| 1. |
- Hudson, Thomas J., et al.
(author)
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International network of cancer genome projects
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Journal article (peer-reviewed)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 2. |
- Teslovich, Tanya M., et al.
(author)
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Biological, clinical and population relevance of 95 loci for blood lipids
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
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Journal article (peer-reviewed)abstract
- Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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| 3. |
- Thorleifsson, Gudmar, et al.
(author)
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Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:10, s. 906-909
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Journal article (peer-reviewed)abstract
- We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[ A], odds ratio (OR) = 1.36, P = 5.0 x 10(-10)). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.
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| 4. |
- Flannick, Jason, et al.
(author)
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Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
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Journal article (peer-reviewed)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
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| 5. |
- Gretarsdottir, Solveig, et al.
(author)
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Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:8, s. 71-692
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Journal article (peer-reviewed)abstract
- We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
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| 6. |
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| 7. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 8. |
- Beijert, Irene J., et al.
(author)
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International Opinions on Grading of Urothelial Carcinoma : A Survey Among European Association of Urology and International Society of Urological Pathology Members
- 2023
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In: European Urology Open Science. - 2666-1691. ; 52, s. 154-165
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Journal article (peer-reviewed)abstract
- Background: Grade of non–muscle-invasive bladder cancer (NMIBC) is an important prognostic factor for progression. Currently, two World Health Organization (WHO) classification systems (WHO1973, categories: grade 1–3, and WHO2004 categories: papillary urothelial neoplasm of low malignant potential [PUNLMP], low-grade [LG], high-grade [HG] carcinoma) are used. Objective: To ask the European Association of Urology (EAU) and International Society of Urological Pathology (ISUP) members regarding their current practice and preferences of grading systems. Design, setting, and participants: A web-based, anonymous questionnaire with ten questions on grading of NMIBC was created. The members of EAU and ISUP were invited to complete an online survey by the end of 2021. Thirteen experts had previously answered the same questions. Outcome measurements and statistical analysis: The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed. Results and limitations: Currently, 53% use only the WHO2004 system and 40% use both systems. According to most respondents, PUNLMP is a rare diagnosis with management similar to Ta-LG carcinoma. The majority (72%) would consider reverting back to WHO1973 if grading criteria were more detailed. Separate reporting of WHO1973-G3 within WHO2004-HG would influence clinical decisions for Ta and/or T1 tumors according the majority (55%). Most respondents preferred a two-tier (41%) or a three-tier (41%) grading system. The current WHO2004 grading system is supported by a minority (20%), whereas nearly half (48%) supported a hybrid three- or four-tier grading system composed of both WHO1973 and WHO2004. The survey results of the experts were comparable with ISUP and EAU respondents. Conclusions: Both the WHO1973 and the WHO2004 grading system are still widely used. Even though opinions on the future of bladder cancer grading were strongly divided, there was limited support for WHO1973 and WHO2004 in their current formats, while the hybrid (three-tier) grading system with LG, HG-G2, and HG-G3 as categories could be considered the most promising alternative. Patient summary: Grading of non–muscle-invasive bladder cancer (NMIBC) is a matter of ongoing debate and lacks international consensus. We surveyed urologists and pathologists of European Association of Urology and International Society of Urological Pathology on their preferences regarding NMIBC grading to generate a multidisciplinary dialogue. Both the “old” World Health Organization (WHO) 1973 and the “new” WHO2004 grading schemes are still used widely. However, continuation of both the WHO1973 and the WHO2004 system showed limited support, while a hybrid grading system composed of both the WHO1973 and the WHO2004 classification system may be considered a promising alternative.
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| 9. |
- Charpin, Laurent, et al.
(author)
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Ageing and air leakage assessment of a nuclear reactor containment mock-up : VERCORS 2nd benchmark
- 2021
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In: Nuclear Engineering and Design. - : Elsevier BV. - 0029-5493. ; 377
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Journal article (peer-reviewed)abstract
- Electricité de France (EDF) operates a large fleet of nuclear reactors and is responsible for demonstrating the safety of facilities, including concrete containment buildings (CCB), which are non-replaceable components. The leak-tightness of CCBs is assessed every 10 years during integrated leak-rate tests (IRLT). For double-wall containments, which have no metallic liners, the leak-tightness is strongly influenced by the degree of cracking of concrete and opening of the cracks, which mostly depends on (a) the prestress decrease due to the delayed strains of concrete and to a lesser extent due to relaxation of tendons steel, and (b) the saturation degree of the Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation concrete wall. Therefore, to optimize the maintenance programs on CCBs, it is important to predict the evolution of drying, creep and shrinkage strains of concrete to be able to correctly assess the pre-stress losses, and finally the air leak-tightness at a structural level during pressure tests or under accidental loadings. To improve our understanding and identify the best modelling practices on this issue, a large experimental program called VERCORS was launched in 2014. VERCORS is a 1/3 mock-up of a 1300 MWe nuclear reactor CCB. It has been widely instrumented, and its concrete thoroughly characterized. A specific attention has been paid to ensure it is consistent with real CBBs features in EDF's nuclear fleet. To complement its internal R&D efforts, EDF decided to associate external partners to this program. One of the means for this is the organization of benchmarks, where all teams are given data and information about the mock-up and are asked to quantitatively predict its behaviour. The present paper reports the organization and findings of the 2nd benchmark which was organized in 2018 and gathered several international teams around the same objective: improve the confidence in the modelling of structural behaviour as well as the leak-tightness of concrete in containment walls under pressure test loading. The benchmark has shown once again that predicting the mechanical and leakage behaviour of containment buildings is a difficult task. The benchmark also yielded interesting information about the possibility to use spatially reduced models to predict the mechanical behaviour and leakage and underlined the fact that more research must be done to better predict the localization of cracks and leakage. Some lessons have been learnt for the next benchmark: EDF will ask to clarify further the calibration methods, will give more data (including drying, creep and shrinkage at different temperatures and moisture measurements in the mock-up), and will help the participants using local leakage data by projecting the raw measurements on a regular grid, so that the local leakage models can be improved.
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| 10. |
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| 11. |
- Gascon Diez, Elena, et al.
(author)
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Influence of a wastewater treatment plant on mercury contamination and sediment characteristics in Vidy Bay (Lake Geneva, Switzerland)
- 2014
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In: Aquatic Sciences. - : Springer Science and Business Media LLC. - 1015-1621 .- 1420-9055. ; 76:S1, s. S21-S32
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Journal article (peer-reviewed)abstract
- Previous direct observations of the sediment surface in Vidy Bay, Lake Geneva (Switzerland), revealed a range of sediment characteristics in terms of colour, texture and morphology. Dives with the MIR submersibles during the éLEMO project permitted the exploration of a large portion of Vidy Bay. It is the most contaminated part of Lake Geneva, due to inputs of treated and untreated waters from a large wastewater treatment plant (WWTP). To evaluate the influence of WWTP effluent on mercury contamination and sediment characteristics, 14 sediment cores were retrieved in the vicinity of the wastewater treatment plant effluent. Total mercury concentrations in sediments ranged between 0.32 and 10.1 mg/kg. Inorganic mercury and monomethylmercury concentrations in overlying and pore waters were also measured. The total partition coefficients of mercury (logK d) ranged from 3.6 to 5.8. The monomethylmercury concentration in pore waters of surface sediments was a large proportion of the total mercury concentration (44 ± 25 %). A Spearman test showed a negative correlation between the distance to the wastewater treatment plant outlet and the concentrations of total mercury in sediments and pore waters. Visual observations from the submersible allowed recognizing six different types of sediment. The areal distribution of these different sediment types clearly showed the influence of the wastewater treatment plant outlet on the sediment surface patterns. However, no relationship with mercury concentrations could be established.
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| 12. |
- Graham, Angus, 1968-, et al.
(author)
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Theban Harbours and Waterscapes Survey, 2015
- 2015
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In: Journal of Egyptian Archaeology. - : SAGE Publications. - 0307-5133 .- 2514-0582. ; 101:1, s. 37-49
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Journal article (peer-reviewed)abstract
- Report on the 2015 season of the Theban Harbours and Waterscapes Survey (THaWS). The paper discusses the extension of geoarchaeological and geophysical investigations to the east of the Ramesseum, the continuing work in and around the Temple of Millions of Years of Amenhotep III, and the topographic survey and geophysical survey of the western mounds of the Birket Habu.
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| 13. |
- Hansen, James, et al.
(author)
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Assessing Dangerous Climate Change : Required Reduction of Carbon Emissions to Protect Young People, Future Generations and Nature
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12, s. e81648-
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Research review (peer-reviewed)abstract
- We assess climate impacts of global warming using ongoing observations and paleoclimate data. We use Earth's measured energy imbalance, paleoclimate data, and simple representations of the global carbon cycle and temperature to define emission reductions needed to stabilize climate and avoid potentially disastrous impacts on today's young people, future generations, and nature. A cumulative industrial-era limit of similar to 500 GtC fossil fuel emissions and 100 GtC storage in the biosphere and soil would keep climate close to the Holocene range to which humanity and other species are adapted. Cumulative emissions of similar to 1000 GtC, sometimes associated with 2 degrees C global warming, would spur slow feedbacks and eventual warming of 3-4 degrees C with disastrous consequences. Rapid emissions reduction is required to restore Earth's energy balance and avoid ocean heat uptake that would practically guarantee irreversible effects. Continuation of high fossil fuel emissions, given current knowledge of the consequences, would be an act of extraordinary witting intergenerational injustice. Responsible policymaking requires a rising price on carbon emissions that would preclude emissions from most remaining coal and unconventional fossil fuels and phase down emissions from conventional fossil fuels.
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| 14. |
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| 15. |
- Mundy, Lee G., et al.
(author)
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Protostellar Condensations within the Orion Ridge
- 1986
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In: Astrophysical Journal. - Philadelphia, PA : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 304:2, s. L51-L55
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Journal article (peer-reviewed)abstract
- Aperture synthesis observations of the CS J = 2 to 1 line and 95 GHz continuum emission from a 2 arcmin x 3 arcmin region around IRc2 in the OMC-1 molecular cloud have been obtained at 7.5 arcsec resolution with the Owens Valley Radio Observatory millimeter interferometer. These observations reveal four distinct condensations with the OMC-1 molecular ridge. The condensations lie along the edge of the bright central part of the H II region, M 42, suggesting that they may have been formed as a result of shock compression driven by the H II region. Their masses and densities, M about 50 solar masses and n about 10 to the 6th - 10 to the 7th/cu cm, suggest that the condensations will undergo further massive star formation on a short time scale (about 20,000 yr).
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| 16. |
- Oddsson, Asmundur, et al.
(author)
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Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
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| 17. |
- Stacey, Simon N, et al.
(author)
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
- 2011
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
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Journal article (peer-reviewed)abstract
- To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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| 18. |
- Treydte, Kerstin, et al.
(author)
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Recent human-induced atmospheric drying across Europe unprecedented in the last 400 years
- 2024
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In: NATURE GEOSCIENCE. - 1752-0894 .- 1752-0908. ; 17, s. 58-65
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Journal article (peer-reviewed)abstract
- The vapor pressure deficit reflects the difference between how much moisture the atmosphere could and actually does hold, a factor that fundamentally affects evapotranspiration, ecosystem functioning, and vegetation carbon uptake. Its spatial variability and long-term trends under natural versus human-influenced climate are poorly known despite being essential for predicting future effects on natural ecosystems and human societies such as crop yield, wildfires, and health. Here we combine regionally distinct reconstructions of pre-industrial summer vapor pressure deficit variability from Europe's largest oxygen-isotope network of tree-ring cellulose with observational records and Earth system model simulations with and without human forcing included. We demonstrate that an intensification of atmospheric drying during the recent decades across different European target regions is unprecedented in a pre-industrial context and that it is attributed to human influence with more than 98% probability. The magnitude of this trend is largest in Western and Central Europe, the Alps and Pyrenees region, and the smallest in southern Fennoscandia. In view of the extreme drought and compound events of the recent years, further atmospheric drying poses an enhanced risk to vegetation, specifically in the densely populated areas of the European temperate lowlands. The atmosphere has dried across most regions of Europe in recent decades, a trend that can be attributed primarily to human impacts, according to tree ring records spanning 400 years and Earth system model simulations.
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