| 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
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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. |
- Heitsch, L., et al.
(författare)
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Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome
- 2021
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Ingår i: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 52:1, s. 132-141
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = Delta NIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes. Methods: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced Delta NIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on Delta NIHSS6-24h was examined. Finally, the association of Delta NIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). Results: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median Delta NIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted Delta NIHSS6-24h (R-2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R-2=0.27), but much of the variance remained unexplained. Delta NIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, Delta NIHSS3-24h was similarly associated with 90-day outcomes. Conclusions: The dynamic phenotype, Delta NIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, Delta NIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.
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| 3. |
- Mola-Caminal, M., et al.
(författare)
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PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome A Genome-Wide Meta-Analysis
- 2019
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Ingår i: Circulation research. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7330 .- 1524-4571. ; 124:1, s. 114-120
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. Methods and Results: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, beta=0.40, P=1.70x10-9). Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.
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| 4. |
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| 5. |
- Brinkmann, I., et al.
(författare)
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Foraminiferal Mn/Ca as Bottom-Water Hypoxia Proxy: An Assessment of Nonionella stella in the Santa Barbara Basin, USA
- 2021
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Ingår i: Paleoceanography and Paleoclimatology. - 2572-4517. ; 36:11
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Tidskriftsartikel (refereegranskat)abstract
- Hypoxia is of increasing concern in marine areas, calling for a better understanding of mechanisms leading to decreasing dissolved oxygen concentrations ([O2]). Much can be learned about the processes and implications of deoxygenation for marine ecosystems using proxy records from low-oxygen sites, provided proxies, such as the manganese (Mn) to calcium (Ca) ratio in benthic foraminiferal calcite, are available and well calibrated. Here we report a modern geochemical data set from three hypoxic sites within the Santa Barbara Basin (SBB), USA, where we study the response of Mn/Caforam in the benthic foraminifer Nonionella stella to variations in sedimentary redox conditions (Mn, Fe) and bottom-water dissolved [O2]. We combine molecular species identification by small subunit rDNA sequencing with morphological characterization and assign the SBB N. stella used here to a new phylotype (T6). Synchrotron-based scanning X-ray fluorescence (XRF) imaging and Secondary Ion Mass Spectrometry (SIMS) show low Mn incorporation (partition coefficient DMn < 0.05) and limited proxy sensitivity of N. stella, at least within the range of dissolved [O2] (2.7–9.6 μmol/l) and Mnpore-water gradients (2.12–21.59 μmol/l). Notably, even though intra- and interspecimen Mn/Ca variability (33% and 58%, respectively) was only partially controlled by the environment, Mn/Caforam significantly correlated with both pore-water Mn and bottom-water [O2]. However, the prevalent suboxic bottom-water conditions and limited dissolved [O2] range complicate the interpretation of trace-elemental trends. Additional work involving other oxygenation proxies and samples from a wider oxygen gradient should be pursued to further develop foraminiferal Mn/Ca as an indicator for hypoxic conditions.
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| 6. |
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| 7. |
- Kotthoff, U., et al.
(författare)
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Reconstructing Holocene temperature and salinity variations in the western Baltic Sea region: a multi-proxy comparison from the Little Belt (IODP Expedition 347, Site M0059)
- 2017
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 14, s. 5607-5632
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Tidskriftsartikel (refereegranskat)abstract
- Sediment records recovered from the Baltic Sea during Integrated Ocean Drilling Program Expedition 347 provide a unique opportunity to study paleoenvironmental and climate change in central and northern Europe. Such studies contribute to a better understanding of how environmental parameters change in continental shelf seas and enclosed basins. Here we present a multi-proxy-based reconstruction of paleotemperature (both marine and terrestrial), paleosalinity, and paleoecosystem changes from the Little Belt (Site M0059) over the past ∼ 8000 years and evaluate the applicability of inorganic- and organic-based proxies in this particular setting. All salinity proxies (diatoms, aquatic palynomorphs, ostracods, diol index) show that lacustrine conditions occurred in the Little Belt until ∼ 7400 cal yr BP. A connection to the Kattegat at this time can thus be excluded, but a direct connection to the Baltic Proper may have existed. The transition to the brackish–marine conditions of the Littorina Sea stage (more saline and warmer) occurred within ∼ 200 years when the connection to the Kattegat became established after ∼ 7400 cal yr BP. The different salinity proxies used here generally show similar trends in relative changes in salinity, but often do not allow quantitative estimates of salinity. The reconstruction of water temperatures is associated with particularly large uncertainties and variations in absolute values by up to 8 °C for bottom waters and up to 16 °C for surface waters. Concerning the reconstruction of temperature using foraminiferal Mg / Ca ratios, contamination by authigenic coatings in the deeper intervals may have led to an overestimation of temperatures. Differences in results based on the lipid paleothermometers (long chain diol index and TEXL86) can partly be explained by the application of modern-day proxy calibrations to intervals that experienced significant changes in depositional settings: in the case of our study, the change from freshwater to marine conditions. Our study shows that particular caution has to be taken when applying and interpreting proxies in coastal environments and marginal seas, where water mass conditions can experience more rapid and larger changes than in open ocean settings. Approaches using a multitude of independent proxies may thus allow a more robust paleoenvironmental assessment.
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| 8. |
- Ni, S., et al.
(författare)
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Seasonal climate variations in the Baltic Sea during the Last Interglacial based on foraminiferal geochemistry
- 2021
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 272
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Tidskriftsartikel (refereegranskat)abstract
- Climate during the Last Interglacial period (LIG, Marine Isotope Stage 5e) was on average warmer than the present, with a higher global sea level but also more unstable conditions. Today, the Baltic Sea interacts strongly with conditions in the North Atlantic region, and this interaction was likely even stronger during the LIG. We here present a reconstruction of seawater conditions during the LIG based on benthic foraminiferal geochemistry (stable isotopes and trace elements) and compare these records with modern marine monitoring data to evaluate seasonal hydrographic conditions in the western and southern Baltic Sea during the first half of the LIG (130–123 ka BP). Our reconstructions reflect the evolution of seasonal temperature and salinity, rather than annual mean conditions. The spring LIG bottom water temperatures in the Skagerrak and Kattegat were ∼2–3 °C higher compared to the modern spring bottom water temperatures. During the LIG, there was an increase in seasonality in bottom water temperature (progressively warmer summers and cooler springs) in the southern Baltic Sea, which can be linked to seasonal insolation changes. Moreover, our data suggest a decreased gradient of bottom water salinity along a transect through the Skagerrak-Kattegat-Danish Straits-southern Baltic Sea, supporting previous investigations inferring a stronger ocean-water influx into the Baltic Sea during the LIG than at present.
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| 9. |
- Zimmermann, F., et al.
(författare)
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Origin of orange color in nominally undoped HVPE GaN crystals
- 2017
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Ingår i: Optical materials (Amsterdam). - : ELSEVIER SCIENCE BV. - 0925-3467 .- 1873-1252. ; 70, s. 127-130
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Tidskriftsartikel (refereegranskat)abstract
- In this article we investigated unintentionally doped (UID) GaN grown by hydride vapor phase epitaxy (HVPE) with respect to point defects and impurity concentration. The samples were orange tinted to different extent. Optical analysis was performed by micro-photoluminescence and absorption spectroscopy. Absorption measurements revealed an absorption peak at 1.5 eV related to an internal transition in Mn3+ impurities and a second band with low energy onset at 1.9 eV, both increasing with the extent of orange color. Electron paramagnetic resonance investigations showed the presence of Mn2+ and Fe3+ in the colored crystals. The overall impurity concentration was verified by secondary ion mass spectrometry. Orange tint is associated with an increase of transition metal contamination, especially Mn. Based on these observations we suggest that the orange coloring in the investigated UID HVPE GaN samples is caused by the presence of Mn impurities. (C) 2017 Elsevier B.V. All rights reserved.
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| 10. |
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