99 research outputs found
Genetic Variants as Predictors of the Success of Colorectal Cancer Treatments
Some colorectal cancer (CRC) outcomes are partially associated with genetics, and different studies have proposed several genetic variants as predictors. However, analysis of their performance in other populations is limited. Thus, our objectives were to assess their use in our cohort and to find additional genetic variants associated with CRC outcomes. We found that some of the genetic variants proposed as predictors could be used in our cohort, although the addition of clinical data improved the performance. In addition, we found additional genetic variants that could be useful to predict the CRC manifestations in our population. Our findings will help to refine the use of genetic polymorphisms to predict CRC outcomes in our population, and we expect that our findings could be useful for other populations.This work was partially founded by Gipuzkoako Foru Aldundia/Diputación Foral de Gipuzkoa (Code: 111/17
Performance of the Use of Genetic Information to Assess the Risk of Colorectal Cancer in the Basque Population
The risk of developing colorectal cancer (CRC) is partially associated with genetics. Different studies have provided valuable genetic information to understand the biology behind CRC and to build models of genetic risk. However, the study of the applicability of such genetic information within the Basque population is limited. Thus, our objectives were to find out if the genetic variants associated with CRC in other populations are the same in the Basque population and to assess the performance of the use of genetic information to calculate the risk of developing CRC. We found that the available genetic information can be applied to the Basque population, although local genetic variation can affect its use. Our findings will help to refine the use of CRC genetic risk calculation in the Basque population, and we expect that our findings could be useful for other populations
Neuropeptide S (NPS) variants modify the signaling and risk effects of NPS Receptor 1 (NPSR1) variants in asthma
Single nucleotide polymorphisms (SNPs) close to the gain-of-function substitution, Asn(107) Ile (rs324981, A>T), in Neuropeptide S Receptor 1 (NPSR1) have been associated with asthma. Furthermore, a functional SNP (rs4751440, G>C) in Neuropeptide S (NPS) encodes a Val(6)Leu substitution on the mature peptide that results in reduced bioactivity. We sought to examine the effects of different combinations of these NPS and NPSR1 variants on downstream signaling and genetic risk of asthma. In transfected cells, the magnitude of NPSR1-induced activation of cAMP/PKA signal transduction pathways and downstream gene expression was dependent on the combination of the NPS and NPSR1 variants with NPS-Val(6)/NPSR1-Ile(107) resulting in strongest and NPS-Leu(6)/NPSR1-Asn(107) in weakest effects, respectively. One or two copies of the NPS-Leu(6) (rs4751440) were associated with physician-diagnosed childhood asthma (OR: 0.67, 95% CI 0.49-0.92, p = 0.01) and together with two other linked NPS variants (rs1931704 and rs10830123) formed a protective haplotype (p = 0.008) in the Swedish birth cohort BAMSE (2033 children). NPS rs10830123 showed epistasis with NPSR1 rs324981 encoding Asn(107)Ile (p = 0.009) in BAMSE and with the linked NPSR1 rs17199659 (p = 0.005) in the German MAGIC/ISAAC II cohort (1454 children). In conclusion, NPS variants modify asthma risk and should be considered in genetic association studies of NPSR1 with asthma and other complex diseases.Peer reviewe
Local genetic variation of inflammatory bowel disease in Basque population and its effect in risk prediction
[EN] Inflammatory bowel disease (IBD) is characterised by chronic inflammation of the gastrointestinal tract. Although its aetiology remains unknown, environmental and genetic factors are involved in its development. Regarding genetics, more than 200 loci have been associated with IBD but the transferability of those signals to the Basque population living in Northern Spain, a population with distinctive genetic background, remains unknown. We have analysed 5,411,568 SNPs in 498 IBD cases and 935 controls from the Basque population. We found 33 suggestive loci (p 0.68. In conclusion, we report on the genetic architecture of IBD in the Basque population, and explore the performance of European-descent genetic risk scores in this population.Samples and data used in the present work were provided by the Basque Biobank (http://www.biobancovasco.org).We want to thank Miguel Angel Vesga from the Basque Centre of Transfusion and Human Tissues for providing the access to control samples. This work was founded to MD by Gipuzkoako Foru Aldundia/Diputacion Foral de Gipuzkoa. The project that gave rise to these results rece
Sustained efficacy and safety of a 300IR daily dose of a sublingual solution of birch pollen allergen extract in adults with allergic rhinoconjunctivitis: results of a double-blind, placebo-controlled study
Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice
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Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
Funder: Kennedy Trust Rheumatology Research Prize StudentshipFunder: DFG Cluster of Excellence “Precision Medicine in Chronic In-flammation” (PMI; ID: EXC2167)Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: “Ideas” Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNLFunder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421Abstract: Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS
Reviewing the use of resilience concepts in forest sciences
Purpose of the review Resilience is a key concept to deal with an uncertain future in forestry. In recent years, it has received increasing attention from both research and practice. However, a common understanding of what resilience means in a forestry context, and how to operationalise it is lacking. Here, we conducted a systematic review of the recent forest science literature on resilience in the forestry context, synthesising how resilience is defined and assessed.
Recent findings Based on a detailed review of 255 studies, we analysed how the concepts of engineering resilience, ecological resilience, and social-ecological resilience are used in forest sciences. A clear majority of the studies applied the concept of engineering resilience, quantifying resilience as the recovery time after a disturbance. The two most used indicators for engineering resilience were basal area increment and vegetation cover, whereas ecological
resilience studies frequently focus on vegetation cover and tree density. In contrast, important social-ecological resilience indicators used in the literature are socio-economic diversity and stock of natural resources. In the context of global change, we expected an increase in studies adopting the more holistic social-ecological resilience concept, but this was not the observed trend. Summary Our analysis points to the nestedness of these three resilience concepts, suggesting that they are complementary rather than contradictory. It also means that the variety of resilience approaches does not need to be an obstacle for operationalisation of the concept. We provide guidance for choosing the most suitable resilience concept and indicators based on the management, disturbance and application context
Detailed stratified GWAS analysis for severe COVID-19 in four European populations
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.S.E.H. and C.A.S. partially supported genotyping through a philanthropic donation. A.F. and D.E. were supported by a grant from the German Federal Ministry of Education and COVID-19 grant Research (BMBF; ID:01KI20197); A.F., D.E. and F.D. were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). D.E. was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). D.E., K.B. and S.B. acknowledge the Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594). T.L.L., A.T. and O.Ö. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. M.W. and H.E. are supported by the German Research Foundation (DFG) through the Research Training Group 1743, ‘Genes, Environment and Inflammation’. L.V. received funding from: Ricerca Finalizzata Ministero della Salute (RF-2016-02364358), Italian Ministry of Health ‘CV PREVITAL’—strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ‘REVEAL’; Fondazione IRCCS Ca’ Granda ‘Ricerca corrente’, Fondazione Sviluppo Ca’ Granda ‘Liver-BIBLE’ (PR-0391), Fondazione IRCCS Ca’ Granda ‘5permille’ ‘COVID-19 Biobank’ (RC100017A). A.B. was supported by a grant from Fondazione Cariplo to Fondazione Tettamanti: ‘Bio-banking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by an MIUR grant to the Department of Medical Sciences, under the program ‘Dipartimenti di Eccellenza 2018–2022’. This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP (The Institute for Health Science Research Germans Trias i Pujol) IGTP is part of the CERCA Program/Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIII-MINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). M.M. received research funding from grant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (European Regional Development Fund (FEDER)-Una manera de hacer Europa’). B.C. is supported by national grants PI18/01512. X.F. is supported by the VEIS project (001-P-001647) (co-funded by the European Regional Development Fund (ERDF), ‘A way to build Europe’). Additional data included in this study were obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, European Institute of Innovation & Technology (EIT), a body of the European Union, COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. A.J. and S.M. were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). A.J. was also supported by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the European Regional Development Fund (FEDER). The Basque Biobank, a hospital-related platform that also involves all Osakidetza health centres, the Basque government’s Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. M.C. received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). M.R.G., J.A.H., R.G.D. and D.M.M. are supported by the ‘Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100) and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón’s team is supported by CIBER of Epidemiology and Public Health (CIBERESP), ‘Instituto de Salud Carlos III’. J.C.H. reports grants from Research Council of Norway grant no 312780 during the conduct of the study. E.S. reports grants from Research Council of Norway grant no. 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). P.K. Bergisch Gladbach, Germany and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF). O.A.C. is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—CECAD, EXC 2030–390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. K.U.L. is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. F.H. was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to A.R. from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme—Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to A.R. P.R. is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). F.T. is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence ‘Precision Medicine in Chronic Inflammation’ (EXC2167). C.L. and J.H. are supported by the German Center for Infection Research (DZIF). T.B., M.M.B., O.W. und A.H. are supported by the Stiftung Universitätsmedizin Essen. M.A.-H. was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. E.C.S. is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).Peer reviewe
Detailed stratified GWAS analysis for severe COVID-19 in four European populations
Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.Andre Franke and David Ellinghaus were supported by a grant from the German
Federal Ministry of Education and Research (01KI20197), Andre Franke, David
Ellinghaus and Frauke Degenhardt were supported by the Deutsche
Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic
Inflammation” (EXC2167). David Ellinghaus was supported by the German Federal
Ministry of Education and Research (BMBF) within the framework of the
Computational Life Sciences funding concept (CompLS grant 031L0165). David
Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk
Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana
Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG,
German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German
Research Foundation (DFG) through the Research Training Group 1743, "Genes,
Environment and Inflammation". This project was supported by a Covid-19 grant from
the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197).
Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione
primaria cardiovascolare primaria nella popolazione italiana; The European Union
(EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project
LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca
corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione
IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi
was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research
(Covid-Bank). This research was partly funded by a MIUR grant to the Department of
Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This
study makes use of data generated by the GCAT-Genomes for Life. Cohort study of
the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program /
Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026);
the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529).
Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en
Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional
(FEDER-Una manera de hacer Europa").Beatriz Cortes is supported by national
grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”).
Additional data included in this study was obtained in part by the COVICAT Study
Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19
Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià
and Sara Marsal were supported by the Spanish Ministry of Economy and
Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36).
Antonio Julià was also supported the by national grant PI17/00019 from the Acción
Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque
Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received
Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal
de Investigación (AEI, Spain) and the European Regional Development Fund
(FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán
and Douglas Maya Miles are supported by the “Spanish Ministry of Economy,
Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404,
PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian
government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed,
COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant
FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud.
Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health
(CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from
Research Council of Norway grant no 312780 during the conduct of the study. Dr.
Solligård: reports grants from Research Council of Norway grant no 312769. The
BioMaterialBank Nord is supported by the German Center for Lung Research (DZL),
Airway Research Center North (ARCN). The BioMaterialBank Nord is member of
popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants
from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne
Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases,
University of Cologne, Cologne, Germany. He is supported by the German Federal
Ministry of Education and Research (BMBF).Oliver A. Cornely is supported by the
German Federal Ministry of Research and Education and is funded by the Deutsche
Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's
Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded
by Technical University of Munich, Munich, Germany. Genotyping was performed by
the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM
Technology Centre, University of Helsinki. This work was supported by grants of the
Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland
and Lower Saxony. Kerstin U. Ludwig is supported by the German Research
Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the
Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported
by the Bavarian State Ministry for Science and Arts. Part of the genotyping was
supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA
BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative
Disease Research (JPND). Additional funding was derived from the German Research
Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is
supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH
state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist
Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision
Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf
are supported by the German Center for Infection Research (DZIF). Thorsen Brenner,
Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung
Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la
Cierva Incorporacion program, grant IJC2018-035131-I funded by
MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche
Forschungsgemeinschaft (DFG; SCHU 2419/2-1).N
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