| 1. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Abonia, J Pablo, et al.
(författare)
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Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung
- 2006
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 108:5, s. 1588-1594
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Tidskriftsartikel (refereegranskat)abstract
- Normal mouse lungs lack appreciable numbers of mast cells (MCs) or MC progenitors (MCp's), yet the appearance of mature MCs in the tracheobronchial epithelial surface is a characteristic of allergic, T-cell-dependent pulmonary inflammation. We hypothesized that pulmonary inflammation would recruit MCp's to inflamed lungs and that this recruitment would be regulated by distinct adhesion pathways. Ovalbumin-sensitized and challenged mice had a greater than 28-fold increase in the number of MCp's in the lungs. In mice lacking endothelial vascular cell adhesion molecule 1 (VCAM-1) and in wild-type mice administered blocking monoclonal antibody (mAb) to VCAM-1 but not to mucosal addressin CAM-1 (MadCAM-1), recruitment of MCp's to the inflamed lung was reduced by greater than 75%. Analysis of the integrin receptors for VCAM-1 showed that in beta7 integrin-deficient mice, recruitment was reduced 73% relative to wild-type controls, and in either BALB/c or C57BL/6 mice, mAb blocking of alpha4, beta1, or beta7 integrins inhibited the recruitment of MCp's to the inflamed lung. Thus, VCAM-1 interactions with both alpha4beta1 and alpha4beta7 integrins are essential for the recruitment and expansion of the MCp populations in the lung during antigen-induced pulmonary inflammation. Furthermore, the MCp is currently unique among inflammatory cells in its partial dependence on alpha4beta7 integrins for lung recruitment.
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| 3. |
- Axfors, Cathrine, et al.
(författare)
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Association between convalescent plasma treatment and mortality in COVID-19 : a collaborative systematic review and meta-analysis of randomized clinical trials
- 2021
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Ingår i: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 21:1
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Forskningsöversikt (refereegranskat)abstract
- Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, ). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I-2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
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| 4. |
- Dans, Madeline G., et al.
(författare)
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Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- With resistance to most antimalarials increasing, it is imperative that new drugs are developed. We previously identified an aryl acetamide compound, MMV006833 (M-833), that inhibited the ring-stage development of newly invaded merozoites. Here, we select parasites resistant to M-833 and identify mutations in the START lipid transfer protein (PF3D7_0104200, PfSTART1). Introducing PfSTART1 mutations into wildtype parasites reproduces resistance to M-833 as well as to more potent analogues. PfSTART1 binding to the analogues is validated using organic solvent-based Proteome Integral Solubility Alteration (Solvent PISA) assays. Imaging of invading merozoites shows the inhibitors prevent the development of ring-stage parasites potentially by inhibiting the expansion of the encasing parasitophorous vacuole membrane. The PfSTART1-targeting compounds also block transmission to mosquitoes and with multiple stages of the parasite’s lifecycle being affected, PfSTART1 represents a drug target with a new mechanism of action.
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| 5. |
- Foox, Jonathan, et al.
(författare)
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The SEQC2 epigenomics quality control (EpiQC) study
- 2021
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Ingår i: Genome Biology. - : BioMed Central (BMC). - 1465-6906 .- 1474-760X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA’s Epigenomics Quality Control Group.ResultsEach sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms.ConclusionsThe data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research.
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| 6. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 7. |
- Noumonvi, Koffi Dodji, et al.
(författare)
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The Kulbäcksliden research infrastructure : a unique setting for northern peatland studies
- 2023
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Ingår i: Frontiers in Earth Science. - : Frontiers Media S.A.. - 2296-6463. ; 11
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Forskningsöversikt (refereegranskat)abstract
- Boreal peatlands represent a biogeochemically unique and diverse environment in high-latitude landscape. They represent a long-term globally significant sink for carbon dioxide and a source of methane, hence playing an important role in regulating the global climate. There is an increasing interest in deciphering peatland biogeochemical processes to improve our understanding of how anthropogenic and climate change effects regulate the peatland biogeochemistry and greenhouse gas balances. At present, most studies investigating land-atmosphere exchanges of peatland ecosystems are commonly based on single-tower setups, which require the assumption of homogeneous conditions during upscaling to the landscape. However, the spatial organization of peatland complexes might feature large heterogeneity due to its varying underlying topography and vegetation composition. Little is known about how well single site studies represent the spatial variations of biogeochemical processes across entire peatland complexes. The recently established Kulbäcksliden Research Infrastructure (KRI) includes five peatland study sites located less than 3 km apart, thus providing a unique opportunity to explore the spatial variation in ecosystem-scale processes across a typical boreal peatland complex. All KRI sites are equipped with eddy covariance flux towers combined with installations for detailed monitoring of biotic and abiotic variables, as well as catchment-scale hydrology and hydrochemistry. Here, we review studies that were conducted in the Kulbäcksliden area and provide a description of the site characteristics as well as the instrumentation available at the KRI. We highlight the value of long-term infrastructures with ecosystem-scale and replicated experimental sites to advance our understanding of peatland biogeochemistry, hydrology, ecology, and its feedbacks on the environment and climate system.
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| 8. |
- Reitsma, Marissa B., et al.
(författare)
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Smoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015 : a systematic analysis from the Global Burden of Disease Study 2015
- 2017
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 389:10082, s. 1885-1906
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Tidskriftsartikel (refereegranskat)abstract
- Background The scale-up of tobacco control, especially after the adoption of the Framework Convention for Tobacco Control, is a major public health success story. Nonetheless, smoking remains a leading risk for early death and disability worldwide, and therefore continues to require sustained political commitment. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) offers a robust platform through which global, regional, and national progress toward achieving smoking-related targets can be assessed. Methods We synthesised 2818 data sources with spatiotemporal Gaussian process regression and produced estimates of daily smoking prevalence by sex, age group, and year for 195 countries and territories from 1990 to 2015. We analysed 38 risk-outcome pairs to generate estimates of smoking-attributable mortality and disease burden, as measured by disability-adjusted life-years (DALYs). We then performed a cohort analysis of smoking prevalence by birth-year cohort to better understand temporal age patterns in smoking. We also did a decomposition analysis, in which we parsed out changes in all-cause smoking-attributable DALYs due to changes in population growth, population ageing, smoking prevalence, and risk-deleted DALY rates. Finally, we explored results by level of development using the Socio-demographic Index (SDI). Findings Worldwide, the age-standardised prevalence of daily smoking was 25.0% (95% uncertainty interval [UI] 24.2-25.7) for men and 5.4% (5.1-5.7) for women, representing 28.4% (25.8-31.1) and 34.4% (29.4-38.6) reductions, respectively, since 1990. A greater percentage of countries and territories achieved significant annualised rates of decline in smoking prevalence from 1990 to 2005 than in between 2005 and 2015; however, only four countries had significant annualised increases in smoking prevalence between 2005 and 2015 (Congo [Brazzaville] and Azerbaijan for men and Kuwait and Timor-Leste for women). In 2015, 11.5% of global deaths (6.4 million [95% UI 5.7-7.0 million]) were attributable to smoking worldwide, of which 52.2% took place in four countries (China, India, the USA, and Russia). Smoking was ranked among the five leading risk factors by DALYs in 109 countries and territories in 2015, rising from 88 geographies in 1990. In terms of birth cohorts, male smoking prevalence followed similar age patterns across levels of SDI, whereas much more heterogeneity was found in age patterns for female smokers by level of development. While smoking prevalence and risk-deleted DALY rates mostly decreased by sex and SDI quintile, population growth, population ageing, or a combination of both, drove rises in overall smoking-attributable DALYs in low-SDI to middle-SDI geographies between 2005 and 2015. Interpretation The pace of progress in reducing smoking prevalence has been heterogeneous across geographies, development status, and sex, and as highlighted by more recent trends, maintaining past rates of decline should not be taken for granted, especially in women and in low-SDI to middle-SDI countries. Beyond the effect of the tobacco industry and societal mores, a crucial challenge facing tobacco control initiatives is that demographic forces are poised to heighten smoking's global toll, unless progress in preventing initiation and promoting cessation can be substantially accelerated. Greater success in tobacco control is possible but requires effective, comprehensive, and adequately implemented and enforced policies, which might in turn require global and national levels of political commitment beyond what has been achieved during the past 25 years.
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| 9. |
- Remme, Roy P., et al.
(författare)
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An ecosystem service perspective on urban nature, physical activity, and health
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:22
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Tidskriftsartikel (refereegranskat)abstract
- Nature underpins human well-being in critical ways, especially in health. Nature provides pollination of nutritious crops, purification of drinking water, protection from floods, and climate security, among other well-studied health benefits. A crucial, yet challenging, research frontier is clarifying how nature promotes physical activity for its many mental and physical health benefits, particularly in densely populated cities with scarce and dwindling access to nature. Here we frame this frontier by conceptually developing a spatial decision-support tool that shows where, how, and for whom urban nature promotes physical activity, to inform urban greening efforts and broader health assessments. We synthesize what is known, present a model framework, and detail the model steps and data needs that can yield generalizable spatial models and an effective tool for assessing the urban nature-physical activity relationship. Current knowledge supports an initial model that can distinguish broad trends and enrich urban planning, spatial policy, and public health decisions. New, iterative research and application will reveal the importance of different types of urban nature, the different subpopulations who will benefit from it, and nature's potential contribution to creating more equitable, green, livable cities with active inhabitants.
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| 10. |
- Ren, Luyao, et al.
(författare)
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Quartet DNA reference materials and datasets for comprehensively evaluating germline variant calling performance
- 2023
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Ingår i: Genome Biology. - : BioMed Central (BMC). - 1465-6906 .- 1474-760X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genomic DNA reference materials are widely recognized as essential for ensuring data quality in omics research. However, relying solely on reference datasets to evaluate the accuracy of variant calling results is incomplete, as they are limited to benchmark regions. Therefore, it is important to develop DNA reference materials that enable the assessment of variant detection performance across the entire genome.RESULTS: We established a DNA reference material suite from four immortalized cell lines derived from a family of parents and monozygotic twins. Comprehensive reference datasets of 4.2 million small variants and 15,000 structural variants were integrated and certified for evaluating the reliability of germline variant calls inside the benchmark regions. Importantly, the genetic built-in-truth of the Quartet family design enables estimation of the precision of variant calls outside the benchmark regions. Using the Quartet reference materials along with study samples, batch effects are objectively monitored and alleviated by training a machine learning model with the Quartet reference datasets to remove potential artifact calls. Moreover, the matched RNA and protein reference materials and datasets from the Quartet project enables cross-omics validation of variant calls from multiomics data.CONCLUSIONS: The Quartet DNA reference materials and reference datasets provide a unique resource for objectively assessing the quality of germline variant calls throughout the whole-genome regions and improving the reliability of large-scale genomic profiling.
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| 11. |
- Tong, Cheuk Hei Marcus, et al.
(författare)
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A drained nutrient-poor peatland forest in boreal Sweden constitutes a net carbon sink after integrating terrestrial and aquatic fluxes
- 2024
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Ingår i: Global Change Biology. - 1354-1013 .- 1365-2486. ; 30
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Tidskriftsartikel (refereegranskat)abstract
- Northern peatlands provide a globally important carbon (C) store. Since the beginning of the 20th century, however, large areas of natural peatlands have been drained for biomass production across Fennoscandia. Today, drained peatland forests constitute a common feature of the managed boreal landscape, yet their ecosystem C balance and associated climate impact are not well understood, particularly within the nutrient-poor boreal region. In this study, we estimated the net ecosystem carbon balance (NECB) from a nutrient-poor drained peatland forest and an adjacent natural mire in northern Sweden by integrating terrestrial carbon dioxide (CO2) and methane (CH4) fluxes with aquatic losses of dissolved organic C (DOC) and inorganic C based on eddy covariance and stream discharge measurements, respectively, over two hydrological years. Since the forest included a dense spruce-birch area and a sparse pine area, we were able to further evaluate the effect of contrasting forest structure on the NECB and component fluxes. We found that the drained peatland forest was a net C sink with a 2-year mean NECB of −115 ± 5 g C m−2 year−1 while the adjacent mire was close to C neutral with 14.6 ± 1.7 g C m−2 year−1. The NECB of the drained peatland forest was dominated by the net CO2 exchange (net ecosystem exchange [NEE]), whereas NEE and DOC export fluxes contributed equally to the mire NECB. We further found that the C sink strength in the sparse pine forest area (−153 ± 8 g C m−2 year−1) was about 1.5 times as high as in the dense spruce-birch forest area (−95 ± 8 g C m−2 year−1) due to enhanced C uptake by ground vegetation and lower DOC export. Our study suggests that historically drained peatland forests in nutrient-poor boreal regions may provide a significant net ecosystem C sink and associated climate benefits.
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