Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.Peer reviewe

Early Diagnosis of Vegetation Health From High-Resolution Hyperspectral and Thermal Imagery: Lessons Learned From Empirical Relationships and Radiative Transfer Modelling

[Purpose of Review] We provide a comprehensive review of the empirical and modelling approaches used to quantify the radiation–vegetation interactions related to vegetation temperature, leaf optical properties linked to pigment absorption and chlorophyll fluorescence emission, and of their capability to monitor vegetation health. Part 1 provides an overview of the main physiological indicators (PIs) applied in remote sensing to detect alterations in plant functioning linked to vegetation diseases and decline processes. Part 2 reviews the recent advances in the development of quantitative methods to assess PI through hyperspectral and thermal images.[Recent Findings] In recent years, the availability of high-resolution hyperspectral and thermal images has increased due to the extraordinary progress made in sensor technology, including the miniaturization of advanced cameras designed for unmanned aerial vehicle (UAV) systems and lightweight aircrafts. This technological revolution has contributed to the wider use of hyperspectral imaging sensors by the scientific community and industry; it has led to better modelling and understanding of the sensitivity of different ranges of the electromagnetic spectrum to detect biophysical alterations used as early warning indicators of vegetation health.[Summary] The review deals with the capability of PIs such as vegetation temperature, chlorophyll fluorescence, photosynthetic energy downregulation and photosynthetic pigments detected through remote sensing to monitor the early responses of plants to different stressors. Various methods for the detection of PI alterations have recently been proposed and validated to monitor vegetation health. The greatest challenges for the remote sensing community today are (i) the availability of high spatial, spectral and temporal resolution image data; (ii) the empirical validation of radiation–vegetation interactions; (iii) the upscaling of physiological alterations from the leaf to the canopy, mainly in complex heterogeneous vegetation landscapes; and (iv) the temporal dynamics of the PIs and the interaction between physiological changes.The authors received funding provided by the FluorFLIGHT (GGR801) Marie Curie Fellowship, the QUERCUSAT and ESPECTRAMED projects (Spanish Ministry of Economy and Competitiveness), the Academy of Finland (grants 266152, 317387) and the European Research Council Synergy grant ERC-2013-SyG-610028 IMBALANCE-P.Peer reviewe

Stroke genetics informs drug discovery and risk prediction across ancestries

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.</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. 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 analysis3, 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 approach4, 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 ancestry5. 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

Evaluation of the DART 3D model in the thermal domain using satellite/airborne imagery and ground-based measurements

This work provides an evaluation of the discrete anisotropy radiative transfer (DART) three-dimensional (3D) model in assessing the simulation of directional brightness temperatures (Tb) at both sensor and surface levels. Satellite imagery acquired with the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER), airborne imagery acquired with the Airborne Hyperspectral Scanner (AHS) sensor and ground-based measurements collected over an agricultural area were used to evaluate the DART model at nadir views. Directional radiometric temperatures measured with a goniometric system at ground level were also used to evaluate modelling results at different view angles. The DART model was evaluated over three homogeneous plots: bare soil (BS), green grass (GG) and sand (NS). The results show good agreement between the simulations and the satellite, airborne and ground-based measurements, with root mean square errors (RMSEs) less than 2.0 K. However, three major discrepancies were found: (1) differences greater than 4.0 K over BS when comparing DART and ASTER, attributed to turbulence-induced temperature fluctuations, (2) higher differences in sensor-level than in surface-level comparisons when using AHS due to thermal heterogeneity of the selected regions of interest in the image and also to differences in atmospheric correction performed over the imagery and the correction included in the DART model, especially for bands located in the lowest atmospheric transmissivity regions and (3) RMSEs greater than 2.0 K when comparing DART results and ground measurements over the NS plot, due to the strong emissivity correction in the 8.0-9.0 μm bands, where the measured emissivity was below 0.75. Despite these discrepancies, we show that the DART model is a useful tool for simulating remotely sensed thermal images over different landscapes. Finally, new versions of this model are continuously being released to solve technical problems and improve the simulation results