduate training programs independent of the university and graduate program environment.
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| 4. |
- Witasse, O., et al.
(författare)
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Interplanetary coronal mass ejection observed at STEREO-A, Mars, comet 67P/Churyumov-Gerasimenko, Saturn, and New Horizons en route to Pluto : Comparison of its Forbush decreases at 1.4, 3.1, and 9.9 AU
- 2017
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Ingår i: Journal of Geophysical Research - Space Physics. - 2169-9380 .- 2169-9402. ; 122:8, s. 7865-7890
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Tidskriftsartikel (refereegranskat)abstract
- We discuss observations of the journey throughout the Solar System of a large interplanetary coronal mass ejection (ICME) that was ejected at the Sun on 14 October 2014. The ICME hit Mars on 17 October, as observed by the Mars Express, Mars Atmosphere and Volatile EvolutioN Mission (MAVEN), Mars Odyssey, and Mars Science Laboratory (MSL) missions, 44h before the encounter of the planet with the Siding-Spring comet, for which the space weather context is provided. It reached comet 67P/Churyumov-Gerasimenko, which was perfectly aligned with the Sun and Mars at 3.1 AU, as observed by Rosetta on 22 October. The ICME was also detected by STEREO-A on 16 October at 1 AU, and by Cassini in the solar wind around Saturn on the 12 November at 9.9AU. Fortuitously, the New Horizons spacecraft was also aligned with the direction of the ICME at 31.6 AU. We investigate whether this ICME has a nonambiguous signature at New Horizons. A potential detection of this ICME by Voyager 2 at 110-111 AU is also discussed. The multispacecraft observations allow the derivation of certain properties of the ICME, such as its large angular extension of at least 116 degrees, its speed as a function of distance, and its magnetic field structure at four locations from 1 to 10 AU. Observations of the speed data allow two different solar wind propagation models to be validated. Finally, we compare the Forbush decreases (transient decreases followed by gradual recoveries in the galactic cosmic ray intensity) due to the passage of this ICME at Mars, comet 67P, and Saturn.
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| 5. |
- Gaziano, Liam, et al.
(författare)
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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19
- 2021
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 27:4
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale Mendelian randomization and colocalization analyses using gene expression and soluble protein data for 1,263 actionable druggable genes, which encode protein targets for approved drugs or drugs in clinical development, identify IFNAR2 and ACE2 as the most promising therapeutic targets for early management of COVID-19. Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 x 10(-6); IFNAR2, P = 9.8 x 10(-11) and IL-10RB, P = 2.3 x 10(-14)) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
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