| 1. |
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| 2. |
- Ramdas, S., et al.
(författare)
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 109:8, s. 1366-1387
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
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| 9. |
- Forouzanfar, Mohammad H, et al.
(författare)
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Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013.
- 2015
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 386:10010, s. 2287-2323
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.FUNDING: Bill & Melinda Gates Foundation.
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| 10. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 11. |
- 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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| 12. |
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| 13. |
- Zouganelis, I., et al.
(författare)
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The Solar Orbiter Science Activity Plan : Translating solar and heliospheric physics questions into action
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 642
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Tidskriftsartikel (refereegranskat)abstract
- Solar Orbiter is the first space mission observing the solar plasma both in situ and remotely, from a close distance, in and out of the ecliptic. The ultimate goal is to understand how the Sun produces and controls the heliosphere, filling the Solar System and driving the planetary environments. With six remote-sensing and four in-situ instrument suites, the coordination and planning of the operations are essential to address the following four top-level science questions: (1) What drives the solar wind and where does the coronal magnetic field originate?; (2) How do solar transients drive heliospheric variability?; (3) How do solar eruptions produce energetic particle radiation that fills the heliosphere?; (4) How does the solar dynamo work and drive connections between the Sun and the heliosphere? Maximising the mission's science return requires considering the characteristics of each orbit, including the relative position of the spacecraft to Earth (affecting downlink rates), trajectory events (such as gravitational assist manoeuvres), and the phase of the solar activity cycle. Furthermore, since each orbit's science telemetry will be downloaded over the course of the following orbit, science operations must be planned at mission level, rather than at the level of individual orbits. It is important to explore the way in which those science questions are translated into an actual plan of observations that fits into the mission, thus ensuring that no opportunities are missed. First, the overarching goals are broken down into specific, answerable questions along with the required observations and the so-called Science Activity Plan (SAP) is developed to achieve this. The SAP groups objectives that require similar observations into Solar Orbiter Observing Plans, resulting in a strategic, top-level view of the optimal opportunities for science observations during the mission lifetime. This allows for all four mission goals to be addressed. In this paper, we introduce Solar Orbiter's SAP through a series of examples and the strategy being followed.
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| 14. |
- 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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| 15. |
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| 16. |
- Bernal, Ximena E., et al.
(författare)
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Empowering Latina scientists
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 363:6429, s. 825-826
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 17. |
- Langefeld, Carl D., et al.
(författare)
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Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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| 18. |
- Lopez-Isac, E, et al.
(författare)
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GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4955-
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Tidskriftsartikel (refereegranskat)abstract
- Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.
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| 19. |
- Allesøe, Rosa Lundbye, et al.
(författare)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 22. |
- Orozco, G., et al.
(författare)
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Study of the role of functional variants of SLC22A4, RUNX1 and SUMO4 in systemic lupus erythematosus
- 2006
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 65:6, s. 791-5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Functional polymorphisms of the solute carrier family 22, member 4 (SLC22A4), runt related transcription factor 1 (RUNX1) and small ubiquitin-like modifier 4 (SUMO4) genes have been shown to be associated with several autoimmune diseases. OBJECTIVE: To test the possible role of these variants in susceptibility to or severity of systemic lupus erythematosus (SLE), on the basis that common genetic bases are shared by autoimmune disorders. METHODS: 597 SLE patients and 987 healthy controls of white Spanish origin were studied. Two additional cohorts of 228 SLE patients from Sweden and 122 SLE patients from Colombia were included. A case-control association study was carried out with six single nucleotide polymorphisms (SNP) spanning the SLC22A4 gene, one SNP in RUNX1 gene, and one additional SNP in SUM04 gene. RESULTS: No significant differences were observed between SLE patients and healthy controls when comparing the distribution of the genotypes or alleles of any of the SLC22A4, RUNX1, or SUMO4 polymorphisms tested. Significant differences were found in the distribution of the SUMO4 genotypes and alleles among SLE patients with and without nephritis, but after multiple testing correction, the significance of the association was lost. The association of SUMO4 with nephritis could not be verified in two independent SLE cohorts from Sweden and Colombia. CONCLUSIONS: These results suggest that the SLC22A4, RUNX1, and SUMO4 polymorphisms analysed do not play a role in the susceptibility to or severity of SLE.
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| 23. |
- 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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| 24. |
- Felipe, T., et al.
(författare)
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Three-dimensional structure of a sunspot light bridge
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 596
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Tidskriftsartikel (refereegranskat)abstract
- Context. Active regions are the most prominent manifestations of solar magnetic fields; their generation and dissipation are fundamental problems in solar physics. Light bridges are commonly present during sunspot decay, but a comprehensive picture of their role in the removal of the photospheric magnetic field is still lacking. Aims. We study the three-dimensional configuration of a sunspot, and in particular, its light bridge, during one of the last stages of its decay. Methods. We present the magnetic and thermodynamical stratification inferred from full Stokes inversions of the photospheric Si I 10 827 angstrom and Ca I 10 839 angstrom lines obtained with the GREGOR Infrared Spectrograph of the GREGOR telescope at the Observatorio del Teide, Tenerife, Spain. The analysis is complemented by a study of continuum images covering the disk passage of the active region, which are provided by the Helioseismic and Magnetic Imager on board the Solar Dynamics Observatory. Results. The sunspot shows a light bridge with penumbral continuum intensity that separates the central umbra from a smaller umbra. We find that in this region the magnetic field lines form a canopy with lower magnetic field strength in the inner part. The photospheric light bridge is dominated by gas pressure (high-beta), as opposed to the surrounding umbra, where the magnetic pressure is higher. A convective flow is observed in the light bridge. This flow is able to bend the magnetic field lines and to produce field reversals. The field lines merge above the light bridge and become as vertical and strong as in the surrounding umbra. We conclude that this occurs because two highly magnetized regions approach each other during the sunspot evolution.
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| 25. |
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| 26. |
- Wieczór, M., et al.
(författare)
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Pre-exascale HPC approaches for molecular dynamics simulations. Covid-19 research : A use case
- 2023
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Ingår i: WIREs Computational Molecular Science. - : Wiley. - 1759-0876 .- 1759-0884. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Exascale computing has been a dream for ages and is close to becoming a reality that will impact how molecular simulations are being performed, as well as the quantity and quality of the information derived for them. We review how the biomolecular simulations field is anticipating these new architectures, making emphasis on recent work from groups in the BioExcel Center of Excellence for High Performance Computing. We exemplified the power of these simulation strategies with the work done by the HPC simulation community to fight Covid-19 pandemics. This article is categorized under: Data Science > Computer Algorithms and Programming Data Science > Databases and Expert Systems Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods.
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| 27. |
- Bertola, Laura D., et al.
(författare)
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A pragmatic approach for integrating molecular tools into biodiversity conservation
- 2024
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Ingår i: Conservation science and practice. - 2578-4854. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Molecular tools are increasingly applied for assessing and monitoring biodiversity and informing conservation action. While recent developments in genetic and genomic methods provide greater sensitivity in analysis and the capacity to address new questions, they are not equally available to all practitioners: There is considerable bias across institutions and countries in access to technologies, funding, and training. Consequently, in many cases, more accessible traditional genetic data (e.g., microsatellites) are still utilized for making conservation decisions. Conservation approaches need to be pragmatic by tackling clearly defined management questions and using the most appropriate methods available, while maximizing the use of limited resources. Here we present some key questions to consider when applying the molecular toolbox for accessible and actionable conservation management. Finally, we highlight a number of important steps to be addressed in a collaborative way, which can facilitate the broad integration of molecular data into conservation. Molecular tools are increasingly applied in conservation management; however, they are not equally available to all practitioners. We here provide key questions when establishing a conservation genetic study and highlight important steps which need to be addressed when these tools are globally applied.image
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| 28. |
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| 29. |
- Han, Shizhong, et al.
(författare)
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Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE)
- 2009
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:6, s. 1171-1180
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Tidskriftsartikel (refereegranskat)abstract
- We recently identified a novel non-synonymous variant, rs1143679, at exon 3 of the ITGAM gene associated with systemic lupus erythematosus (SLE) susceptibility in European-Americans (EAs) and African-Americans. Using genome-wide association approach, three other studies also independently reported an association between SLE susceptibility and ITGAM or ITGAM-ITGAX region. The primary objectives of this study are to assess whether single or multiple causal variants from the same gene or any nearby gene(s) are involved in SLE susceptibility and to confirm a robust ITGAM association across nine independent data sets (n = 8211). First, we confirmed our previously reported association of rs1143679 (risk allele 'A') with SLE in EAs (P = 1.0 x 10(-8)) and Hispanic-Americans (P = 2.9 x 10(-5)). Secondly, using a comprehensive imputation-based association test, we found that ITGAM is one of the major non-human leukocyte antigen susceptibility genes for SLE, and the strongest association for EA is the same coding variant rs1143679 (log(10)Bayes factor=20, P = 6.17 x 10(-24)). Thirdly, we determined the robustness of rs1143679 association with SLE across three additional case-control samples, including UK (P = 6.2 x 10(-8)), Colombian (P = 3.6 x 10(-7)), Mexican (P = 0.002), as well as two independent sets of trios from UK (P(TDT) = 1.4 x 10(-5)) and Mexico (P(TDT) = 0.015). A meta-analysis combing all independent data sets greatly reinforces the association (P(meta) = 7.1 x 10(-50), odds ratio = 1.83, 95% confidence interval = 1.69-1.98, n = 10 046). However, this ITGAM association was not observed in the Korean or Japanese samples, in which rs1143679 is monomorphic for the non-risk allele (G). Taken together along with our earlier findings, these results demonstrate that the coding variant, rs1143679, best explains the ITGAM-SLE association, especially in European- and African-derived populations, but not in Asian populations.
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| 30. |
- Ishigaki, Kazuyoshi, et al.
(författare)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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| 31. |
- Joshi, Jayant, et al.
(författare)
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Upper chromospheric magnetic field of a sunspot penumbra : observations of fine structure
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 596
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Tidskriftsartikel (refereegranskat)abstract
- Aims. The fine-structure of the magnetic field in a sunspot penumbra in the upper chromosphere is to be explored and compared to that in the photosphere. Methods. Spectropolarimetric observations with high spatial resolution were recorded with the 1.5-m GREGOR telescope using the GREGOR Infrared Spectrograph (GRIS). The observed spectral domain includes the upper chromospheric Hei triplet at 10 830 angstrom and the photospheric Si I 10 827.1 angstrom and Ca I 10 833.4 angstrom spectral lines. The upper chromospheric magnetic field is obtained by inverting the Hei triplet assuming a Milne-Eddington-type model atmosphere. A height-dependent inversion was applied to the Si I 10 827.1 angstrom and Ca I 10 833.4 angstrom lines to obtain the photospheric magnetic field. Results. We find that the inclination of the magnetic field varies in the azimuthal direction in the photosphere and in the upper chromosphere. The chromospheric variations coincide remarkably well with the variations in the inclination of the photospheric field and resemble the well-known spine and interspine structure in the photospheric layers of penumbrae. The typical peak-to-peak variations in the inclination of the magnetic field in the upper chromosphere are found to be 10 degrees-15 degrees, which is roughly half the variation in the photosphere. In contrast, the magnetic field strength of the observed penumbra does not vary on small spatial scales in the upper chromosphere. Conclusions. Thanks to the high spatial resolution of the observations that is possible with the GREGOR telescope at 1.08 microns, we find that the prominent small-scale fluctuations in the magnetic field inclination, which are a salient part of the property of sunspot penumbral photospheres, also persist in the chromosphere, although at somewhat reduced amplitudes. Such a complex magnetic configuration may facilitate penumbral chromospheric dynamic phenomena, such as penumbral micro-jets or transient bright dots.
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| 32. |
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| 33. |
- Calderón-Contreras, Rafael, et al.
(författare)
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A regional PECS node built from place-based social-ecological sustainability research in Latin America and the Caribbean
- 2022
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Ingår i: Ecosystems and People. - : Informa UK Limited. - 2639-5908 .- 2639-5916. ; 18:1, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Sustainability requires a combination of meaningful co-production of locally relevant solutions, synthesis of insights gained across regions, and increased cooperation between science, policy and practice. The Programme for Ecosystem Change and Society (PECS) has been coordinating Place-Based Social-Ecological Sustainability Research (PBSESR) across the globe and emphasizes the need for regional scientific nodes from diverse biocultural regions to inform sustainability science and action. In this paper, we assess the strengths of the PBSESR communities in Latin America and the Caribbean (LAC). We provide an overview of PBSESR literature associated with this region and highlight the achievements of two prominent regional networks: The Social-Ecological Systems and Sustainability Research Network from Mexico (SocioEcoS) and the South American Institute for Resilience and Sustainability Studies from Uruguay (SARAS Institute). Finally, we identify the potential in these nodes to constitute a regional PECS node in Latin America and discuss the capacity needed to ensure such function. The results of the literature review show that while still loosely interconnected across the region, networks play key roles in connecting otherwise cloistered teams and we illustrate how the SocioEcoS network (focusing on transdisciplinary co-production of knowledge towards sustainability) and the SARAS Institute (focusing on innovative approaches for looking at complex social-ecological problems, rooted in slow science and arts) operate as key connectors in the region. We conclude that these organizations combined can embody a Latin American node for PECS, and would thereby not only contribute to regional but also global capacities to advance the sustainability agenda.
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| 34. |
- Evans, Matthew L., et al.
(författare)
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Developments and applications of the OPTIMADE API for materials discovery, design, and data exchange
- 2024
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Ingår i: Digital Discovery. - : ROYAL SOC CHEMISTRY. - 2635-098X.
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Tidskriftsartikel (refereegranskat)abstract
- The Open Databases Integration for Materials Design (OPTIMADE) application programming interface (API) empowers users with holistic access to a growing federation of databases, enhancing the accessibility and discoverability of materials and chemical data. Since the first release of the OPTIMADE specification (v1.0), the API has undergone significant development, leading to the v1.2 release, and has underpinned multiple scientific studies. In this work, we highlight the latest features of the API format, accompanying software tools, and provide an update on the implementation of OPTIMADE in contributing materials databases. We end by providing several use cases that demonstrate the utility of the OPTIMADE API in materials research that continue to drive its ongoing development. The Open Databases Integration for Materials Design (OPTIMADE) application programming interface (API) empowers users with holistic access to a federation of databases, enhancing the accessibility and discoverability of materials and chemical data.
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| 35. |
- Green, Damian J, et al.
(författare)
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Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model.
- 2015
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 125:13, s. 2111-9
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Tidskriftsartikel (refereegranskat)abstract
- α-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, (211)At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to (211)At-labeled 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor-bearing animals treated with doses of up to 48 µCi of (211)At-labeled anti-CD20 mAb ([(211)At]1F5-B10) experienced modest responses (0% cures but two- to threefold prolongation of survival compared with negative controls). In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with (211)At-B10-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity was observed in the cured animals receiving 15 µCi of [(211)At]1F5-B10. These findings suggest that α-emitters are highly efficacious in MRD settings, where isolated cells and small tumor clusters prevail.
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| 36. |
- Löfqvist, Chatarina, 1964, et al.
(författare)
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Oxygen Monitoring Reduces the Risk for Retinopathy of Prematurity in a Mexican Population
- 2016
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Ingår i: Neonatology. - : S. Karger AG. - 1661-7800 .- 1661-7819. ; 110:2, s. 135-140
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Tidskriftsartikel (refereegranskat)abstract
- Background: Retinopathy of prematurity (ROP), a potentially blinding disease, affects preterm infants. High levels of oxygen saturation are a well-known risk factor for ROP. Objectives: To assess the frequency of ROP type 1 needing treatment after improved oxygen monitoring (2011) in a Mexican preterm population selected for WINROP analyses and to retrospectively revalidate WINROP, an online surveillance system identifying infants at risk of developing ROP type 1. Methods: Preterm infants born with birth weight (BW) < 1,750 g and/or at gestational age (GA) <= 34 weeks, screened for ROP in 2012-2014 at the Hospital Civil de Guadalajara, Mexico were included (n = 151). Eighty-five infants with GA < 32 weeks qualified for WINROP analyses. GA, BW, maximal ROP stage, ROP treatment and weekly weights were recorded. The results in the present study were compared to those of a previous WINROP study in the same hospital (2005-2010; n = 352). Results: In the present WINROP cohort, 11.8% of the infants born at GA < 32 weeks received treatment compared to 51.0% of the infants in the previous WINROP cohort. One infant (3%) born at GA >= 32 weeks received treatment during the present study period compared to 35.6% during the previous period. WINROP displayed 80.0% sensitivity in infants born at GA < 32 weeks in the present study compared to 84.7% in the previous study. Conclusions: Uncontrolled oxygen supplementation is the major risk factor for severe ROP in infants born at GA >= 32 weeks. After improved oxygen monitoring, the frequency of ROP treatment was dramatically reduced at the Hospital Civil de Guadalajara, Mexico. (C) 2016 S. Karger AG, Basel.
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| 37. |
- Noda, C. Quintero, et al.
(författare)
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Chromospheric polarimetry through multiline observations of the 850-nm spectral region - II. A magnetic flux tube scenario
- 2017
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 472:1, s. 727-737
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Tidskriftsartikel (refereegranskat)abstract
- In this publication, we continue the work started in Quintero Noda et al., examining this time a numerical simulation of a magnetic flux tube concentration. Our goal is to study if the physical phenomena that take place in it, in particular, the magnetic pumping, leaves a specific imprint on the examined spectral lines. We find that the profiles from the interior of the flux tube are periodically doppler shifted following an oscillation pattern that is also reflected in the amplitude of the circular polarization signals. In addition, we analyse the properties of the Stokes profiles at the edges of the flux tube discovering the presence of linear polarization signals for the Ca II lines, although they are weak with an amplitude around 0.5 per cent of the continuum intensity. Finally, we compute the response functions to perturbations in the longitudinal field, and we estimate the field strength using the weak-field approximation. Our results indicate that the height of formation of the spectral lines changes during the magnetic pumping process, which makes the interpretation of the inferred magnetic field strength and its evolution more difficult. These results complement those from previous works, demonstrating the capabilities and limitations of the 850-nm spectrum for chromospheric Zeeman polarimetry in a very dynamic and complex atmosphere.
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| 38. |
- Noda, C. Quintero, et al.
(författare)
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Diagnostic capabilities of spectropolarimetric observations for understanding solar phenomena : I. Zeeman-sensitive photospheric lines
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 652
-
Tidskriftsartikel (refereegranskat)abstract
- Future ground-based telescopes will expand our capabilities for simultaneous multi-line polarimetric observations in a wide range of wavelengths, from the near-ultraviolet to the near-infrared. This creates a strong demand to compare candidate spectral lines to establish a guideline of the lines that are most appropriate for each observation target. We focused in this first work on Zeeman-sensitive photospheric lines in the visible and infrared. We first examined their polarisation signals and response functions using a 1D semi-empirical atmosphere. Then we studied the spatial distribution of the line core intensity and linear and circular polarisation signals using a realistic 3D numerical simulation. We ran inversions of synthetic profiles, and we compared the heights at which we obtain a high correlation between the input and the inferred atmosphere. We also used this opportunity to revisit the atomic information we have on these lines and computed the broadening cross-sections due to collisions with neutral hydrogen atoms for all the studied spectral lines. The results reveal that four spectral lines stand out from the rest for quiet-Sun and network conditions: Fe I 5250.2, 6302, 8468, and 15 648 angstrom. The first three form higher in the atmosphere, and the last line is mainly sensitive to the atmospheric parameters at the bottom of the photosphere. However, as they reach different heights, we strongly recommend using at least one of the first three candidates together with the Fe I 15 648 angstrom line to optimise our capabilities for inferring the thermal and magnetic properties of the lower atmosphere.
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| 39. |
- Ollila, Hanna M., et al.
(författare)
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Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix (R). Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix (R).
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| 40. |
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| 41. |
- Orozco, Gisela, et al.
(författare)
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Association of STAT4 with rheumatoid arthritis : a replication study in three European populations
- 2008
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 58:7, s. 1974-1980
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study was undertaken to investigate the previously reported association of the STAT4 polymorphism rs7574865 with rheumatoid arthritis (RA) in 3 different European populations from Spain, Sweden, and The Netherlands, comprising a total of 2,072 patients and 2,474 controls. METHODS: Three different cohorts were included in the study: 923 RA patients and 1,296 healthy controls from Spain, 273 RA patients and 285 healthy controls from Sweden, and 876 RA patients and 893 healthy controls from The Netherlands. DNA from patients and controls was obtained from peripheral blood. Samples were genotyped for the STAT4 single-nucleotide polymorphism rs7574865 using a TaqMan 5'-allele discrimination assay. The chi-square test was performed to compare allele and genotype distributions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: We observed a significantly increased frequency of the minor T allele in RA patients compared with healthy controls in the Spanish population (24.8% versus 20.8%; P = 0.001, OR 1.26 [95% CI 1.09-1.45]). This association was confirmed in both the Swedish population (P = 0.03, OR 1.35 [95% CI 1.03-1.77]) and the Dutch population (P = 0.03, OR 1.45 [95% CI 1.21-1.73]). The overall P value for all 3 populations was 9.79 x 10(-6) (OR 1.25 [95% CI 1.13-1.37]). No association between rs7574865 and the presence of rheumatoid factor or anti-cyclic citrullinated peptide autoantibodies was observed. A meta-analysis of all published STAT4 associations revealed an OR of 1.25 (95% CI 1.19-1.33) (P = 1 x 10(-5)). CONCLUSION: Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data.
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| 42. |
- Quintero Noda, C., et al.
(författare)
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A study of the capabilities for inferring atmospheric information from high-spatial-resolution simulations
- 2023
-
Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 675
-
Tidskriftsartikel (refereegranskat)abstract
- In this work, we study the accuracy that can be achieved when inferring the atmospheric information from realistic numerical magnetohydrodynamic simulations that reproduce the spatial resolution we will obtain with future observations made by the 4 m class telescopes DKIST and EST. We first study multiple inversion configurations using the SIR code and the Fe i transitions at 630 nm until we obtain minor differences between the input and the inferred atmosphere in a wide range of heights. Also, we examine how the inversion accuracy depends on the noise level of the Stokes profiles. The results indicate that when the majority of the inverted pixels come from strongly magnetised areas, there are almost no restrictions in terms of the noise, obtaining good results for noise amplitudes up to 1 x 10(-3) of I-c. At the same time, the situation is different for observations where the dominant magnetic structures are weak, and noise restraints are more demanding. Moreover, we find that the accuracy of the fits is almost the same as that obtained without noise when the noise levels are on the order of 1 x 10(-4) of I-c. We, therefore, advise aiming for noise values on the order of or lower than 5 x 10(-4) of I-c if observers seek reliable interpretations of the results for the magnetic field vector reliably. We expect those noise levels to be achievable by next-generation 4m class telescopes thanks to an optimised polarisation calibration and the large collecting area of the primary mirror.
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| 43. |
- Quintero Noda, C., et al.
(författare)
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Chromospheric polarimetry through multiline observations of the 850nm spectral region III : Chromospheric jets driven by twisted magnetic fields
- 2019
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 486:3, s. 4203-4215
-
Tidskriftsartikel (refereegranskat)abstract
- We investigate the diagnostic potential of the spectral lines at 850 nm for understanding the magnetism of the lower atmosphere. For that purpose, we use a newly developed 3D simulation of a chromospheric jet to check the sensitivity of the spectral lines to this phenomenon as well as our ability to infer the atmospheric information through spectropolarimetric inversions of noisy synthetic data. We start comparing the benefits of inverting the entire spectrum at 850 nm versus only the Ca II 8542 angstrom spectral line. We found a better match of the input atmosphere for the former case, mainly at lower heights. However, the results at higher layers were not accurate. After several tests, we determined that we need to weight more the chromospheric lines than the photospheric ones in the computation of the goodness of the fit. The new inversion configuration allows us to obtain better fits and consequently more accurate physical parameters. Therefore, to extract the most from multiline inversions, a proper set of weights needs to be estimated. Besides that, we conclude again that the lines at 850 nm, or a similar arrangement with Ca II 8542 angstrom plus Zeeman-sensitive photospheric lines, pose the best-observing configuration for examining the thermal and magnetic properties of the lower solar atmosphere.
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| 44. |
- Suarez, David Orozco, et al.
(författare)
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CMAG : A Mission to Study and Monitor the Inner Corona Magnetic Field
- 2023
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Ingår i: Aerospace. - 2226-4310. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- Measuring magnetic fields in the inner corona, the interface between the solar chromosphere and outer corona, is of paramount importance if we aim to understand the energetic transformations taking place there, and because it is at the origin of processes that lead to coronal heating, solar wind acceleration, and of most of the phenomena relevant to space weather. However, these measurements are more difficult than mere imaging because polarimetry requires differential photometry. The coronal magnetograph mission (CMAG) has been designed to map the vector magnetic field, line-of-sight velocities, and plane-of-the-sky velocities of the inner corona with unprecedented spatial and temporal resolutions from space. This will be achieved through full vector spectropolarimetric observations using a coronal magnetograph as the sole instrument on board a spacecraft, combined with an external occulter installed on another spacecraft. The two spacecraft will maintain a formation flight distance of 430 m for coronagraphic observations, which requires a 2.5 m occulter disk radius. The mission will be preferentially located at the Lagrangian L5 point, offering a significant advantage for solar physics and space weather research. Existing ground-based instruments face limitations such as atmospheric turbulence, solar scattered light, and long integration times when performing coronal magnetic field measurements. CMAG overcomes these limitations by performing spectropolarimetric measurements from space with an external occulter and high-image stability maintained over time. It achieves the necessary sensitivity and offers a spatial resolution of 2.5 '' and a temporal resolution of approximately one minute, in its nominal mode, covering the range from 1.02 solar radii to 2.5 radii. CMAG relies on proven European technologies and can be adapted to enhance any other solar mission, offering potential significant advancements in coronal physics and space weather modeling and monitoring.
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| 45. |
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| 46. |
- Benjet, Corina, et al.
(författare)
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A longitudinal study on the impact of Internet gaming disorder on self‐perceived health, academic performance, and social life of first‐year college students
- 2023
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Ingår i: American Journal on Addictions. - : John Wiley & Sons. - 1055-0496 .- 1521-0391. ; 32:4, s. 343-351
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives: Internet gaming disorder (IGD) is associated with health, social, and academic problems but whether these are consequences of the disorder rather than precursors or correlates is unclear. We aimed to evaluate whether IGD in the 1st year of university predicts health, academic and social problems 1 year later, controlling for baseline health, academic and social problems, demographics, and mental health symptoms.Methods: In a prospective cohort study, 1741 university students completed both a baseline online survey in their 1st year and a follow-up survey 1 year later. Log-binomial models examined the strength of prospective associations between baseline predictor variables (IGD, baseline health, academic and social problems, sex, age, and mental health symptoms) and occurrence of health, academic and social problems at follow-up.Results: When extensively adjusted by the corresponding outcome at baseline, any mental disorder symptoms, sex, and age, baseline IGD was associated only with severe school impairment and poor social life (risk ratio [RR] = 1.77; 95% confidence interval [CI] = 1.14-2.75, p = .011; RR = 1.22; 95% CI = 1.07-1.38, p = .002, respectively).Conclusions and scientific significance: University authorities and counselors should consider that incoming 1st-year students that meet criteria for IGD are likely to have increased academic and social impairments during their 1st year for which they may want to intervene. This study adds to the existing literature by longitudinally examining a greater array of negative outcomes of IGD than previously documented.
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| 47. |
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| 48. |
- Dejea, Hector, et al.
(författare)
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In Situ Loading and Time-Resolved Synchrotron-Based Phase Contrast Tomography for the Mechanical Investigation of Connective Knee Tissues : A Proof-of-Concept Study
-
Ingår i: Advanced Science. - 2198-3844.
-
Tidskriftsartikel (refereegranskat)abstract
- Articular cartilage and meniscus transfer and distribute mechanical loads in the knee joint. Degeneration of these connective tissues occurs during the progression of knee osteoarthritis, which affects their composition, microstructure, and mechanical properties. A deeper understanding of disease progression can be obtained by studying them simultaneously. Time-resolved synchrotron-based X-ray phase-contrast tomography (SR-PhC-µCT) allows to capture the tissue dynamics. This proof-of-concept study presents a rheometer setup for simultaneous in situ unconfined compression and SR-PhC-µCT of connective knee tissues. The microstructural response of bovine cartilage (n = 16) and meniscus (n = 4) samples under axial continuously increased strain, or two steps of 15% strain (stress–relaxation) is studied. The chondrocyte distribution in cartilage and the collagen fiber orientation in the meniscus are assessed. Variations in chondrocyte density reveal an increase in the top 40% of the sample during loading, compared to the lower half. Meniscus collagen fibers reorient perpendicular to the loading direction during compression and partially redisperse during relaxation. Radiation damage, image repeatability, and image quality assessments show little to no effects on the results. In conclusion, this approach is highly promising for future studies of human knee tissues to understand their microstructure, mechanical response, and progression in degenerative diseases.
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| 49. |
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| 50. |
- Escher, Sylvia E., et al.
(författare)
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Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action
- 2022
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Ingår i: Toxicology in Vitro. - : Elsevier. - 0887-2333 .- 1879-3177. ; 79
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Tidskriftsartikel (refereegranskat)abstract
- Read-across approaches often remain inconclusive as they do not provide sufficient evidence on a common mode of action across the category members. This read-across case study on thirteen, structurally similar, branched aliphatic carboxylic acids investigates the concept of using human-based new approach methods, such as in vitro and in silico models, to demonstrate biological similarity.Five out of the thirteen analogues have preclinical in vivo studies. Three out of them induced lipid accumulation or hypertrophy in preclinical studies with repeated exposure, which leads to the read-across hypothesis that the analogues can potentially induce hepatic steatosis.To confirm the selection of analogues, the expression patterns of the induced differentially expressed genes (DEGs) were analysed in a human liver model. With increasing dose, the expression pattern within the tested analogues got more similar, which serves as a first indication of a common mode of action and suggests differences in the potency of the analogues.Hepatic steatosis is a well-known adverse outcome, for which over 55 adverse outcome pathways have been identified. The resulting adverse outcome pathway (AOP) network, comprised a total 43 MIEs/KEs and enabled the design of an in vitro testing battery. From the AOP network, ten MIEs, early and late KEs were tested to systematically investigate a common mode of action among the grouped compounds.The targeted testing of AOP specific MIE/KEs shows that biological activity in the category decreases with side chain length. A similar trend was evident in measuring liver alterations in zebra fish embryos. However, activation of single MIEs or early KEs at in vivo relevant doses did not necessarily progress to the late KE “lipid accumulation”. KEs not related to the read-across hypothesis, testing for example general mitochondrial stress responses in liver cells, showed no trend or biological similarity.Testing scope is a key issue in the design of in vitro test batteries. The Dempster-Shafer decision theory predicted those analogues with in vivo reference data correctly using one human liver model or the CALUX reporter assays.The case study shows that the read-across hypothesis is the key element to designing the testing strategy. In the case of a good mechanistic understanding, an AOP facilitates the selection of reliable human in vitro models to demonstrate a common mode of action. Testing DEGs, MIEs and early KEs served to show biological similarity, whereas the late KEs become important for confirmation, as progression from MIEs to AO is not always guaranteed.
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