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Small-molecule acti...
Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
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- Michel, M. (author)
- RISE,Karolinska Institutet,Karolinska Institute, Sweden,Kemiska processer och läkemedel
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- Benítez-Buelga, C. (author)
- Karolinska Institute, Sweden; CSIC Instituto de Investigaciones Biomédicas Alberto Sols, Spain,Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.;Inst Invest Biomed Alberto Sols CSIC UAM, Madrid 28029, Spain.
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- Calvo, P. A. (author)
- CISC-UAM Centro de Biología Molecular, Spain,Ctr Biol Mol Severo Ochoa CSIC UAM, Madrid 28049, Spain.
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- Hanna, B. M. F. (author)
- Karolinska Institute, Sweden
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- Mortusewicz, O. (author)
- Karolinska Institutet,Karolinska Institute, Sweden
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- Masuyer, Geoffrey (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,University of Bath, United Kingdom,Univ Bath, Ctr Therapeut Innovat, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England.;Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
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- Davies, Jonathan R. (author)
- Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.,Stockholm University, Sweden
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- Wallner, O. (author)
- Karolinska Institutet,Karolinska Institute, Sweden
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- Sanjiv, K. (author)
- Karolinska Institutet,Karolinska Institute, Sweden
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- Albers, J. J. (author)
- Karolinska Institutet,Karolinska Institute, Sweden,Leibniz Institute for Natural Product Research and Infection Biology, Germany
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- Castañeda-Zegarra, S. (author)
- Karolinska Institute, Sweden; NTNU Norwegian University of Science and Technology, Norway,Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.;Norwegian Univ Sci & Technol, Dept Clin & Mol Med IKOM, N-7491 Trondheim, Norway.
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- Jemth, Ann-Sofie (author)
- Stockholms universitet,Science for Life Laboratory (SciLifeLab),Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Visnes, T. (author)
- SINTEF Ind, Dept Biotechnol & Nanomed, N-7465 Trondheim, Norway.
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- Sastre-Perona, A. (author)
- Hospital La Paz Institute for Health Research, Spain,Hosp La Paz Inst Hlth Res IdiPAZ, Expt Therapies & Novel Biomarkers Canc, Madrid, Spain.
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- Danda, A. N. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Homan, E. J. (author)
- Karolinska Institutet
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- Marimuthu, K. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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Zhenjun, Z. (author)
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- Chi, Celestine N. (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Uppsala University, Sweden
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- Sarno, A. (author)
- SINTEF Ocean, Dept Environm & New Resources, N-7496 Trondheim, Norway.
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- Wiita, E. (author)
- Karolinska Institutet
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- von Nicolai, C. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Komor, A. J. (author)
- Leibniz Institute for Natural Product Research and Infection Biology, Germany,Leibniz Inst Nat Prod Res & Infect Biol, Hans Knoll Inst, Dept Biomol Chem, D-07745 Jena, Germany.
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- Rajagopal, V. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Müller, S. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Hank, E. C. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Varga, M. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Scaletti, Emma Rose (author)
- Stockholm University,Lund University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.;Lund Univ, Dept Expt Med Sci, Lund, Sweden.,Strukturell biokemi,Forskargrupper vid Lunds universitet,Structural Biochemistry,Lund University Research Groups,University of Sheffield, United Kingdom
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- Pandey, M. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.;Univ Sheffield, Sheffield Canc Ctr, Dept Oncol & Metab, Sheffield S10 2RX, S Yorkshire, England.
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- Karsten, S. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Haslene-Hox, H. (author)
- SINTEF Ind, Dept Biotechnol & Nanomed, N-7465 Trondheim, Norway.
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- Loevenich, S. (author)
- SINTEF Ind, Dept Biotechnol & Nanomed, N-7465 Trondheim, Norway.
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- Marttila, P. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Rasti, A. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Mamonov, K. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Ortis, F. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Schömberg, F. (author)
- Friedrich Schiller University Jena, Germany,Friedrich Schiller Univ Jena, Inst Organ & Macromol Chem, D-07743 Jena, Germany.
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- Loseva, O. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Stewart, J. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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D'Arcy-Evans, N. (author)
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- Koolmeister, T. (author)
- Karolinska Institutet
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- Henriksson, M. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Michel, Dana (author)
- RISE,Kemiska processer och läkemedel
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- de Ory Lopez, Ana (author)
- Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut,Stockholm Univ, Wenner Gren Inst, Dept Mol Biosci, S-10691 Stockholm, Sweden.,Stockholm University, Sweden
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- Acero, L. (author)
- Hosp La Paz Inst Hlth Res IdiPAZ, Expt Therapies & Novel Biomarkers Canc, Madrid, Spain.
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- Calvete, O. (author)
- Spanish National Cancer Research Centre, Spain,Spanish Natl Canc Res Ctr CNIO, Familial Canc Clin Unit, Human Canc Genet Programme, Madrid 28029, Spain.
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- Scobie, M. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Hertweck, C. (author)
- Friedrich-Schiller University Jena, Germany,Leibniz Inst Nat Prod Res & Infect Biol, Hans Knoll Inst, Dept Biomol Chem, D-07745 Jena, Germany.;Friedrich Schiller Univ Jena, Inst Microbiol, D-07743 Jena, Germany.
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- Vilotijevic, I. (author)
- Friedrich Schiller Univ Jena, Inst Organ & Macromol Chem, D-07743 Jena, Germany.
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- Kalderén, C. (author)
- Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, S-17176 Stockholm, Sweden.
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- Osorio, A. (author)
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Spain,Spanish Natl Canc Res Ctr CNIO, Familial Canc Clin Unit, Human Canc Genet Programme, Madrid 28029, Spain.;Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain.
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- Perona, R. (author)
- Inst Invest Biomed Alberto Sols CSIC UAM, Madrid 28029, Spain.;Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid 28029, Spain.
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- Stolz, A. (author)
- University Frankfurt, Germany,Goethe Univ Frankfurt, Inst Biochem 2, D-60590 Frankfurt, Germany.;Goethe Univ Frankfurt, Buchmann Inst Mol Life Sci, D-60590 Frankfurt, Germany.
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- Stenmark, Pål (author)
- Stockholm University,Lund University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.;Lund Univ, Dept Expt Med Sci, Lund, Sweden.,Strukturell biokemi,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Structural Biochemistry,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Berglund, U. W. (author)
- Karolinska Institutet
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de Vega, M. (author)
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- Helleday, T. (author)
- Karolinska Institutet,University of Sheffield
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- ISSN 1095-9203
- Stockholm : American Association for the Advancement of Science, 2022
- 2022
- English.
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In: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
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Abstract
Subject headings
Close
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
Subject headings
- TEKNIK OCH TEKNOLOGIER -- Kemiteknik (hsv//swe)
- ENGINEERING AND TECHNOLOGY -- Chemical Engineering (hsv//eng)
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- 8 oxoguanine DNA glycosylase 1
- DNA glycosyltransferase
- glycine
- phenylalanine
- polynucleotide kinase phosphatase 1
- small molecule transport agent
- th 1078
- unclassified drug
- DNA (apurinic or apyrimidinic site) lyase
- activation energy
- amino acid
- catalysis
- catalyst
- cell
- DNA
- enzyme activity
- nitrogen
- phosphatase
- aging
- Article
- controlled study
- DNA repair
- drug structure
- enzyme active site
- human
- in vitro study
- DNA damage
- enzyme specificity
- metabolism
- oxidative stress
- DNA Glycosylases
- DNA-(Apurinic or Apyrimidinic Site) Lyase
- Substrate Specificity
- 8 oxoguanine DNA glycosylase 1
- DNA glycosyltransferase
- glycine
- phenylalanine
- polynucleotide kinase phosphatase 1
- small molecule transport agent
- th 1078
- unclassified drug
- DNA (apurinic or apyrimidinic site) lyase
- activation energy
- amino acid
- catalysis
- catalyst
- cell
- DNA
- enzyme activity
- nitrogen
- phosphatase
- aging
- Article
- controlled study
- DNA repair
- drug structure
- enzyme active site
- human
- in vitro study
- DNA damage
- enzyme specificity
- metabolism
- oxidative stress
- DNA Damage
- DNA Glycosylases
- DNA Repair
- DNA-(Apurinic or Apyrimidinic Site) Lyase
- Oxidative Stress
- Substrate Specificity
Publication and Content Type
- ref (subject category)
- art (subject category)
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Michel, M.
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Benítez-Buelga, ...
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Calvo, P. A.
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Hanna, B. M. F.
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Mortusewicz, O.
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Masuyer, Geoffre ...
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show more...
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Davies, Jonathan ...
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Wallner, O.
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Sanjiv, K.
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Albers, J. J.
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Castañeda-Zegarr ...
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Jemth, Ann-Sofie
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Visnes, T.
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Sastre-Perona, A ...
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Danda, A. N.
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Homan, E. J.
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Marimuthu, K.
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Zhenjun, Z.
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Chi, Celestine N ...
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Sarno, A.
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Wiita, E.
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von Nicolai, C.
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Komor, A. J.
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Rajagopal, V.
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Müller, S.
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Hank, E. C.
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Varga, M.
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Scaletti, Emma R ...
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Pandey, M.
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Karsten, S.
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Haslene-Hox, H.
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Loevenich, S.
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Marttila, P.
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Rasti, A.
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Mamonov, K.
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Ortis, F.
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Schömberg, F.
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Loseva, O.
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Stewart, J.
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D'Arcy-Evans, N.
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Koolmeister, T.
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Henriksson, M.
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Michel, Dana
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de Ory Lopez, An ...
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Acero, L.
-
Calvete, O.
-
Scobie, M.
-
Hertweck, C.
-
Vilotijevic, I.
-
Kalderén, C.
-
Osorio, A.
-
Perona, R.
-
Stolz, A.
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Stenmark, Pål
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Berglund, U. W.
-
de Vega, M.
-
Helleday, T.
-
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RISE
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Stockholm University
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Karolinska Institutet
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Uppsala University
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Lund University