| 1. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 2. |
- Hedman, Linnea, et al.
(författare)
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Receiving support to quit smoking and quit attempts among smokers with and without smoking related diseases : Findings from the EUREST-PLUS ITC Europe Surveys
- 2018
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Ingår i: Tobacco Induced Diseases. - Heraklion : European Publishing. - 1617-9625. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION Having a chronic disease either caused or worsened by tobacco smoking does not always translate into quitting smoking. Although smoking cessation is one of the most cost-effective medical interventions, it remains poorly implemented in healthcare settings. The aim was to examine whether smokers with chronic and respiratory diseases were more likely to receive support to quit smoking by a healthcare provider or make a quit attempt than smokers without these diseases.METHODS This population-based study included a sample of 6011 adult smokers in six European countries. The participants were interviewed face-to-face and asked questions on sociodemographic characteristics, current diagnoses for chronic diseases, healthcare visits in the last 12 months and, if so, whether they had received any support to quit smoking. Questions on smoking behavior included nicotine dependence, motivation to quit smoking and quit attempts in the last 12 months. The results are presented as weighted percentages with 95% confidence intervals (CI) and as adjusted odds ratios with 95% CI based on logistic regression analyses.RESULTS Smokers with chronic respiratory disease, those aged 55 years and older, as well as those with one or more chronic diseases were more likely to receive smoking cessation advice from a healthcare professional. Making a quit attempt in the last year was related to younger age, high educational level, higher motivation to quit, lower nicotine dependence and having received advice to quit from a healthcare professional but not with having chronic diseases. There were significant differences between countries with smokers in Romania consistently reporting more support to quit as well as quit attempts.CONCLUSIONS Although smokers with respiratory disease did indeed receive smoking cessation support more often than smokers without disease, many smokers did not receive any advice or support to quit during a healthcare visit.
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| 3. |
- Davies, Neil, et al.
(författare)
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The founding charter of the Genomic Observatories Network
- 2014
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Ingår i: GigaScience. - 2047-217X. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- Abstract The co-authors of this paper hereby state their intention to work together to launch the Genomic Observatories Network (GOs Network) for which this document will serve as its Founding Charter. We define a Genomic Observatory as an ecosystem and/or site subject to long-term scientific research, including (but not limited to) the sustained study of genomic biodiversity from single-celled microbes to multicellular organisms.An international group of 64 scientists first published the call for a global network of Genomic Observatories in January 2012. The vision for such a network was expanded in a subsequent paper and developed over a series of meetings in Bremen (Germany), Shenzhen (China), Moorea (French Polynesia), Oxford (UK), Pacific Grove (California, USA), Washington (DC, USA), and London (UK). While this community-building process continues, here we express our mutual intent to establish the GOs Network formally, and to describe our shared vision for its future. The views expressed here are ours alone as individual scientists, and do not necessarily represent those of the institutions with which we are affiliated.
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| 4. |
- Karalis, Theodoros, et al.
(författare)
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Identification of a Small Molecule Inhibitor of Hyaluronan Synthesis, DDIT, Targeting Breast Cancer Cells
- 2022
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 14:23
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The most aggressive subtype of breast cancer, triple-negative breast cancer, is characterized by an excessive accumulation of hyaluronan in the cancer and its peritumoral stroma, which has been linked to poor prognosis of the patients. Inhibitors of hyaluronan synthesis would thus have a potential clinical value. We have identified the thymidine analog 5 '-Deoxy-5 '-(1,3-Diphenyl-2-Imidazolidinyl)-Thymidine (DDIT) as a new non-toxic inhibitor of hyaluronan synthesis. DDIT is more potent than the available inhibitor 4-Methylumbelliferone (4-MU), and significantly suppressed the aggressiveness of triple-negative breast cancer cells grown in tissue culture. Breast cancer is a common cancer in women. Breast cancer cells synthesize large amounts of hyaluronan to assist their proliferation, survival, migration and invasion. Accumulation of hyaluronan and overexpression of its receptor CD44 and hyaluronidase TMEM2 in breast tumors correlate with tumor progression and reduced overall survival of patients. Currently, the only known small molecule inhibitor of hyaluronan synthesis is 4-methyl-umbelliferone (4-MU). Due to the importance of hyaluronan for breast cancer progression, our aim was to identify new, potent and chemically distinct inhibitors of its synthesis. Here, we report a new small molecule inhibitor of hyaluronan synthesis, the thymidine analog 5 '-Deoxy-5 '-(1,3-Diphenyl-2-Imidazolidinyl)-Thymidine (DDIT). This compound is more potent than 4-MU and displays significant anti-tumorigenic properties. Specifically, DDIT inhibits breast cancer cell proliferation, migration, invasion and cancer stem cell self-renewal by suppressing HAS-synthesized hyaluronan. DDIT appears as a promising lead compound for the development of inhibitors of hyaluronan synthesis with potential usefulness in breast cancer treatment.
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| 5. |
- Opgenoorth, Lars, et al.
(författare)
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The GenTree Platform : growth traits and tree-level environmental data in 12 European forest tree species
- 2021
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Ingår i: GigaScience. - : Oxford University Press. - 2047-217X. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in the field of evolutionary forest ecology has been hampered by the huge challenge of phenotyping trees across their ranges in their natural environments, and the limitation in high-resolution environmental information.Findings: The GenTree Platform contains phenotypic and environmental data from 4,959 trees from 12 ecologically and economically important European forest tree species: Abies alba Mill. (silver fir), Betula pendula Roth. (silver birch), Fagus sylvatica L. (European beech), Picea abies (L.) H. Karst (Norway spruce), Pinus cembra L. (Swiss stone pine), Pinus halepensis Mill. (Aleppo pine), Pinus nigra Arnold (European black pine), Pinus pinaster Aiton (maritime pine), Pinus sylvestris L. (Scots pine), Populus nigra L. (European black poplar), Taxus baccata L. (English yew), and Quercus petraea (Matt.) Liebl. (sessile oak). Phenotypic (height, diameter at breast height, crown size, bark thickness, biomass, straightness, forking, branch angle, fructification), regeneration, environmental in situ measurements (soil depth, vegetation cover, competition indices), and environmental modeling data extracted by using bilinear interpolation accounting for surrounding conditions of each tree (precipitation, temperature, insolation, drought indices) were obtained from trees in 194 sites covering the species' geographic ranges and reflecting local environmental gradients.Conclusion: The GenTree Platform is a new resource for investigating ecological and evolutionary processes in forest trees. The coherent phenotyping and environmental characterization across 12 species in their European ranges allow for a wide range of analyses from forest ecologists, conservationists, and macro-ecologists. Also, the data here presented can be linked to the GenTree Dendroecological collection, the GenTree Leaf Trait collection, and the GenTree Genomic collection presented elsewhere, which together build the largest evolutionary forest ecology data collection available.
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| 6. |
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| 7. |
- Cotman, Andrej Emanuel, et al.
(författare)
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Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold- Based DNA Gyrase Inhibitors with Potent Activity against Acinetobacter baumannii and Pseudomonas aeruginosa
- 2023
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:2, s. 1380-1425
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Tidskriftsartikel (refereegranskat)abstract
- We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aerugi-nosa, which are both on the WHO priority list of antibiotic -resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase II alpha, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.
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| 8. |
- Cournia, Zoe, et al.
(författare)
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Membrane Protein Structure, Function, and Dynamics : a Perspective from Experiments and Theory
- 2015
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Ingår i: Journal of Membrane Biology. - : Springer. - 0022-2631 .- 1432-1424. ; 248:4, s. 611-640
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Tidskriftsartikel (refereegranskat)abstract
- Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins.
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| 9. |
- Donker, Erik M., et al.
(författare)
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The European List of Key Medicines for Medical Education: A Modified Delphi Study
- 2024
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Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 115:3, s. 515-524
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Tidskriftsartikel (refereegranskat)abstract
- Rational prescribing is essential for the quality of health care. However, many final-year medical students and junior doctors lack prescribing competence to perform this task. The availability of a list of medicines that a junior doctor working in Europe should be able to independently prescribe safely and effectively without supervision could support and harmonize teaching and training in clinical pharmacology and therapeutics (CPT) in Europe. Therefore, our aim was to achieve consensus on such a list of medicines that are widely accessible in Europe. For this, we used a modified Delphi study method consisting of three parts. In part one, we created an initial list based on a literature search. In part two, a group of 64 coordinators in CPT education, selected via the Network of Teachers in Pharmacotherapy of the European Association for Clinical Pharmacology and Therapeutics, evaluated the accessibility of each medicine in his or her country, and provided a diverse group of experts willing to participate in the Delphi part. In part three, 463 experts from 24 European countries were invited to participate in a 2-round Delphi study. In total, 187 experts (40%) from 24 countries completed both rounds and evaluated 416 medicines, 98 of which were included in the final list. The top three Anatomical Therapeutic Chemical code groups were (1) cardiovascular system (n = 23), (2) anti-infective (n = 21), and (3) musculoskeletal system (n = 11). This European List of Key Medicines for Medical Education could be a starting point for country-specific lists and could be used for the training and assessment of CPT.
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