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- Ibanez, L., et al.
(författare)
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Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:7, s. 2394-2406
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Tedengren, Michael, et al.
(författare)
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Heat pretreatment increase cadmium resistance and HSP 70 levels in Baltic Sea mussels
- 2000
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Ingår i: Aquatic Toxicology. - 0166-445X .- 1879-1514. ; 48:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- The effects of heat treatment and cadmium exposure on the synthesis of a major stress inducible protein (hsp 70) and on the metabolism of the blue mussel Mytilus edulis L. from the Baltic Sea, were studied in a laboratory experiment. The mussels were kept in sea water of ambient salinity (6.3‰) and temperature (4°C). The effects of cadmium (20 μg l−1), measured as changes in physiological rates (oxygen consumption, ammonia excretion, clearance rates and scope for growth) and hsp 70 expression were studied at 4°C and in combination with a rapid rise in temperature to 20°C. Relatively low levels of hsp 70 were detected but the negative effect was reflected in a reduction of scope for growth of the exposed mussels compared to controls. This effect was more pronounced at 20°C. Mussels not exposed to cadmium in the first experiment were used in a second set of experiments. Heat shocked mussels were allowed to reacclimatise to 4°C for 5 days and then, along with the mussels already at 4°C, exposed to cadmium (20 μg l−1). The results clearly indicated that the mussels exposed to 20°C in the first experiment more rapidly induced synthesis of hsp 70 after cadmium exposure in the second experiment. Also the reacclimatised mussels exposed to heat shock but not to cadmium in the first experiment, induced some hsp 70 in the second experiment. This suggests that the rate of induction of heat shock or stress proteins in Baltic mussels is slower than what has been described for mussels from more marine environments. The mussels kept at 4°C throughout the experiment and exposed to cadmium showed low levels of hsp 70, again indicating a low rate of induction. The increasing levels of hsp 70 correlated well with a maintained level of physiological fitness, in terms of scope for growth, although the mussels showed increasing body burdens of cadmium.
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