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- 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. |
- Gunst, Jesper D., et al.
(författare)
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Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial
- 2021
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Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 35
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Tidskriftsartikel (refereegranskat)abstract
- Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials.Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001,200-42.Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05).Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality.
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| 3. |
- Sarneel, Judith M., et al.
(författare)
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Reading tea leaves worldwide : decoupled drivers of initial litter decomposition mass-loss rate and stabilization
- 2024
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Ingår i: Ecology Letters. - : John Wiley & Sons. - 1461-023X .- 1461-0248. ; 27:5
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Tidskriftsartikel (refereegranskat)abstract
- The breakdown of plant material fuels soil functioning and biodiversity. Currently, process understanding of global decomposition patterns and the drivers of such patterns are hampered by the lack of coherent large-scale datasets. We buried 36,000 individual litterbags (tea bags) worldwide and found an overall negative correlation between initial mass-loss rates and stabilization factors of plant-derived carbon, using the Tea Bag Index (TBI). The stabilization factor quantifies the degree to which easy-to-degrade components accumulate during early-stage decomposition (e.g. by environmental limitations). However, agriculture and an interaction between moisture and temperature led to a decoupling between initial mass-loss rates and stabilization, notably in colder locations. Using TBI improved mass-loss estimates of natural litter compared to models that ignored stabilization. Ignoring the transformation of dead plant material to more recalcitrant substances during early-stage decomposition, and the environmental control of this transformation, could overestimate carbon losses during early decomposition in carbon cycle models.
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| 4. |
- Holm, Jennifer A., et al.
(författare)
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Exploring the impacts of unprecedented climate extremes on forest ecosystems : Hypotheses to guide modeling and experimental studies
- 2023
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Ingår i: Biogeosciences. - 1726-4170. ; 20:11, s. 2117-2142
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Tidskriftsartikel (refereegranskat)abstract
- Climatic extreme events are expected to occur more frequently in the future, increasing the likelihood of unprecedented climate extremes (UCEs) or record-breaking events. UCEs, such as extreme heatwaves and droughts, substantially affect ecosystem stability and carbon cycling by increasing plant mortality and delaying ecosystem recovery. Quantitative knowledge of such effects is limited due to the paucity of experiments focusing on extreme climatic events beyond the range of historical experience. Here, we present a road map of how dynamic vegetation demographic models (VDMs) can be used to investigate hypotheses surrounding ecosystem responses to one type of UCE: unprecedented droughts. As a result of nonlinear ecosystem responses to UCEs that are qualitatively different from responses to milder extremes, we consider both biomass loss and recovery rates over time by reporting a time-integrated carbon loss as a result of UCE, relative to the absence of drought. Additionally, we explore how unprecedented droughts in combination with increasing atmospheric CO2 and/or temperature may affect ecosystem stability and carbon cycling. We explored these questions using simulations of pre-drought and post-drought conditions at well-studied forest sites using well-tested models (ED2 and LPJ-GUESS). The severity and patterns of biomass losses differed substantially between models. For example, biomass loss could be sensitive to either drought duration or drought intensity depending on the model approach. This is due to the models having different, but also plausible, representations of processes and interactions, highlighting the complicated variability of UCE impacts that still need to be narrowed down in models. Elevated atmospheric CO2 concentrations (eCO2) alone did not completely buffer the ecosystems from carbon losses during UCEs in the majority of our simulations. Our findings highlight the consequences of differences in process formulations and uncertainties in models, most notably related to availability in plant carbohydrate storage and the diversity of plant hydraulic schemes, in projecting potential ecosystem responses to UCEs. We provide a summary of the current state and role of many model processes that give way to different underlying hypotheses of plant responses to UCEs, reflecting knowledge gaps which in future studies could be tested with targeted field experiments and an iterative modeling-experimental conceptual framework.
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| 5. |
- Holmstrup, Martin, et al.
(författare)
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Long-term and realistic global change manipulations had low impact on diversity of soil biota in temperate heathland
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- In a dry heathland ecosystem we manipulated temperature (warming), precipitation (drought) and atmospheric concentration of CO2 in a full-factorial experiment in order to investigate changes in below-ground biodiversity as a result of future climate change. We investigated the responses in community diversity of nematodes, enchytraeids, collembolans and oribatid mites at two and eight years of manipulations. We used a structural equation modelling (SEM) approach analyzing the three manipulations, soil moisture and temperature, and seven soil biological and chemical ariables. The analysis revealed a persistent and positive effect of elevated CO2 on litter C:N ratio. After two years of treatment, the fungi to bacteria ratio was increased by warming, and the diversities within oribatid mites, collembolans and nematode groups were all affected by elevated CO2 mediated through increased litter C:N ratio. After eight years of treatment, however, the CO2-increased litter C:N ratio did not influence the diversity in any of the four fauna groups. The number of significant correlations between treatments, food source quality, and soil biota diversities was reduced from six to three after two and eight years, respectively. These results suggest a remarkable resilience within the soil biota against global climate change treatments in the long term.
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| 6. |
- Hvidtfeldt, Morten, et al.
(författare)
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Bronchoscopic mucosal cryobiopsies as a method for studying airway disease
- 2019
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 49:1, s. 27-34
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Tidskriftsartikel (refereegranskat)abstract
- Background: Investigating disease mechanisms and treatment responses in obstructive airway diseases with invasive sampling are hampered by the small size and mechanical artefacts that conventional forceps biopsies suffer from. Endoscopic cryobiopsies are larger and more intact and are being increasingly used. However, the technique has not yet been explored for obtaining mucosa biopsies. Objective: To investigate differences in size and quality of endobronchial mucosal biopsies obtained with cryotechnique and forceps. Further, to check for eligibility of cryobiopsies to be evaluated with immunohistochemistry and in situ hybridization and to investigate tolerability and safety of the technique. Methods: Endobronchial mucosal biopsies were obtained with cryotechnique and forceps from patients with haemoptysis undergoing bronchoscopy and evaluated by quantitative morphometry, automated immunohistochemistry and in situ hybridization. Results: A total of 40 biopsies were obtained from 10 patients. Cross-sectional areas were threefold larger in cryobiopsies (median: 3.08 mm2 (IQR: 1.79) vs 1.03 mm2 (IQR: 1.10), P < 0.001). Stretches of intact epithelium were 8-fold longer (median: 4.61 mm (IQR: 4.50) vs 0.55 mm (IQR: 1.23), P = 0.001). Content of glands (median: 0.095 mm2 (IQR: 0.30) vs 0.00 mm2 (IQR: 0.01), P = 0.002) and airway smooth muscle (median: 0.25 mm2 (IQR: 0.30) vs 0.060 mm2 (IQR: 0.11), P = 0.02) was higher in the cryobiopsies compared with forceps biopsies. Further, the cryobiopsies had well-preserved protein antigens and mRNA. Mild to moderate bleeding was the only complication observed. Conclusion and clinical relevance: By yielding significantly larger and more intact biopsies, the cryotechnique represents a valuable new research tool to explore the bronchi in airway disease. Ultimately with the potential to create better understanding of underlying disease mechanisms and improvement of treatments.
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