| 1. |
- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)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.
(author)
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Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome
- 2021
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In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 52:1, s. 132-141
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Journal article (peer-reviewed)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. |
- Brinkmann, I., et al.
(author)
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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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In: Paleoceanography and Paleoclimatology. - 2572-4517. ; 36:11
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Journal article (peer-reviewed)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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| 4. |
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| 5. |
- Ni, S., et al.
(author)
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Seasonal climate variations in the Baltic Sea during the Last Interglacial based on foraminiferal geochemistry
- 2021
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In: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 272
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Journal article (peer-reviewed)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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| 6. |
- Hyttinen, O., et al.
(author)
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Deglaciation dynamics of the Fennoscandian Ice Sheet in the Kattegat, the gateway between the North Sea and the Baltic Sea Basin
- 2021
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In: Boreas. - : John Wiley & Sons. - 0300-9483 .- 1502-3885. ; 50:2, s. 351-368
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Journal article (peer-reviewed)abstract
- This paper presents an age–depth model based on an ultra-high-resolution, 80-m-thick sedimentary succession from a marine continental shelf basin, the Kattegat. This is an area of dynamic deglaciation of the Fennoscandian Ice Sheet during the Late Pleistocene. The Kattegat is also a transitional area between the saline North Sea and the brackish Baltic Sea. As such, it records general development of currents and exchange between these two systems. Data for the succession were provided through the Integrated Ocean Drilling Program Site M0060. The site indicates onset of deglaciation at c. 18 ka BP and relatively continuous sedimentation until 13 ka BP. At this point, sediments record a hiatus until c. 9–7 ka BP. The uppermost sedimentary unit contains redeposited material, but it is estimated to represent only the last c. 9–7 ka BP. The age–depth model is based on 17 select, radiocarbon-dated samples and is integrated with a set of physical and chemical proxies. The integrated records provide novel constraints on the timing of major palaeoenvironmental changes, such as the transition from glaciomarine proximal to glaciomarine distal and marine conditions, and their connections to known major events and processes in the region and the North Atlantic. Depositional evidence specifically documents connections between the Fennoscandian Ice Sheet behaviour and atmospheric and oceanic warming. Glacial retreat may have also depended on topographic factors such as changes in basin width and depth, linked to relative sea level changes and land uplift. The results indicate an early response of the Fennoscandian Ice Sheet to changing climate, and the ice sheet's possible influence on oceanic circulation during the Late Pleistocene deglaciation.
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| 7. |
- Ni, S., et al.
(author)
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Early diagenesis of foraminiferal calcite under anoxic conditions : A case study from the Landsort Deep, Baltic Sea (IODP Site M0063)
- 2020
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In: Chemical Geology. - : Elsevier BV. - 0009-2541. ; 558
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Journal article (peer-reviewed)abstract
- The chemical composition of foraminiferal calcite is widely used for studying past environmental conditions and biogeochemistry. However, high rates of microbial organic matter degradation and abundant dissolved metal sources in sediments and pore waters may impede the application of foraminifera-based proxies due to formation of secondary carbonates or other authigenic minerals on and/or inside of foraminiferal tests. Secondary carbonate precipitation severely alters the bulk foraminiferal geochemistry and can be difficult to eliminate through standard foraminiferal trace element cleaning procedures. We present results showing the mineral composition and formation sequence of diagenetic coatings on foraminiferal tests formed under extreme anoxic conditions in the Baltic Sea's deepest basin (the Landsort Deep, IODP Exp. 347, Site M0063). Our study focuses primarily on the diagenetic carbonates present on and in the tests of the low-oxygen tolerant benthic foraminiferal species Elphidium selseyensis and Elphidium clavatum. We applied various geochemical and imaging methods to ascertain the diagenesis processes and the authigenic mineral formation sequence on foraminifera. The authigenic carbonates were enriched in Mn, Mg, Fe and Ba, depending on the environmental redox conditions when the authigenic carbonates were precipitated. Concentrations of redox-sensitive elements such as Mn and Fe were particularly elevated in bottom waters and sedimentary pore waters under oxygen-depleted conditions in the Landsort Deep, resulting in formation of carbonates with highly elevated Mn and Fe contents. In addition to Mn- and Fe carbonates, several other types of authigenic minerals also formed on and in the foraminiferal chambers, including authigenic calcite, and non-carbonate accessory minerals. The formation sequence reveals the redox sensitivities of different elements and the preferential sequence of oxidants used by the microbes during organic matter oxidation and secondary redox reactions. This study provides a case study of extreme early diagenesis of foraminiferal calcite and may serve as a valuable guide when interpreting foraminiferal trace element records from low oxygen environments.
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| 8. |
- Ni, S., et al.
(author)
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Holocene Hydrographic Variations From the Baltic-North Sea Transitional Area (IODP Site M0059)
- 2020
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In: Paleoceanography and Paleoclimatology. - 2572-4517. ; 35:2
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Journal article (peer-reviewed)abstract
- Deoxygenation affects many continental shelf seas across the world today and results in increasing areas of hypoxia (dissolved oxygen concentration ([O2]) <1.4 ml/L). The Baltic Sea is increasingly affected by deoxygenation. Deoxygenation correlates with other environmental variables such as changing water temperature and salinity and is directly linked to ongoing global climate change. To place the ongoing environmental changes into a larger context and to further understand the complex Baltic Sea history and its impact on North Atlantic climate, we investigated a high accumulation-rate brackish-marine sediment core from the Little Belt (Site M0059), Danish Straits, NW Europe, retrieved during the Integrated Ocean Drilling Program (IODP) Expedition 347. We combined benthic foraminiferal geochemistry, faunal assemblages, and pore water stable isotopes to reconstruct seawater conditions (e.g., oxygenation, temperature, and salinity) over the past 7.7 thousand years (ka). Bottom water salinity in the Little Belt reconstructed from modeled pore water oxygen isotope data increased between 7.7 and 7.5 ka BP as a consequence of the transition from freshwater to brackish-marine conditions. Salinity decreased gradually (from 30 to 24) from 4.1 to ~2.5 ka BP. By using the trace elemental composition (Mg/Ca, Mn/Ca, and Ba/Ca) and stable carbon and oxygen isotopes of foraminiferal species Elphidium selseyensis and E. clavatum, we identified that generally warming and hypoxia occurred between about 7.5 and 3.3 ka BP, approximately coinciding in time with the Holocene Thermal Maximum (HTM). These changes of bottom water conditions were coupled to the North Atlantic Oscillation (NAO) and relative sea level change.
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