| 1. |
- Andréasson, Måns, 1994-, et al.
(författare)
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Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands
- 2024
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 67:3, s. 2202-2219
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Tidskriftsartikel (refereegranskat)abstract
- G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.
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| 2. |
- Kurilshikov, Alexander, et al.
(författare)
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Large-scale association analyses identify host factors influencing human gut microbiome composition
- 2021
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 53:2, s. 156-165
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Tidskriftsartikel (refereegranskat)abstract
- To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 x 10(-8)) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 x 10(-20)), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 x 10(-10) < P < 5 x 10(-8)) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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| 3. |
- Nadkarni, A, et al.
(författare)
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Brief interventions for alcohol use disorders in low- and middle-income countries: barriers and potential solutions
- 2022
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Ingår i: International journal of mental health systems. - : Springer Science and Business Media LLC. - 1752-4458. ; 16:1, s. 36-
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Tidskriftsartikel (refereegranskat)abstract
- Global alcohol consumption and harmful use of alcohol is projected to increase in the coming decades, and most of the increase will occur in low- and middle-income countries (LMICs); which calls for cost-effective measures to reduce alcohol exposure in these countries. One such evidence based measure is screening and brief intervention (BI) for alcohol problems. Some of the characteristics of BI make them a particularly appealing choice of interventions in low-resource settings. However, despite evidence of effectiveness, implementation of BI in LMICs is rare. In this paper we discuss barriers to implementation of BI in LMICs, with examples from Latin America and India. Key barriers to implementation of BI in LMICs are the lack of financial and structural resources. Specialized services for alcohol use disorders are limited or non-existent. Hence primary care is often the only possible alternative to implement BI. However, health professionals in such settings generally lack training to deal with these disorders. In our review of BI research in these countries, we find some promising results, primarily in countries from Latin America, but so far there is limited research on effectiveness. Appropriate evaluation of efficacy and effectiveness of BI is undermined by lack of generalisability and methodological limitations. No systematic and scientific efforts to explore the implementation and evaluation of BI in primary and community platforms of care have been published in India. Innovative strategies need to be deployed to overcome supply side barriers related to specialist manpower shortages in LMICs. There is a growing evidence on the effectiveness of non-specialist health workers, including lay counsellors, in delivering frontline psychological interventions for a range of disorders including alcohol use disorders in LMICs. This paper is intended to stimulate discussion among researchers, practitioners and policy-makers in LMICs because increasing access to evidence based care for alcohol use disorders in LMICs would need a concerted effort from all these stakeholders.
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