| 1. |
- Justice, A. E., et al.
(author)
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Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
- 2017
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
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| 4. |
- Wessel, Jennifer, et al.
(author)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Journal article (peer-reviewed)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 5. |
- Scott, Robert A., et al.
(author)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Journal article (peer-reviewed)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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| 6. |
- Ledoux, X., et al.
(author)
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The Neutrons for Science Facility at SPIRAL-2
- 2018
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In: Radiation Protection Dosimetry. - : OXFORD UNIV PRESS. - 0144-8420 .- 1742-3406. ; 180:1-4, s. 115-119
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Journal article (peer-reviewed)abstract
- The neutrons for science (NFS) facility is a component of SPIRAL-2, the new superconducting linear accelerator built at GANIL in Caen (France). The proton and deuteron beams delivered by the accelerator will allow producing intense neutron fields in the 100 keV-40 MeV energy range. Continuous and quasi-mono-kinetic energy spectra, respectively, will be available at NFS, produced by the interaction of a deuteron beam on a thick Be converter and by the Li-7(p, n) reaction on thin converter. The pulsed neutron beam, with a flux up to two orders of magnitude higher than those of other existing time-of-flight facilities, will open new opportunities of experiments in fundamental research as well as in nuclear data measurements. In addition to the neutron beam, irradiation stations for neutron-, proton- and deuteron-induced reactions will be available for cross-sections measurements and for the irradiation of electronic devices or biological cells. NFS, whose first experiment is foreseen in 2018, will be a very powerful tool for physics, fundamental research as well as applications like the transmutation of nuclear waste, design of future fission and fusion reactors, nuclear medicine or test and development of new detectors.
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| 7. |
- Ledoux, X., et al.
(author)
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The neutrons for science facility at SPIRAL-2
- 2017
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In: ND 2016. - Les Ulis : EDP Sciences.
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Conference paper (peer-reviewed)abstract
- Numerous domains, in fundamental research as well as in applications, require the study of reactions induced by neutrons with energies from few MeV up to few tens of MeV. Reliable measurements also are necessary to improve the evaluated databases used by nuclear transport codes. This energy range covers a large number of topics like transmutation of nuclear waste, design of future fission and fusion reactors, nuclear medicine or test and development of new detectors. A new facility called Neutrons For Science (NFS) is being built for this purpose on the GANIL site at Caen (France). NFS is composed of a pulsed neutron beam for time-of-flight facility as well as irradiation stations for cross-section measurements. Neutrons will be produced by the interaction of deuteron and proton beams, delivered by the SPIRAL-2 linear accelerator, with thick or thin converters made of beryllium or lithium. Continuous and quasi-mono-energetic spectra will be available at NFS up to 40 MeV. In this fast energy region, the neutron flux is expected to be up to 2 orders of magnitude higher than at other existing time-of-flight facilities. In addition, irradiation stations for neutron-, proton- and deuteron-induced reactions will allow performing cross-section measurements by the activation technique. After a description of the facility and its characteristics, the experiments to be performed in the short and medium term will be presented.
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| 8. |
- Reusch, T. B. H., et al.
(author)
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The Baltic Sea as a time machine for the future coastal ocean
- 2018
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 4:5
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Journal article (peer-reviewed)abstract
- Coastal global oceans are expected to undergo drastic changes driven by climate change and increasing anthropogenic pressures in coming decades. Predicting specific future conditions and assessing the best management strategies to maintain ecosystem integrity and sustainable resource use are difficult, because of multiple interacting pressures, uncertain projections, and a lack of test cases for management. We argue that the Baltic Sea can serve as a time machine to study consequences and mitigation of future coastal perturbations, due to its unique combination of an early history of multistressor disturbance and ecosystem deterioration and early implementation of cross-border environmental management to address these problems. The Baltic Sea also stands out in providing a strong scientific foundation and accessibility to long-term data series that provide a unique opportunity to assess the efficacy of management actions to address the breakdown of ecosystem functions. Trend reversals such as the return of top predators, recovering fish stocks, and reduced input of nutrient and harmful substances could be achieved only by implementing an international, cooperative governance structure transcending its complex multistate policy setting, with integrated management of watershed and sea. The Baltic Sea also demonstrates how rapidly progressing global pressures, particularly warming of Baltic waters and the surrounding catchment area, can offset the efficacy of current management approaches. This situation calls for management that is (i) conservative to provide a buffer against regionally unmanageable global perturbations, (ii) adaptive to react to new management challenges, and, ultimately, (iii) multisectorial and integrative to address conflicts associated with economic trade-offs.
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| 9. |
- Makii, H., et al.
(author)
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Effects of the nuclear structure of fission fragments on the high-energy prompt fission γ -ray spectrum in U 235 (nth,f)
- 2019
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In: Physical Review C. - 2469-9985. ; 100:4
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Journal article (peer-reviewed)abstract
- The prompt fission γ-ray energy spectrum for cold-neutron-induced fission of U235 was measured in the energy range Eγ=0.8-20MeV, by gaining a factor of about 105 in statistics compared to the measurements performed so far. The spectrum exhibits local bump structures at Eγ≈4MeV and ≈6MeV, and also a broad one at ≈15MeV. In order to understand the origins of these bumps, the γ-ray spectra were calculated using a statistical Hauser-Feshbach model, taking into account the deexcitation of all the possible primary fission fragments. It is shown that the bump at ≈4MeV is created by the transitions between the discrete levels in the fragments around Sn132, and the bump at ≈6MeV mostly comes from the complementary light fragments. It is also indicated that a limited number of nuclides, which have high-spin states at low excitation energies, can contribute to the bump structure around Eγ≈15MeV, induced by the transition feeding into the low-lying high-spin states.
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| 10. |
- Jiguet, Frédéric, et al.
(author)
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Unravelling migration connectivity reveals unsustainable hunting of the declining ortolan bunting
- 2019
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:5
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Journal article (peer-reviewed)abstract
- In France, illegal hunting of the endangered ortolan bunting Emberiza hortulana has been defended for the sake of tradition and gastronomy. Hunters argued that ortolan buntings trapped in southwest France originate from large and stable populations across the whole of Europe. Yet, the European Commission referred France to the Court of Justice of the European Union (EU) in December 2016 for infringements to legislation (IP/16/4213). To better assess the impact of hunting in France, we combined Pan-European data from archival light loggers, stable isotopes, and genetics to determine the migration strategy of the species across continents. Ortolan buntings migrating through France come from northern and western populations, which are small, fragmented and declining. Population viability modeling further revealed that harvesting in southwest France is far from sustainable and increases extinction risk. These results provide the sufficient scientific evidence for justifying the ban on ortolan harvesting in France.
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