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- Bonomi, A, et al.
(författare)
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Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study
- 2020
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Ingår i: Genes and immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 21:2, s. 100-108
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Tidskriftsartikel (refereegranskat)abstract
- The genes regulating circulating levels of soluble gp130 (sgp130), the antagonist of the inflammatory response in atherosclerosis driven by interleukin 6, are largely unknown. Aims of the present study were to identify genetic loci associated with circulating sgp130 and to explore the potential association between variants associated with sgp130 and markers of subclinical atherosclerosis. The study is based on IMPROVE (n = 3703), a cardiovascular multicentre study designed to investigate the determinants of carotid intima media thickness, a measure of subclinical atherosclerosis. Genomic DNA was genotyped by the CardioMetaboChip and ImmunoChip. About 360,842 SNPs were tested for association with log-transformed sgp130, using linear regression adjusted for age, gender, and population stratification using PLINK v1.07. A p value of 1 × 10−5 was chosen as threshold for significance value. In an exploratory analysis, SNPs associated with sgp130 were tested for association with c-IMT measures. We identified two SNPs significantly associated with sgp130 levels and 24 showing suggestive association with sgp130 levels. One SNP (rs17688225) on chromosome 14 was positively associated with sgp130 serum levels (β = 0.03 SE = 0.007, p = 4.77 × 10−5) and inversely associated with c-IMT (c-IMTmean–maxβ = −0.001 SE = 0.005, p = 0.0342). Our data indicate that multiple loci regulate sgp130 levels and suggest a possible common pathway between sgp130 and c-IMT measures.
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- Talibov, Vladimir O, 1991-, et al.
(författare)
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Discovery of an allosteric ligand binding site in SMYD3 lysine methyltransferase
- 2021
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Ingår i: ChemBioChem (Print). - : Wiley. - 1439-4227 .- 1439-7633. ; 22:9, s. 1597-1608
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Tidskriftsartikel (refereegranskat)abstract
- SMYD3 is a multifunctional epigenetic enzyme with lysine methyl transferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened using a biosensor-based competition assay. Diperodon was identified as an allosteric ligand. The ( R )-and ( S )-enantiomers of the racemic drug were isolated and their affinities determined ( K D > = 42 and 84 ÎŒM). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although HSP90-SMYD3 binding was confirmed ( K D = 13 ÎŒM). The allosteric site appears to be druggable and suitable for exploration of non-catalytic SMYD3 functions and therapeutics with new mechanisms of action.
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- Willis, Megan D., et al.
(författare)
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Polar oceans and sea ice in a changing climate
- 2023
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Ingår i: Elementa. - 2325-1026. ; 11:1
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Forskningsöversikt (refereegranskat)abstract
- Polar oceans and sea ice cover 15% of the Earth's ocean surface, and the environment is changing rapidly at both poles. Improving knowledge on the interactions between the atmospheric and oceanic realms in the polar regions, a Surface Ocean-Lower Atmosphere Study (SOLAS) project key focus, is essential to understanding the Earth system in the context of climate change. However, our ability to monitor the pace and magnitude of changes in the polar regions and evaluate their impacts for the rest of the globe is limited by both remoteness and sea-ice coverage. Sea ice not only supports biological activity and mediates gas and aerosol exchange but can also hinder some in-situ and remote sensing observations. While satellite remote sensing provides the baseline climate record for sea-ice properties and extent, these techniques cannot provide key variables within and below sea ice. Recent robotics, modeling, and in-situ measurement advances have opened new possibilities for understanding the ocean-sea ice-atmosphere system, but critical knowledge gaps remain. Seasonal and long-term observations are clearly lacking across all variables and phases. Observational and modeling efforts across the sea-ice, ocean, and atmospheric domains must be better linked to achieve a system-level understanding of polar ocean and sea-ice environments. As polar oceans are warming and sea ice is becoming thinner and more ephemeral than before, dramatic changes over a suite of physicochemical and biogeochemical processes are expected, if not already underway. These changes in sea-ice and ocean conditions will affect atmospheric processes by modifying the production of aerosols, aerosol precursors, reactive halogens and oxidants, and the exchange of greenhouse gases. Quantifying which processes will be enhanced or reduced by climate change calls for tailored monitoring programs for high-latitude ocean environments. Open questions in this coupled system will be best resolved by leveraging ongoing international and multidisciplinary programs, such as efforts led by SOLAS, to link research across the ocean-sea ice-atmosphere interface.
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