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  • 1. Aad, G
    et al.
    Bélanger-Champagne, Camille
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Brenner, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Buszello, Claus P.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ekelöf, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellert, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ferrari, Arnaud
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Hansen, C. J.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy.
    Zwalinski, L
    Measurement of the inelastic proton-proton cross-section at root s=7 TeV with the ATLAS detector2011In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 2, p. 463-Article in journal (Refereed)
    Abstract [en]

    The dependence of the rate of proton-proton interactions on the centre-of-mass collision energy, root s, is of fundamental importance for both hadron collider physics and particle astrophysics. The dependence cannot yet be calculated from first principles; therefore, experimental measurements are needed. Here we present the first measurement of the inelastic proton-proton interaction cross-section at a centre-of-mass energy, root s, of 7 TeV using the ATLAS detector at the Large Hadron Collider. Events are selected by requiring hits on scintillation counters mounted in the forward region of the detector. An inelastic crosssection of 60.3 +/- 2.1 mb is measured for xi > 5x10(-6), where xi is calculated from the invariant mass, M(X), of hadrons selected using the largest rapidity gap in the event. For diffractive events, this corresponds to requiring at least one of the dissociation masses to be larger than 15.7 GeV.

  • 2.
    Allum, Fiona
    et al.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Hedman, Asa K.
    Karolinska Inst, Cardiovasc Med Unit, Dept Med Solna, S-17176 Stockholm, Sweden.
    Shaol, Xiaojian
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Cheung, Warren A.
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Vijay, Jinchu
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Guenard, Frederic
    Univ Laval, Inst Nutr & Funct Foods INAF, Quebec City, PQ G1V 0A6, Canada.
    Kwan, Tony
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Simon, Marie-Michelle
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Ge, Bing
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Moura, Cristiano
    McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.
    Boulier, Elodie
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bernatsky, Sasha
    McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada.
    Lathropl, Mark
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada.
    McCarthy, Mark, I
    Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England;Univ Oxford, Wellcome Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England;Oxford Univ Hosp NHS Fdn Trust, John Radcliffe Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 9DU, England.
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, Charterhouse Sq, London EC1M 6BQ, England.
    Tchernof, Andre
    Univ Laval, Quebec Heart & Lung Inst, Quebec City, PQ G1V 0A6, Canada.
    Pastinen, Tomi
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Vohl, Marie-Claude
    Univ Laval, Inst Nutr & Funct Foods INAF, Quebec City, PQ G1V 0A6, Canada.
    Grundberg, Elin
    McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada;McGill Univ, Montreal, PQ H3A 0G1, Canada;Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada;Childrens Mercy Hosp & Clin, Kansas City, MO 64108 USA.
    Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1209Article in journal (Refereed)
    Abstract [en]

    Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of similar to 200 adipose tissue and matched blood samples (N-total similar to 400), providing high- resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in similar to 800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.

  • 3. Allum, Fiona
    et al.
    Shao, Xiaojian
    Guénard, Frédéric
    Simon, Marie-Michelle
    Busche, Stephan
    Caron, Maxime
    Lambourne, John
    Lessard, Julie
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kwan, Tony
    Ge, Bing
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    McCarthy, Mark I
    Deloukas, Panos
    Richmond, Todd
    Burgess, Daniel
    Spector, Timothy D
    Tchernof, André
    Marceau, Simon
    Lathrop, Mark
    Vohl, Marie-Claude
    Pastinen, Tomi
    Grundberg, Elin
    Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7211Article in journal (Refereed)
    Abstract [en]

    Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

  • 4.
    Almqvist, Helena
    et al.
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Axelsson, Hanna
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Jafari, Rozbeh
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Dan, Chen
    School of Biological Sciences, Nanyang Technological University.
    Mateus, André
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Haraldsson, Martin
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Larsson, Andreas
    School of Biological Sciences, Nanyang Technological University.
    Martinez-Molina, Daniel
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Nordlund, Pär
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11040Article in journal (Refereed)
    Abstract [en]

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.

  • 5.
    Andersson, Sandra
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sundberg, Mårten
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Pristovsek, Nusa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ibrahim, Ahmed
    KTH Royal Inst Technol, Sch Biotechnol, Div Prote & Nanotechnol, Sci Life Lab, S-17121 Solna, Sweden.;Natl Res Ctr, Div Pharmaceut Ind, Dokki 12622, Egypt..
    Jonsson, Philip
    Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA.;Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Human Oncol & Pathogenesis Program, New York, NY 10065 USA..
    Katona, Borbala
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Clausson, Carl-Magnus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zieba, Agata
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramström, Margareta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Williams, Cecilia
    KTH Royal Inst Technol, Sch Biotechnol, Div Prote & Nanotechnol, Sci Life Lab, S-17121 Solna, Sweden.;Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA.;Karolinska Inst, Dept Biosci & Nutr, S-14183 Stockholm, Sweden..
    Asplund, Anna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Insufficient antibody validation challenges oestrogen receptor beta research2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15840Article in journal (Refereed)
    Abstract [en]

    The discovery of oestrogen receptor beta (ER beta/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ER alpha (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ER beta antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ER beta in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ER beta protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray.

  • 6. Bailey, W. E.
    et al.
    Cheng, C.
    Knut, Ronny
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Karis, Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Auffret, S.
    Zohar, S.
    Keavney, D.
    Warnicke, P.
    Lee, J. -S
    Arena, D. A.
    Detection of microwave phase variation in nanometre-scale magnetic heterostructures2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 2025-Article in journal (Refereed)
    Abstract [en]

    The internal phase profile of electromagnetic radiation determines many functional properties of metal, oxide or semiconductor heterostructures. In magnetic heterostructures, emerging spin electronic phenomena depend strongly upon the phase profile of the magnetic field (H) over tilde at gigahertz frequencies. Here we demonstrate nanometre-scale, layer-resolved detection of electromagnetic phase through the radio frequency magnetic field (H) over tilde (rf) in magnetic heterostructures. Time-resolved X-ray magnetic circular dichroism reveals the local phase of the radio frequency magnetic field acting on individual magnetizations (M) over tilde (i) through the susceptibility as (M) over tilde = (chi) over tilde(H) over tilde (rf). An unexpectedly large phase variation, similar to 40 degrees, is detected across spin-valve trilayers driven at 3 GHz. The results have implications for the identification of novel effects in spintronics and suggest general possibilities for electromagnetic-phase profile measurement in heterostructures.

  • 7.
    Bartoschek, Michael
    et al.
    Lund Univ, Dept Lab Med, Div Translat Canc Res, BioCARE, S-22381 Lund, Sweden.
    Oskolkov, Nikolay
    Lund Univ, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol, Solvegatan 35, S-22362 Lund, Sweden.
    Bocci, Matteo
    Lund Univ, Dept Lab Med, Div Translat Canc Res, BioCARE, S-22381 Lund, Sweden.
    Lovrot, John
    Karolinska Inst, Dept Oncol & Pathol, Karolinska Univ Sjukhuset Z1 01, S-17176 Stockholm, Sweden.
    Larsson, Christer
    Lund Univ, Dept Lab Med, Div Translat Canc Res, BioCARE, S-22381 Lund, Sweden.
    Sommarin, Mikael
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, BMC B12, S-22184 Lund, Sweden.
    Madsen, Chris D.
    Lund Univ, Dept Lab Med, Div Translat Canc Res, BioCARE, S-22381 Lund, Sweden.
    Lindgren, David
    Lund Univ, Dept Lab Med, Div Translat Canc Res, BioCARE, S-22381 Lund, Sweden.
    Pekar, Gyula
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Skane Univ Hosp, S-22185 Lund, Sweden.
    Karlsson, Goran
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, BMC B12, S-22184 Lund, Sweden.
    Ringner, Markus
    Lund Univ, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol, Solvegatan 35, S-22362 Lund, Sweden.
    Bergh, Jonas
    Karolinska Inst, Dept Oncol & Pathol, Karolinska Univ Sjukhuset Z1 01, S-17176 Stockholm, Sweden.
    Björklund, Åsa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pietras, Kristian
    Lund Univ, Dept Lab Med, Div Translat Canc Res, BioCARE, S-22381 Lund, Sweden.
    Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 5150Article in journal (Refereed)
    Abstract [en]

    Cancer-associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, although their origin and roles in shaping disease initiation, progression and treatment response remain unclear due to significant heterogeneity. Here, following a negative selection strategy combined with single-cell RNA sequencing of 768 transcriptomes of mesenchymal cells from a genetically engineered mouse model of breast cancer, we define three distinct subpopulations of CAFs. Validation at the transcriptional and protein level in several experimental models of cancer and human tumors reveal spatial separation of the CAF subclasses attributable to different origins, including the peri-vascular niche, the mammary fat pad and the transformed epithelium. Gene profiles for each CAF subtype correlate to distinctive functional programs and hold independent prognostic capability in clinical cohorts by association to metastatic disease. In conclusion, the improved resolution of the widely defined CAF population opens the possibility for biomarker-driven development of drugs for precision targeting of CAFs.

  • 8.
    Bastiaans, Eric
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Wageningen University.
    Debets, Alfons J. M.
    Aanen, Duur K.
    Experimental evolution reveals that high relatedness protects multicellular cooperation from cheaters2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11435Article in journal (Refereed)
    Abstract [en]

    In multicellular organisms, there is a potential risk that cheating mutants gain access to the germline. Development from a single-celled zygote resets relatedness among cells to its maximum value each generation, which should accomplish segregation of cheating mutants from non-cheaters and thereby protect multicellular cooperation. Here we provide the crucial direct comparison between high- and low-relatedness conditions to test this hypothesis. We allow two variants of the fungus Neurospora crassa to evolve, one with and one without the ability to form chimeras with other individuals, thus generating two relatedness levels. While multicellular cooperation remains high in the high-relatedness lines, it significantly decreases in all replicate low-relatedness lines, resulting in an average threefold decrease in spore yield. This reduction is caused by cheating mutants with reduced investment in somatic functions, but increased competitive success when fusing with non-cheaters. Our experiments demonstrate that high-genetic relatedness is crucial to sustain multicellular cooperation.

  • 9.
    Beinik, Igor
    et al.
    Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, DK-8000 Aarhus, Denmark..
    Hellström, Matti
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström.
    Jensen, Thomas N.
    Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, DK-8000 Aarhus, Denmark..
    Broqvist, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry.
    Lauritsen, Jeppe V.
    Aarhus Univ, Interdisciplinary Nanosci Ctr iNANO, DK-8000 Aarhus, Denmark..
    Enhanced wetting of Cu on ZnO by migration of subsurface oxygen vacancies2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 8845Article in journal (Refereed)
    Abstract [en]

    Metal adhesion on metal oxides is strongly controlled by the oxide surface structure and composition, but lack of control over the surface conditions often limits the possibilities to exploit this in opto- and micro-electronics applications and heterogeneous catalysis where nanostructural control is of utmost importance. The Cu/ZnO system is among the most investigated of such systems in model studies, but the presence of subsurface ZnO defects and their important role for adhesion on ZnO have been unappreciated so far. Here we reveal that the surface- directed migration of subsurface defects affects the Cu adhesion on polar ZnO(0001) in the technologically interesting temperature range up to 550 K. This leads to enhanced adhesion and ultimately complete wetting of ZnO(0001) by a Cu overlayer. On the basis of our experimental and computational results we demonstrate a mechanism which implies that defect concentrations in the bulk are an important, and possibly controllable, parameter for the metal-on-oxide growth.

  • 10.
    Berglund, Emelie
    et al.
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Maaskola, Jonas
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Schultz, Niklas
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Friedrich, Stefanie
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Marklund, Maja
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Bergenstråhle, Joseph
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Tarish, Firas
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Tanoglidi, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Vickovic, Sanja
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Larsson, Ludvig
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Salmen, Fredrik
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Ogris, Christoph
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Wallenborg, Karolina
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Lagergren, Jens
    Royal Inst Technol KTH, Dept Computat Biol, Sch Comp Sci & Commun, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Ståhl, Patrik
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Sonnhammer, Erik
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Helleday, Thomas
    Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Lundeberg, Joakim
    Royal Inst Technol KTH, Sci Life Lab, Dept Gene Technol, Sch Engn Sci Chem Biotechnol & Hlth, Tomtebodavagen 23, S-17165 Solna, Sweden.
    Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2419Article in journal (Refereed)
    Abstract [en]

    Intra-tumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.

  • 11.
    Berndt, Sonja I.
    et al.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Camp, Nicola J.
    Huntsman Canc Inst, Dept Internal Med, Div Hematol & Hematol Malignancies, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Salt Lake City, UT 84112 USA..
    Skibola, Christine F.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA.;Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA.;Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA..
    Vijai, Joseph
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Wang, Zhaoming
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Gu, Jian
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA..
    Nieters, Alexandra
    Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, D-79108 Freiburg, Baden Wurttembe, Germany..
    Kelly, Rachel S.
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
    Smedby, Karin E.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    Monnereau, Alain
    Sorbonne Paris Cite CRESS, INSERM, Ctr Res Epidemiol & Stat, Epidemiol Childhood & Adolescent Canc Grp, F-94807 Paris, France.;Univ Paris 05, F-75270 Paris, France.;Inst Bergonie, Registre Hemopathies Malignes Gironde, F-33076 Bordeaux, France..
    Cozen, Wendy
    Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA.;Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA..
    Cox, Angela
    Univ Sheffield, Dept Oncol, Sheffield S10 1NS, S Yorkshire, England..
    Wang, Sophia S.
    City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Duarte, CA 91030 USA..
    Lan, Qing
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Teras, Lauren R.
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA..
    Machado, Moara
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.;Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, BR-31270901 Belo Horizonte, MG, Brazil..
    Yeager, Meredith
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Brooks-Wilson, Angela R.
    BC Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada.;Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada..
    Hartge, Patricia
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Purdue, Mark P.
    Ontario Hlth Study, Toronto, ON M5G 0A3, Canada..
    Birmann, Brenda M.
    Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Vajdic, Claire M.
    Univ New S Wales, Ctr Big Data Res Hlth, Sydney, NSW 2052, Australia..
    Cocco, Pierluigi
    Univ Cagliari, Dept Publ Hlth Clin & Mol Med, I-09042 Cagliari, Italy..
    Zhang, Yawei
    Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA..
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia.;Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia..
    Zeleniuch-Jacquotte, Anne
    NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA.;NYU, Sch Med, Dept Environm Med, New York, NY 10016 USA.;NYU, Langone Med Ctr, Perlmutter Canc Ctr, New York, NY 10016 USA..
    Lawrence, Charles
    WESTAT Corp, Rockville, MD 20850 USA..
    Montalvan, Rebecca
    WESTAT Corp, Rockville, MD 20850 USA..
    Burdett, Laurie
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Hutchinson, Amy
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Ye, Yuanqing
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA..
    Call, Timothy G.
    Mayo Clin, Div Hematol, Rochester, MN 55905 USA..
    Shanafelt, Tait D.
    Mayo Clin, Dept Med, Rochester, MN 55905 USA..
    Novak, Anne J.
    Mayo Clin, Dept Med, Rochester, MN 55905 USA..
    Kay, Neil E.
    Mayo Clin, Div Hematol, Rochester, MN 55905 USA..
    Liebow, Mark
    Mayo Clin, Dept Med, Rochester, MN 55905 USA..
    Cunningham, Julie M.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA..
    Allmer, Cristine
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Hjalgrim, Henrik
    Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Adami, Hans-Olov
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden..
    Melbye, Mads
    Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark.;Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Chang, Ellen T.
    Exponent Inc, Ctr Epidemiol & Computat Biol, Hlth Sci, Menlo Pk, CA 94025 USA.;Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA..
    Glenn, Martha
    Huntsman Canc Inst, Dept Internal Med, Salt Lake City, UT 84112 USA..
    Curtin, Karen
    Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84108 USA..
    Cannon-Albright, Lisa A.
    Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84108 USA.;Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84148 USA..
    Diver, W. Ryan
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA..
    Link, Brian K.
    Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA..
    Weiner, George J.
    Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA..
    Conde, Lucia
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA.;Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA.;Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA..
    Bracci, Paige M.
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA..
    Riby, Jacques
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA.;Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA.;Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA..
    Arnett, Donna K.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA.;Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA..
    Zhi, Degui
    Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35233 USA..
    Leach, Justin M.
    Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35233 USA..
    Holly, Elizabeth A.
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA..
    Jackson, Rebecca D.
    Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA..
    Tinker, Lesley F.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98117 USA..
    Benavente, Yolanda
    Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Programme, Barcelona 08908, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08036, Spain..
    Sala, Nuria
    Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona 08908, Spain.;Catalan Inst Oncol IDIBELL, Translat Res Lab, Barcelona 08908, Spain..
    Casabonne, Delphine
    Inst Catala Oncol, IDIBELL, Canc Epidemiol Res Programme, Unit Infect & Canc UNIC, Barcelona 08908, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain..
    Becker, Nikolaus
    German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Baden Wurttembe, Germany..
    Boffetta, Paolo
    Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA..
    Brennan, Paul
    Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France..
    Foretova, Lenka
    Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno 65653, Czech Republic.;MF MU, Brno 65653, Czech Republic..
    Maynadie, Marc
    Univ Burgundy, Registre Hemopathies Malignes Cote dOr, EA 4184, F-21070 Dijon, France.;Dijon Univ Hosp, F-21070 Dijon, France..
    McKay, James
    Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France..
    Staines, Anthony
    Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland..
    Chaffee, Kari G.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Achenbach, Sara J.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Vachon, Celine M.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Goldin, Lynn R.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Strom, Sara S.
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA..
    Leis, Jose F.
    Mayo Clin, Div Hematol Oncol, Phoenix, AZ 85054 USA..
    Weinberg, J. Brice
    Duke Univ, Dept Med, Durham, NC 27710 USA.;VA Med Ctr, Durham, NC 27710 USA..
    Caporaso, Neil E.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Norman, Aaron D.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    De Roos, Anneclaire J.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98117 USA.;Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA..
    Morton, Lindsay M.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Severson, Richard K.
    Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA..
    Riboli, Elio
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 1PG, England..
    Vineis, Paolo
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Human Genet Fdn, I-10126 Turin, Italy..
    Kaaks, Rudolph
    German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Baden Wurttembe, Germany..
    Masala, Giovanna
    Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, I-50139 Florence, Italy..
    Weiderpass, Elisabete
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.;Arctic Univ Norway, Univ Tromso, Dept Community Med, Fac Hlth Sci, N-9037 Tromso, Norway.;Canc Registry Norway, Inst Populat Based Canc Res, Dept Res, N-0304 Oslo, Norway.;Folkhalsan Res Ctr, Genet Epidemiol Grp, FI-00250 Helsinki, Finland..
    Chirlaque, Maria-Dolores
    CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08036, Spain.;Murcia Reg Hlth Author, Dept Epidemiol, E-30008 Murcia, Spain..
    Vermeulen, Roel C. H.
    Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands.;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3584 CX Utrecht, Netherlands..
    Travis, Ruth C.
    Univ Oxford, Canc Epidemiol Unit, Oxford OX3 7LF, England..
    Southey, Melissa C.
    Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3010, Australia..
    Milne, Roger L.
    Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia.;Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia..
    Albanese, Demetrius
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Virtamo, Jarmo
    Natl Inst Hlth & Welf, Chron Dis Prevent Unit, FI-00271 Helsinki, Finland..
    Weinstein, Stephanie
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Clavel, Jacqueline
    Sorbonne Paris Cite CRESS, INSERM, Ctr Res Epidemiol & Stat, Epidemiol Childhood & Adolescent Canc Grp, F-94807 Paris, France.;Univ Paris 05, F-75270 Paris, France..
    Zheng, Tongzhang
    Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA..
    Holford, Theodore R.
    Yale Univ, Sch Publ Hlth, Dept Stat, New Haven, CT 06520 USA..
    Villano, Danylo J.
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Maria, Ann
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Spinelli, John J.
    BC Canc Agcy, Canc Control Res, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, Canada..
    Gascoyne, Randy D.
    BC Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Dept Pathol, Vancouver, BC V6T 1Z3, Canada..
    Connors, Joseph M.
    BC Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Dept Med, Vancouver, BC V6T 1Z3, Canada..
    Bertrand, Kimberly A.
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Giovannucci, Edward
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Kraft, Peter
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Kricker, Anne
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia..
    Turner, Jenny
    Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW 2109, Australia.;Douglass Hanly Moir Pathol, Dept Histopathol, N Ryde, NSW 2113, Australia..
    Ennas, Maria Grazia
    Univ Cagliari, Dept Biomed Sci, I-09042 Cagliari, Italy..
    Ferri, Giovanni M.
    Univ Bari, Interdisciplinary Dept Med, I-70124 Bari, Italy..
    Miligi, Lucia
    Canc Prevent & Res Inst ISPO, Environm & Occupat Epidemiol Unit, I-50139 Florence, Italy..
    Liang, Liming
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Ma, Baoshan
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian 116026, Liaoning Provin, Peoples R China..
    Huang, Jinyan
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Crouch, Simon
    Univ York, Dept Hlth Sci, York Y010 5DD, N Yorkshire, England..
    Park, Ju-Hyun
    Dongguk Univ, Dept Stat, Seoul 100715, South Korea..
    Chatterjee, Nilanjan
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    North, Kari E.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA..
    Snowden, John A.
    Univ Sheffield, Dept Oncol, Sheffield S10 1NS, S Yorkshire, England.;Sheffield Teaching Hosp NHS Fdn Trust, Royal Hallamshire Hosp, Dept Haematol, Sheffield S10 2TN, S Yorkshire, England..
    Wright, Josh
    Univ Sheffield, Dept Oncol, Sheffield S10 1NS, S Yorkshire, England.;Sheffield Teaching Hosp NHS Fdn Trust, Royal Hallamshire Hosp, Dept Haematol, Sheffield S10 2TN, S Yorkshire, England..
    Fraumeni, Joseph F.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Offit, Kenneth
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Wu, Xifeng
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA..
    de Sanjose, Silvia
    Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Programme, Barcelona 08908, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08036, Spain..
    Cerhan, James R.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Rothman, Nathaniel
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Slager, Susan L.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10933Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P = 2.55 x 10(-11)), 6p25.2 (rs73718779, SERPINB6, P = 1.97 x 10(-8)) and 3q28 (rs9815073, LPP, P = 3.62 x 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P = 1.00 x 10(-11)) in the combined analysis. We find suggestive evidence (P<5 x 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P = 7.19 x 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P = 2.12 x 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

  • 12. Bolnick, D.I.
    et al.
    Snowberg, Lisa K.
    Hirsch, Philippe E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Lauber, Christian L.
    Org, Elin
    Parks, Brian
    Lusis, Aldons J.
    Knight, Rob
    Caporaso, J. Gregory
    Svanbäck, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Individual diet has sex-dependent
effects on vertebrate gut microbiota2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 4500-Article in journal (Refereed)
  • 13.
    Bravo, Andrea G.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bouchet, Sylvain
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden..
    Tolu, Julie
    Umea Univ, Dept Ecol & Environm Sci, SE-90187 Umea, Sweden..
    Bjorn, Erik
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden..
    Mateos-Rivera, Alejandro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Molecular composition of organic matter controls methylmercury formation in boreal lakes2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14255Article in journal (Refereed)
    Abstract [en]

    A detailed understanding of the formation of the potent neurotoxic methylmercury is needed to explain the large observed variability in methylmercury levels in aquatic systems. While it is known that organic matter interacts strongly with mercury, the role of organic matter composition in the formation of methylmercury in aquatic systems remains poorly understood. Here we show that phytoplankton-derived organic compounds enhance mercury methylation rates in boreal lake sediments through an overall increase of bacterial activity. Accordingly, in situ mercury methylation defines methylmercury levels in lake sediments strongly influenced by planktonic blooms. In contrast, sediments dominated by terrigenous organic matter inputs have far lower methylation rates but higher concentrations of methylmercury, suggesting that methylmercury was formed in the catchment and imported into lakes. Our findings demonstrate that the origin and molecular composition of organic matter are critical parameters to understand and predict methylmercury formation and accumulation in boreal lake sediments.

  • 14.
    Caban, Kelvin
    et al.
    Columbia Univ, Dept Chem, 3000 Broadway,MC3126, New York, NY 10027 USA..
    Pavlov, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Ehrenberg, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Gonzalez, Ruben L., Jr.
    Columbia Univ, Dept Chem, 3000 Broadway,MC3126, New York, NY 10027 USA..
    A conformational switch in initiation factor 2 controls the fidelity of translation initiation in bacteria2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 1475Article in journal (Refereed)
    Abstract [en]

    Initiation factor (IF) 2 controls the fidelity of translation initiation by selectively increasing the rate of 50S ribosomal subunit joining to 30S initiation complexes (ICs) that carry an N-formyl-methionyl-tRNA (fMet-tRNA(fMet)). Previous studies suggest that rapid 50S subunit joining involves a GTP- and fMet-tRNA(fMet)-dependent "activation" of IF2, but a lack of data on the structure and conformational dynamics of 30S IC-bound IF2 has precluded a mechanistic understanding of this process. Here, using an IF2-tRNA single-molecule fluorescence resonance energy transfer signal, we directly observe the conformational switch that is associated with IF2 activation within 30S ICs that lack IF3. Based on these results, we propose a model of IF2 activation that reveals how GTP, fMet-tRNA(fMet), and specific structural elements of IF2 drive and regulate this conformational switch. Notably, we find that domain III of IF2 plays a pivotal, allosteric, role in IF2 activation, suggesting that this domain can be targeted for the development of novel antibiotics.

  • 15.
    Calafat, Francisco M.
    et al.
    Natl Oceanog Ctr, Joseph Proudman Bldg,6 Brownlow St, Liverpool L3 5DA, Merseyside, England.
    Wahl, Thomas
    Univ Cent Florida, Natl Ctr Integrated Coastal Res, 12800 Pegasus Dr,Suite 211, Orlando, FL 32816 USA;Univ Cent Florida, Dept Civil Environm & Construct Engn, 12800 Pegasus Dr,Suite 211, Orlando, FL 32816 USA.
    Lindsten, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
    Williams, Joanne
    Natl Oceanog Ctr, Joseph Proudman Bldg,6 Brownlow St, Liverpool L3 5DA, Merseyside, England.
    Frajka-Williams, Eleanor
    Univ Southampton, Ocean & Earth Sci, European Way, Southampton SO14 3ZH, Hants, England.
    Coherent modulation of the sea-level annual cycle in the United States by Atlantic Rossby waves2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2571Article in journal (Refereed)
    Abstract [en]

    Changes in the sea-level annual cycle (SLAC) can have profound impacts on coastal areas, including increased flooding risk and ecosystem alteration, yet little is known about the magnitude and drivers of such changes. Here we show, using novel Bayesian methods, that there are significant decadal fluctuations in the amplitude of the SLAC along the United States Gulf and Southeast coasts, including an extreme event in 2008-2009 that is likely (probability = 68%) unprecedented in the tide-gauge record. Such fluctuations are coherent along the coast but decoupled from deep-ocean changes. Through the use of numerical and analytical ocean models, we show that the primary driver of these fluctuations involves incident Rossby waves that generate fast western-boundary waves. These Rossby waves project onto the basin-wide upper mid-ocean transport (top 1000 m) leading to a link with the SLAC, wherein larger SLAC amplitudes coincide with enhanced transport variability.

  • 16.
    Campeau, Audrey
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Bishop, Kevin
    Swedish Univ Agr Sci, Dept Aquat Sci & Assessment, Lennart Hjelms Vag 9, S-75651 Uppsala, Sweden.
    Amvrosiadi, Nino
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Billett, Mike
    Garnett, Mark
    Laudon, Hjalmar
    Öquist, Mats
    Wallin, Marcus
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Current forest carbon fixation fuels stream CO2 emissions2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1876Article in journal (Refereed)
    Abstract [en]

    Stream CO2 emissions contribute significantly to atmospheric climate forcing. While there are strong indications that groundwater inputs sustain these emissions, the specific biogeochemical pathways and timescales involved in this lateral CO2 export are still obscure. Here, via an extensive radiocarbon (C-14) characterisation of CO2 and DOC in stream water and its groundwater sources in an old-growth boreal forest, we demonstrate that the C-14-CO2 is consistently in tune with the current atmospheric C-14-CO2 level and shows little association with the C-14-DOC in the same waters. Our findings thus indicate that stream CO2 emissions act as a shortcut that returns CO2 recently fixed by the forest vegetation to the atmosphere. Our results expose a positive feedback mechanism within the C budget of forested catchments, where stream CO2 emissions will be highly sensitive to changes in forest C allocation patterns associated with climate and land-use changes.

  • 17.
    Cao, Yiming
    et al.
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photon & Interfaces, CH-1015 Lausanne, Switzerland..
    Saygili, Yasemin
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photomol Sci, CH-1015 Lausanne, Switzerland..
    Ummadisingu, Amita
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photon & Interfaces, CH-1015 Lausanne, Switzerland..
    Teuscher, Joel
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Photochem Dynam Grp, CH-1015 Lausanne, Switzerland..
    Luo, Jingshan
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photon & Interfaces, CH-1015 Lausanne, Switzerland..
    Pellet, Norman
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photon & Interfaces, CH-1015 Lausanne, Switzerland..
    Giordano, Fabrizio
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photon & Interfaces, CH-1015 Lausanne, Switzerland..
    Zakeeruddin, Shaik Mohammed
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photon & Interfaces, CH-1015 Lausanne, Switzerland..
    Moser, Jacques-E.
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Photochem Dynam Grp, CH-1015 Lausanne, Switzerland..
    Freitag, Marina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photomol Sci, CH-1015 Lausanne, Switzerland..
    Hagfeldt, Anders
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photomol Sci, CH-1015 Lausanne, Switzerland..
    Graetzel, Michael
    Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn, Lab Photon & Interfaces, CH-1015 Lausanne, Switzerland..
    11% efficiency solid-state dye-sensitized solar cells with copper(II/I) hole transport materials2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15390Article in journal (Refereed)
    Abstract [en]

    Solid-state dye-sensitized solar cells currently suffer from issues such as inadequate nanopore filling, low conductivity and crystallization of hole-transport materials infiltrated in the mesoscopic TiO2 scaffolds, leading to low performances. Here we report a record 11% stable solid-state dye-sensitized solar cell under standard air mass 1.5 global using a hole-transport material composed of a blend of [Cu (4,4',6,6'-tetramethyl-2,2'-bipyridine)2(bis(trifluoromethylsulfonyl)imide)2 and [Cu (4,4',6,6'-tetramethyl-2,2'-bipyridine)2](bis(trifluoromethylsulfonyl)imide). The amorphous Cu(II/I) conductors that conduct holes by rapid hopping infiltrated in a 6.5 mm-thick mesoscopic TiO2 scaffold are crucial for achieving such high efficiency. Using time-resolved laser photolysis, we determine the time constants for electron injection from the photoexcited sensitizers Y123 into the TiO2 and regeneration of the Y123 by Cu(I) to be 25 ps and 3.2 μs, respectively. Our work will foster the development of low-cost solid-state photovoltaic based on transition metal complexes as hole conductors.

  • 18.
    Caron, Jean-Bernard
    et al.
    Royal Ontario Museum, Toronto.
    Gaines, Robert
    Pamona College.
    Aria, Cédric
    Mangano, Gabriela
    University of Saskatchewan.
    Streng, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    A new phyllopod bed-like assemblage from the Burgess Shale of the Canadian Rockies2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 3210-Article in journal (Refereed)
    Abstract [en]

    Burgess Shale-type fossil assemblages provide the best evidence of the ‘Cambrian explosion’. Here we report the discovery of an extraordinary new soft-bodied fauna from the Burgess Shale. Despite its proximity (ca. 40km) to Walcott’s original locality, the Marble Canyon fossil assemblage is distinct, and offers new insights into the initial diversification of metazoans, their early morphological disparity, and the geographic ranges and longevity of many Cambrian taxa. The arthropod-dominated assemblage is remarkable for its high density and diversity of soft-bodied fossils, as well as for its large proportion of new species (22% of total diversity) and for the preservation of hitherto unreported anatomical features, including in the chordate Metaspriggina and the arthropod Mollisonia. The presence of the stem arthropods Misszhouia and Primicaris, previously known only from the early Cambrian of China, suggests that the palaeogeographic ranges and longevity of Burgess Shale taxa may be underestimated.

  • 19.
    Carreras-Puigvert, Jordi
    et al.
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Zitnik, Marinka
    Univ Ljubljana, Fac Comp & Informat Sci, SI-1000 Ljubljana, Slovenia.; Stanford Univ, Dept Comp Sci, Palo Alto, CA 94305 USA.
    Jemth, Ann-Sofie
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Carter, Megan
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Unterlass, Judith E
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Hallström, Björn
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Loseva, Olga
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Karem, Zhir
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Calderón-Montaño, José Manuel
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Edqvist, Per-Henrik D
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Matuszewski, Damian J.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ait Blal, Hammou
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Berntsson, Ronnie P A
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Häggblad, Maria
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Martens, Ulf
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Studham, Matthew
    Stockholm Univ, Dept Biochem & Biophys, Stockholm Bioinformat Ctr, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Lundgren, Bo
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Biochem & Cellular Screening Facil, S-17165 Stockholm, Sweden.
    Wählby, Carolina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Sonnhammer, Erik L L
    Stockholm Univ, Dept Biochem & Biophys, Stockholm Bioinformat Ctr, Sci Life Lab, Box 1031, S-17121 Solna, Sweden.
    Lundberg, Emma
    KTH Royal Inst Technol, Sci Life Lab, Cell Profiling Affin Prote, S-17165 Stockholm, Sweden.
    Stenmark, Pål
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.
    Zupan, Blaz
    Univ Ljubljana, Fac Comp & Informat Sci, SI-1000 Ljubljana, Slovenia.; Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Mol Biochem & Biophys, Sci Life Lab, S-17165 Stockholm, Sweden.
    A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, no 1, article id 1541Article in journal (Refereed)
    Abstract [en]

    The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

  • 20.
    Carter, Megan
    et al.
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Jemth, Ann-Sofie
    Hagenkort, Anna
    Page, Brent D. G.
    Gustafsson, Robert
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Griese, Julia J.
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Gad, Helge
    Valerie, Nicholas C. K.
    Desroses, Matthieu
    Boström, Johan
    Berglund, Ulrika Warpman
    Helleday, Thomas
    Stenmark, Pål
    Stockholms universitet, Institutionen för biokemi och biofysik.
    Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH22015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7871Article in journal (Refereed)
    Abstract [en]

    Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date.

  • 21.
    Couch, Fergus J.
    et al.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA.;Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Kuchenbaecker, Karoline B.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Michailidou, Kyriaki
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Mendoza-Fandino, Gustavo A.
    Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA..
    Nord, Silje
    Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway..
    Lilyquist, Janna
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Olswold, Curtis
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Hallberg, Emily
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Agata, Simona
    IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy..
    Ahsan, Habibul
    Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA.;Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA.;Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA..
    Aittomaeki, Kristiina
    Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland..
    Ambrosone, Christine
    Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA..
    Andrulis, Irene L.
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada.;Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada..
    Anton-Culver, Hoda
    Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA..
    Arndt, Volker
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany..
    Arun, Banu K.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Arver, Brita
    Karolinska Univ Hosp, Dept Oncol, SE-17176 Stockholm, Sweden..
    Barile, Monica
    Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy..
    Barkardottir, Rosa B.
    Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland.;Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland..
    Barrowdale, Daniel
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Beckmann, Lars
    Inst Qual & Efficiency Hlth Care IQWiG, D-50670 Cologne, Germany..
    Beckmann, Matthias W.
    Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany..
    Benitez, Javier
    Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain.;Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Genotyping Unit CeGen, Madrid 28029, Spain.;Biomed Network Rare Dis CIBERER, Madrid 28029, Spain..
    Blank, Stephanie V.
    NYU, Sch Med, NYU Womens Canc Program, New York, NY 10016 USA..
    Blomqvist, Carl
    Univ Helsinki, Dept Oncol, FI-00029 Helsinki, Finland.;Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland..
    Bogdanova, Natalia V.
    Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany..
    Bojesen, Stig E.
    Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark..
    Bolla, Manjeet K.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Bonanni, Bernardo
    Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy..
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany.;Univ Tubingen, D-72074 Tubingen, Germany..
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany.;German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany..
    Burwinkel, Barbara
    Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany..
    Buys, Saundra S.
    Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
    Caldes, Trinidad
    IdISSC, Hosp Clin San Carlos, Mol Oncol Lab, Madrid 28040, Spain..
    Caligo, Maria A.
    Univ Pisa, Dept Lab Med, Sect Genet Oncol, I-56126 Pisa, Italy.;Univ Hosp Pisa, I-56126 Pisa, Italy..
    Canzian, Federico
    German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany..
    Carpenter, Jane
    Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Sydney, NSW 2145, Australia..
    Chang-Claude, Jenny
    German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany..
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA..
    Chung, Wendy K.
    Columbia Univ, Dept Pediat, New York, NY 10032 USA.;Columbia Univ, Dept Med, New York, NY 10032 USA..
    Claes, Kathleen B. M.
    Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium..
    Cox, Angela
    Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield S10 2RX, S Yorkshire, England..
    Cross, Simon S.
    Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2HQ, S Yorkshire, England..
    Cunningham, Julie M.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA..
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Daly, Mary B.
    Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA..
    Damiola, Francesca
    Univ Lyon, CNRS, UMR5286, Ctr Rech Cancerol Lyon,INSERM,U1052, F-69373 Lyon, France..
    Darabi, Hatef
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    de la Hoya, Miguel
    IdISSC, Hosp Clin San Carlos, Mol Oncol Lab, Madrid 28040, Spain..
    Devilee, Peter
    Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZC Leiden, Netherlands..
    Diez, Orland
    Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona 08035, Spain.;Univ Autonoma Barcelona, Barcelona 08035, Spain..
    Ding, Yuan C.
    City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA..
    Dolcetti, Riccardo
    CRO Aviano Natl Canc Inst, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy..
    Domchek, Susan M.
    Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA..
    Dorfling, Cecilia M.
    Univ Pretoria, Dept Genet, ZA-0007 Pretoria, South Africa..
    dos-Santos-Silva, Isabel
    Univ London London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, Keppel St, London WC1E 7HT, England..
    Dumont, Martine
    Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ G1V 4G2, Canada.;Univ Laval, Quebec City, PQ G1V 4G2, Canada..
    Dunning, Alison M.
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Eccles, Diana M.
    Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England..
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden..
    Ekici, Arif B.
    Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany.;Comprehens Canc Ctr EMN, D-91054 Erlangen, Germany..
    Eliassen, Heather
    Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Ellis, Steve
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Fasching, Peter A.
    Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany..
    Figueroa, Jonine
    NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA..
    Flesch-Janys, Dieter
    Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, D-20246 Hamburg, Germany.;Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany..
    Foersti, Asta
    German Canc Res Ctr, Div Mol Genet Epidemiol, D-69120 Heidelberg, Germany.;Lund Univ, Ctr Primary Hlth Care Res, SE-22100 Malmo, Sweden..
    Fostira, Florentia
    Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece..
    Foulkes, William D.
    McGill Univ, Program Canc Genet, Montreal, PQ H3A 0G4, Canada..
    Friebel, Tara
    Univ Philadelphia, Philadelphia, PA 19104 USA..
    Friedman, Eitan
    Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel..
    Frost, Debra
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Gabrielson, Marike
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Gammon, Marilie D.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA..
    Ganz, Patricia A.
    Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, Los Angeles, CA 90095 USA.;Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, Los Angeles, CA 90095 USA..
    Gapstur, Susan M.
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA..
    Garber, Judy
    Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02215 USA..
    Gaudet, Mia M.
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA..
    Gayther, Simon A.
    Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA..
    Gerdes, Anne-Marie
    Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark..
    Ghoussaini, Maya
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3010, Australia..
    Glendon, Gord
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada..
    Godwin, Andrew K.
    Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66205 USA..
    Goldberg, Mark S.
    McGill Univ, Dept Med, Montreal, PQ H3G 2M1, Canada.;McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H4A 3J1, Canada..
    Goldgar, David E.
    Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT 84132 USA..
    Gonzalez-Neira, Anna
    Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid 28029, Spain..
    Greene, Mark H.
    NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA..
    Gronwald, Jacek
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    Guenel, Pascal
    CESP Ctr Res Epidemiol & Populat Hlth, Inserm Natl Inst Hlth & Med Res, U1018, Environm Epidemiol Canc, F-70115 Villejuif, France..
    Gunter, Marc
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England..
    Haeberle, Lothar
    Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany..
    Haiman, Christopher A.
    Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Hamann, Ute
    German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany..
    Hansen, Thomas V. O.
    Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark..
    Hart, Steven
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Healey, Sue
    QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4029, Australia..
    Heikkinen, Tuomas
    Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany.;Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland..
    Henderson, Brian E.
    Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Herzog, Josef
    City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA 91010 USA..
    Hogervorst, Frans B. L.
    Netherlands Canc Inst, Family Canc Clin, NL-1000 BE Amsterdam, Netherlands..
    Hollestelle, Antoinette
    Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands..
    Hooning, Maartje J.
    Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands..
    Hoover, Robert N.
    NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA..
    Hopper, John L.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia..
    Humphreys, Keith
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Hunter, David J.
    Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA..
    Huzarski, Tomasz
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    Imyanitov, Evgeny N.
    NN Petrov Oncol Res Inst, St Petersburg 197758, Russia..
    Isaacs, Claudine
    Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA..
    Jakubowska, Anna
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    James, Paul
    Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic 8006, Australia.;Univ Melbourne, Dept Oncol, Melbourne, Vic 8006, Australia..
    Janavicius, Ramunas
    State Res Inst, Ctr Innovat Med, LT-08661 Vilnius, Lithuania..
    Jensen, Uffe Birk
    Aarhus Univ Hosp, Dept Clin Genet, DK-8200 Aarhus N, Denmark..
    John, Esther M.
    Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA..
    Jones, Michael
    Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England..
    Kabisch, Maria
    German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany..
    Kar, Siddhartha
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Karlan, Beth Y.
    Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA..
    Khan, Sofia
    Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland.;Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland..
    Khaw, Kay-Tee
    Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England..
    Kibriya, Muhammad G.
    Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA..
    Knight, Julia A.
    Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada..
    Ko, Yon-Dschun
    Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, D-53113 Bonn, Germany..
    Konstantopoulou, Irene
    Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece..
    Kosma, Veli-Matti
    Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, FI-70211 Kuopio, Finland..
    Kristensen, Vessela
    Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway..
    Kwong, Ava
    Hong Kong Hereditary Breast Canc Family Registry, Canc Genet Ctr, Hong Kong Sanat & Hosp, Hong Kong, Hong Kong, Peoples R China.;Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China..
    Laitman, Yael
    Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel..
    Lambrechts, Diether
    VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium..
    Lazaro, Conxi
    IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona 08908, Spain..
    Lee, Eunjung
    Univ So Calif, Dept Prevent Med, Los Angeles, CA 90032 USA..
    Le Marchand, Loic
    Univ Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA..
    Lester, Jenny
    Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA..
    Lindblom, Annika
    Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden..
    Lindor, Noralane
    Mayo Clin, Hlth Sci Res, Scotsdale, AZ 85259 USA..
    Lindstrom, Sara
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA..
    Liu, Jianjun
    Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore..
    Long, Jirong
    Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA.;Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA..
    Lubinski, Jan
    Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland..
    Mai, Phuong L.
    NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA..
    Makalic, Enes
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia..
    Malone, Kathleen E.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA.;Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA..
    Mannermaa, Arto
    Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, FI-70211 Kuopio, Finland..
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy..
    Margolin, Sara
    Karolinska Univ Hosp, Dept Oncol, SE-17176 Stockholm, Sweden..
    Marme, Frederik
    Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany..
    Martens, John W. M.
    Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands..
    McGuffog, Lesley
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Meindl, Alfons
    Tech Univ Munich, Dept Obstet & Gynaecol, D-81675 Munich, Germany..
    Miller, Austin
    Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA..
    Milne, Roger L.
    Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3010, Australia..
    Miron, Penelope
    Case Western Reserve Univ, Sch Med, Dept Genom & Genome Sci, Cleveland, OH 44106 USA..
    Montagna, Marco
    IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy..
    Mazoyer, Sylvie
    Univ Lyon, CNRS, UMR5286, Ctr Rech Cancerol Lyon,INSERM,U1052, F-69373 Lyon, France..
    Mulligan, Anna M.
    Univ Hlth Network, Lab Med Program, Toronto, ON M5B 1W8, Canada.;Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada..
    Muranen, Taru A.
    Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany.;Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland..
    Nathanson, Katherine L.
    Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA..
    Neuhausen, Susan L.
    City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA..
    Nevanlinna, Heli
    Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland.;Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland..
    Nordestgaard, Borge G.
    Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark..
    Nussbaum, Robert L.
    Invitae Corp, San Francisco, CA 94107 USA..
    Offit, Kenneth
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Olah, Edith
    Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary..
    Olopade, Olufunmilayo I.
    Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA..
    Olson, Janet E.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Osorio, Ana
    Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain..
    Park, Sue K.
    Seoul Natl Univ, Coll Med, Dept Prevent Med & Biomed Sci, Seoul 110799, South Korea.;Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea..
    Peeters, Petra H.
    Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3508 GA Utrecht, Netherlands.;Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London SW7 2AZ, England..
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy..
    Peterlongo, Paolo
    Fdn Ist FIRC Oncol Mol, IFOM, I-20133 Milan, Italy..
    Peto, Julian
    Univ London London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, Keppel St, London WC1E 7HT, England..
    Phelan, Catherine M.
    Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA..
    Pilarski, Robert
    Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA..
    Poppe, Bruce
    Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium..
    Pylkaes, Katri
    Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland.;Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland.;Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Bioctr Oulu, FI-90220 Oulu, Finland..
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy..
    Rahman, Nazneen
    Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England..
    Rantala, Johanna
    Karolinska Univ Hosp, Dept Clin Genet, SE-17176 Stockholm, Sweden..
    Rappaport, Christine
    Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria..
    Rennert, Gad
    Clalit Natl Israeli Canc Control Ctr, IL-34362 Haifa, Israel.;Carmel Hosp, Dept Community Med & Epidemiol, IL-34362 Haifa, Israel.;B Rappaport Fac Med, IL-34362 Haifa, Israel..
    Richardson, Andrea
    Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA..
    Robson, Mark
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Romieu, Isabelle
    Int Agcy Res Canc, F-69008 Lyon, France..
    Rudolph, Anja
    German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany..
    Rutgers, Emiel J.
    Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands..
    Sanchez, Maria-Jose
    Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, E-18014 Granada, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain..
    Santella, Regina M.
    Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA..
    Sawyer, Elinor J.
    Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England..
    Schmidt, Daniel F.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia..
    Schmidt, Marjanka K.
    Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands..
    Schmutzler, Rita K.
    Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany.;Univ Hosp Cologne, Fac Med, CIO, D-50931 Cologne, Germany. Univ Cologne, CMMC, D-50931 Cologne, Germany..
    Schumacher, Fredrick
    Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA..
    Scott, Rodney
    John Hunter Hosp, Hunter Area Pathol Serv, Div Genet, Newcastle, NSW 2305, Australia..
    Senter, Leigha
    Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA..
    Sharma, Priyanka
    Univ Kansas, Med Ctr, Dept Hematol & Oncol, Kansas City, KS 66205 USA..
    Simard, Jacques
    Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada..
    Singer, Christian F.
    Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria..
    Sinilnikova, Olga M.
    Univ Lyon, CNRS, UMR5286, Ctr Rech Cancerol Lyon,INSERM,U1052, F-69373 Lyon, France.;Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon, France..
    Soucy, Penny
    Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada..
    Southey, Melissa
    Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia..
    Steinemann, Doris
    Hannover Med Sch, D-30625 Hannover, Germany..
    Stenmark-Askmalm, Marie
    Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, SE-58185 Linkoping, Sweden..
    Stoppa-Lyonnet, Dominique
    Inst Curie, Dept Tumour Biol, F-75248 Paris, France.;Univ Paris 05, Sorbonne Paris Cite, F-75248 Paris, France..
    Swerdlow, Anthony
    Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England..
    Szabo, Csilla I.
    NHGRI, NIH, Bethesda, MD 20892 USA..
    Tamimi, Rulla
    Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA..
    Tapper, William
    Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England..
    Teixeira, Manuel R.
    Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal.;Univ Porto, Biomed Sci Inst ICBAS, P-4200072 Oporto, Portugal..
    Teo, Soo-Hwang
    Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia.;Univ Malaya, Med Ctr, Canc Res Inst, Fac Med, Kuala Lumpur 50603, Malaysia..
    Terry, Mary B.
    Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA..
    Thomassen, Mads
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark..
    Thompson, Deborah
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Tihomirova, Laima
    Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia..
    Toland, Amanda E.
    Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA..
    Tollenaar, Robert A. E. M.
    Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands..
    Tomlinson, Ian
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England..
    Truong, Therese
    CESP Ctr Res Epidemiol & Populat Hlth, Inserm Natl Inst Hlth & Med Res, U1018, Environm Epidemiol Canc, F-70115 Villejuif, France..
    Tsimiklis, Helen
    Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia..
    Teule, Alex
    IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona 08908, Spain..
    Tumino, Rosario
    Civ MP Arezzo Hosp, Canc Registry, I-97100 Asp Ragusa, Italy.;Civ MP Arezzo Hosp, Histopathol Unit, I-97100 Asp Ragusa, Italy..
    Tung, Nadine
    Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA..
    Turnbull, Clare
    Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England..
    Ursin, Giski
    Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway..
    van Deurzen, Carolien H. M.
    Erasmus Univ, Med Ctr, Family Canc Clin, Dept Pathol, NL-3000 CA Rotterdam, Netherlands..
    van Rensburg, Elizabeth J.
    Univ Pretoria, Dept Genet, ZA-0007 Pretoria, South Africa..
    Varon-Mateeva, Raymonda
    Charite, Inst Human Genet, D-13353 Berlin, Germany..
    Wang, Zhaoming
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Wang-Gohrke, Shan
    Univ Hosp Ulm, D-89075 Ulm, Germany..
    Weiderpass, Elisabete
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden.;Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway.;Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway.;Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki 2016, Finland..
    Weitzel, Jeffrey N.
    City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA 91010 USA..
    Whittemore, Alice
    Stanford Univ, Sch Med, Dept Hlth Res Policy Epidemiol, Stanford, CA 94305 USA..
    Wildiers, Hans
    Univ Hosp, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium..
    Winqvist, Robert
    Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland.;Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland.;Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Bioctr Oulu, FI-90220 Oulu, Finland..
    Yang, Xiaohong R.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Yannoukakos, Drakoulis
    Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece..
    Yao, Song
    Zamora, M. Pilar
    Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain..
    Zheng, Wei
    Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA.;Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA..
    Hall, Per
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Kraft, Peter
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Vachon, Celine
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Slager, Susan
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Chenevix-Trench, Georgia
    QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia..
    Pharoah, Paul D. P.
    Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Monteiro, Alvaro A. N.
    Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA..
    Garcia-Closas, Montserrat
    NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA..
    Easton, Douglas F.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Antoniou, Antonis C.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England..
    Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11375Article in journal (Refereed)
    Abstract [en]

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

  • 22. Cozen, W.
    et al.
    Timofeeva, M. N.
    Li, D.
    Diepstra, A.
    Hazelett, D.
    Delahaye-Sourdeix, M.
    Edlund, C. K.
    Franke, L.
    Rostgaard, K.
    Van Den Berg, D. J.
    Cortessis, V. K.
    Smedby, K. E.
    Glaser, S. L.
    Westra, H. -J
    Robison, L. L.
    Mack, T. M.
    Ghesquieres, H.
    Hwang, A. E.
    Nieters, A.
    de Sanjose, S.
    Lightfoot, T.
    Becker, N.
    Maynadie, M.
    Foretova, L.
    Roman, E.
    Benavente, Y.
    Rand, K. A.
    Nathwani, B. N.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Staines, A.
    Boffetta, P.
    Link, B. K.
    Kiemeney, L.
    Ansell, S. M.
    Bhatia, S.
    Strong, L. C.
    Galan, P.
    Vatten, L.
    Habermann, T. M.
    Duell, E. J.
    Lake, A.
    Veenstra, R. N.
    Visser, L.
    Liu, Y.
    Urayama, K. Y.
    Montgomery, D.
    Gaborieau, V.
    Weiss, L. M.
    Byrnes, G.
    Lathrop, M.
    Cocco, P.
    Best, T.
    Skol, A. D.
    Adami, H. -O
    Melbye, M.
    Cerhan, J. R.
    Gallagher, A.
    Taylor, G. M.
    Slager, S. L.
    Brennan, P.
    Coetzee, G. A.
    Conti, D. V.
    Onel, K.
    Jarrett, R. F.
    Hjalgrim, H.
    van den Berg, A.
    Mckay, J. D.
    A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 3856-Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR) = 0.81, 95% confidence interval (95% CI) = 0.76-0.86, P-combined 3.5 x 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B-and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

  • 23.
    Cruys, Bert
    et al.
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Wong, Brian W.
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Kuchnio, Anna
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Verdegem, Dries
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Cantelmo, Anna Rita
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Conradi, Lena-Christin
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Vandekeere, Saar
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Bouche, Ann
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Cornelissen, Ivo
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Vinckier, Stefan
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Merks, Roeland M. H.
    Ctr Wiskunde & Informat, Life Sci Grp, Sci Pk 123, NL-1098 XG Amsterdam, Netherlands.;Leiden Univ, Math Inst, Niels Bohrweg 1, NL-2333 CA Leiden, Netherlands..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Via Adamello 16, I-20139 Milan, Italy.;Univ Milan, Dept Oncol & Hematooncol, I-20139 Milan, Italy..
    Gerhardt, Holger
    Katholieke Univ Leuven, Vasc Patterning Lab, Dept Oncol, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Vasc Patterning Lab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;Max Delbruck Ctr Mol Med, Integrat Vasc Biol Lab, Robert Rossle Str 10, D-13125 Berlin, Germany..
    Dewerchin, Mieke
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Dept Pathol, Computat Biol Lab, Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA..
    Carmeliet, Peter
    Katholieke Univ Leuven, Dept Oncol, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium.;VIB, Vesalius Res Ctr, Lab Angiogenesis & Vasc Metab, Herestr 49 Box 912, B-3000 Leuven, Belgium..
    Glycolytic regulation of cell rearrangement in angiogenesis2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12240Article in journal (Refereed)
    Abstract [en]

    During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases.

  • 24. Dadaev, Tokhir
    et al.
    Saunders, Edward J
    Newcombe, Paul J
    Anokian, Ezequiel
    Leongamornlert, Daniel A
    Brook, Mark N
    Cieza-Borrella, Clara
    Mijuskovic, Martina
    Wakerell, Sarah
    Olama, Ali Amin Al
    Schumacher, Fredrick R
    Berndt, Sonja I
    Benlloch, Sara
    Ahmed, Mahbubl
    Goh, Chee
    Sheng, Xin
    Zhang, Zhuo
    Muir, Kenneth
    Govindasami, Koveela
    Lophatananon, Artitaya
    Stevens, Victoria L
    Gapstur, Susan M
    Carter, Brian D
    Tangen, Catherine M
    Goodman, Phyllis
    Thompson, Ian M
    Batra, Jyotsna
    Chambers, Suzanne
    Moya, Leire
    Clements, Judith
    Horvath, Lisa
    Tilley, Wayne
    Risbridger, Gail
    Gronberg, Henrik
    Aly, Markus
    Nordström, Tobias
    Pharoah, Paul
    Pashayan, Nora
    Schleutker, Johanna
    Tammela, Teuvo L J
    Sipeky, Csilla
    Auvinen, Anssi
    Albanes, Demetrius
    Weinstein, Stephanie
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hakansson, Niclas
    West, Catharine
    Dunning, Alison M
    Burnet, Neil
    Mucci, Lorelei
    Giovannucci, Edward
    Andriole, Gerald
    Cussenot, Olivier
    Cancel-Tassin, Géraldine
    Koutros, Stella
    Freeman, Laura E Beane
    Sorensen, Karina Dalsgaard
    Orntoft, Torben Falck
    Borre, Michael
    Maehle, Lovise
    Grindedal, Eli Marie
    Neal, David E
    Donovan, Jenny L
    Hamdy, Freddie C
    Martin, Richard M
    Travis, Ruth C
    Key, Tim J
    Hamilton, Robert J
    Fleshner, Neil E
    Finelli, Antonio
    Ingles, Sue Ann
    Stern, Mariana C
    Rosenstein, Barry
    Kerns, Sarah
    Ostrer, Harry
    Lu, Yong-Jie
    Zhang, Hong-Wei
    Feng, Ninghan
    Mao, Xueying
    Guo, Xin
    Wang, Guomin
    Sun, Zan
    Giles, Graham G
    Southey, Melissa C
    MacInnis, Robert J
    FitzGerald, Liesel M
    Kibel, Adam S
    Drake, Bettina F
    Vega, Ana
    Gómez-Caamaño, Antonio
    Fachal, Laura
    Szulkin, Robert
    Eklund, Martin
    Kogevinas, Manolis
    Llorca, Javier
    Castaño-Vinyals, Gemma
    Penney, Kathryn L
    Stampfer, Meir
    Park, Jong Y
    Sellers, Thomas A
    Lin, Hui-Yi
    Stanford, Janet L
    Cybulski, Cezary
    Wokolorczyk, Dominika
    Lubinski, Jan
    Ostrander, Elaine A
    Geybels, Milan S
    Nordestgaard, Børge G
    Nielsen, Sune F
    Weisher, Maren
    Bisbjerg, Rasmus
    Røder, Martin Andreas
    Iversen, Peter
    Brenner, Hermann
    Cuk, Katarina
    Holleczek, Bernd
    Maier, Christiane
    Luedeke, Manuel
    Schnoeller, Thomas
    Kim, Jeri
    Logothetis, Christopher J
    John, Esther M
    Teixeira, Manuel R
    Paulo, Paula
    Cardoso, Marta
    Neuhausen, Susan L
    Steele, Linda
    Ding, Yuan Chun
    De Ruyck, Kim
    De Meerleer, Gert
    Ost, Piet
    Razack, Azad
    Lim, Jasmine
    Teo, Soo-Hwang
    Lin, Daniel W
    Newcomb, Lisa F
    Lessel, Davor
    Gamulin, Marija
    Kulis, Tomislav
    Kaneva, Radka
    Usmani, Nawaid
    Slavov, Chavdar
    Mitev, Vanio
    Parliament, Matthew
    Singhal, Sandeep
    Claessens, Frank
    Joniau, Steven
    Van den Broeck, Thomas
    Larkin, Samantha
    Townsend, Paul A
    Aukim-Hastie, Claire
    Gago-Dominguez, Manuela
    Castelao, Jose Esteban
    Martinez, Maria Elena
    Roobol, Monique J
    Jenster, Guido
    van Schaik, Ron H N
    Menegaux, Florence
    Truong, Thérèse
    Koudou, Yves Akoli
    Xu, Jianfeng
    Khaw, Kay-Tee
    Cannon-Albright, Lisa
    Pandha, Hardev
    Michael, Agnieszka
    Kierzek, Andrzej
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Schaid, Daniel J
    Lindstrom, Sara
    Turman, Constance
    Ma, Jing
    Hunter, David J
    Riboli, Elio
    Siddiq, Afshan
    Canzian, Federico
    Kolonel, Laurence N
    Le Marchand, Loic
    Hoover, Robert N
    Machiela, Mitchell J
    Kraft, Peter
    Freedman, Matthew
    Wiklund, Fredrik
    Chanock, Stephen
    Henderson, Brian E
    Easton, Douglas F
    Haiman, Christopher A
    Eeles, Rosalind A
    Conti, David V
    Kote-Jarai, Zsofia
    Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 2256Article in journal (Refereed)
    Abstract [en]

    Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

  • 25. Defourny, Jean
    et al.
    Poirrier, Anne-Lise
    Lallemend, Francois
    Sanchez, Susana Mateo
    Neef, Jakob
    Vanderhaeghen, Pierre
    Soriano, Eduardo
    Peuckert, Christiane
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
    Fritzsch, Bernd
    Nguyen, Laurent
    Moonen, Gustave
    Moser, Tobias
    Malgrange, Brigitte
    Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 1438-Article in journal (Refereed)
    Abstract [en]

    Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.

  • 26.
    Dejana, Elisabetta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, Vasc Biol Unit, I-20129 Milan, Italy..
    Hirschi, Karen K.
    Yale Cardiovasc Res Ctr, Dept Internal Med, New Haven, CT 06511 USA.;Yale Cardiovasc Res Ctr, Dept Genet, New Haven, CT 06511 USA.;Yale Cardiovasc Res Ctr, Dept Biomed Engn, New Haven, CT 06511 USA..
    Simons, Michael
    Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, Dept Internal Med, 333 Cedar St, New Haven, CT 06511 USA.;Yale Univ, Sch Med, Dept Cell Biol, 333 Cedar St, New Haven, CT 06511 USA..
    The molecular basis of endothelial cell plasticity2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 14361Article, review/survey (Refereed)
    Abstract [en]

    The endothelium is capable of remarkable plasticity. In the embryo, primitive endothelial cells differentiate to acquire arterial, venous or lymphatic fates. Certain endothelial cells also undergo hematopoietic transition giving rise to multi-lineage hematopoietic stem and progenitors while others acquire mesenchymal properties necessary for heart development. In the adult, maintenance of differentiated endothelial state is an active process requiring constant signalling input. The failure to do so leads to the development of endothelial-to-mesenchymal transition that plays an important role in pathogenesis of a number of diseases. A better understanding of these phenotypic changes may lead to development of new therapeutic interventions.

  • 27.
    Di Marco, Igor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Thunström, Patrik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Katsnelson, M. I.
    Sadowski, J.
    Karlsson, K.
    Lebegue, S.
    Kanski, J.
    Eriksson, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Electron correlations in MnxGa1-xAs as seen by resonant electron spectroscopy and dynamical mean field theory2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 2645-Article in journal (Refereed)
    Abstract [en]

    After two decades since the discovery of ferromagnetism in manganese-doped gallium arsenide, its origin is still debated, and many doubts are related to the electronic structure. Here we report an experimental and theoretical study of the valence electron spectrum of manganese-doped gallium arsenide. The experimental data are obtained through the differences between off- and on-resonance photo emission data. The theoretical spectrum is calculated by means of a combination of density-functional theory in the local density approximation and dynamical mean field theory, using exact diagonalization as impurity solver. Theory is found to accurately reproduce measured data and illustrates the importance of correlation effects. Our results demonstrate that the manganese states extend over a broad range of energy, including the top of the valence band, and that no impurity band splits-off from the valence band edge, whereas the induced holes seem located primarily around the manganese impurity.

  • 28.
    Dussaux, A.
    et al.
    Swiss Fed Inst Technol, Dept Phys, Otto Stern Weg 1, CH-8093 Zurich, Switzerland.
    Shoenherr, P
    Swiss Fed Inst Technol, Dept Mat, Vladimir Prelog Weg 4, CH-8093 Zurich, Switzerland.
    Koumpouras, Konstantinos
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Chico, Jonathan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Chang, K
    Swiss Fed Inst Technol, Dept Phys, Otto Stern Weg 1, CH-8093 Zurich, Switzerland.
    Lorenzelli, L
    Swiss Fed Inst Technol, Dept Phys, Otto Stern Weg 1, CH-8093 Zurich, Switzerland.
    Kanazawa, N
    Univ Tokyo, Dept Appl Phys, Tokyo 1138656, Japan.
    Tokura, Y
    Univ Tokyo, Dept Appl Phys, Tokyo 1138656, Japan.; RIKEN Ctr Emergent Matter Sci CEMS, Wako, Saitama 3510198, Japan.
    Garst, M
    Univ Cologne, Inst Theoret Phys, D-50937 Cologne, Germany.
    Bergman, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Degen, C.L.
    Swiss Fed Inst Technol, Dept Phys, Otto Stern Weg 1, CH-8093 Zurich, Switzerland.
    Meier, D.
    Swiss Fed Inst Technol, Dept Mat, Vladimir Prelog Weg 4, CH-8093 Zurich, Switzerland.; Norwegian Univ Sci & Technol, Dept Mat Sci & Engn, N-7491 Trondheim, Norway .
    Local dynamics of topological magnetic defects in the itinerant helimagnet FeGe.2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12430Article in journal (Refereed)
    Abstract [en]

    Chiral magnetic interactions induce complex spin textures including helical and conical spin spirals, as well as particle-like objects such as magnetic skyrmions and merons. These spin textures are the basis for innovative device paradigms and give rise to exotic topological phenomena, thus being of interest for both applied and fundamental sciences. Present key questions address the dynamics of the spin system and emergent topological defects. Here we analyse the micromagnetic dynamics in the helimagnetic phase of FeGe. By combining magnetic force microscopy, single-spin magnetometry and Landau-Lifschitz-Gilbert simulations we show that the nanoscale dynamics are governed by the depinning and subsequent motion of magnetic edge dislocations. The motion of these topologically stable objects triggers perturbations that can propagate over mesoscopic length scales. The observation of stochastic instabilities in the micromagnetic structure provides insight to the spatio-temporal dynamics of itinerant helimagnets and topological defects, and discloses open challenges regarding their technological usage.

  • 29. Dussaux, Antoine
    et al.
    Schoenherr, P.
    Koumpouras, Konstantinos
    Chico, Jonathan
    Chang, K
    Lorenzelli, L
    Kanazawa, N
    Tokura, Y
    Garst, M
    Bergman, Anders
    Degen, C. L.
    Meier, D.
    Local dynamics of topological magnetic defects in theitinerant helimagnet FeGeIn: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723Article in journal (Refereed)
  • 30.
    Dyakova, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Lee, Yu-Jen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Longden, Kit D.
    Kiselev, Valerij G.
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    A higher order visual neuron tuned to the spatial amplitude spectra of natural scenes2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 8522Article in journal (Refereed)
    Abstract [en]

    Animal sensory systems are optimally adapted to those features typically encountered in natural surrounds, thus allowing neurons with limited bandwidth to encode challengingly large input ranges. Natural scenes are not random, and peripheral visual systems in vertebrates and insects have evolved to respond efficiently to their typical spatial statistics. The mammalian visual cortex is also tuned to natural spatial statistics, but less is known about coding in higher order neurons in insects. To redress this we here record intracellularly from a higher order visual neuron in the hoverfly. We show that the cSIFE neuron, which is inhibited by stationary images, is maximally inhibited when the slope constant of the amplitude spectrum is close to the mean in natural scenes. The behavioural optomotor response is also strongest to images with naturalistic image statistics. Our results thus reveal a close coupling between the inherent statistics of natural scenes and higher order visual processing in insects.

  • 31.
    Eckhard, Ulrich
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Univ British Columbia, Fac Dent, Dept Oral Biol & Med Sci, Inst Life Sci, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada.
    Bandukwala, Hina
    Univ Waterloo, Dept Biol, 200 Univ Ave West, Waterloo, ON N2L 3G1, Canada..
    Mansfield, Michael J.
    Univ Waterloo, Dept Biol, 200 Univ Ave West, Waterloo, ON N2L 3G1, Canada..
    Marino, Giada
    Univ British Columbia, Fac Dent, Dept Oral Biol & Med Sci, Inst Life Sci, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada..
    Cheng, Jiujun
    Univ Waterloo, Dept Biol, 200 Univ Ave West, Waterloo, ON N2L 3G1, Canada..
    Wallace, Iain
    Univ Waterloo, Dept Biol, 200 Univ Ave West, Waterloo, ON N2L 3G1, Canada..
    Holyoak, Todd
    Univ Waterloo, Dept Biol, 200 Univ Ave West, Waterloo, ON N2L 3G1, Canada..
    Charles, Trevor C.
    Univ Waterloo, Dept Biol, 200 Univ Ave West, Waterloo, ON N2L 3G1, Canada..
    Austin, John
    Hlth Canada, Hlth Prod & Food Branch, Bur Microbial Hazards, Ottawa, ON K1A 0K9, Canada..
    Overall, Christopher M.
    Univ British Columbia, Fac Dent, Dept Oral Biol & Med Sci, Inst Life Sci, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada..
    Doxey, Andrew C.
    Univ Waterloo, Dept Biol, 200 Univ Ave West, Waterloo, ON N2L 3G1, Canada..
    Discovery of a proteolytic flagellin family in diverse bacterial phyla that assembles enzymatically active flagella2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 521Article in journal (Refereed)
    Abstract [en]

    Bacterial flagella are cell locomotion and occasional adhesion organelles composed primarily of the polymeric protein flagellin, but to date have not been associated with any enzymatic function. Here, we report the bioinformatics-driven discovery of a class of enzymatic flagellins that assemble to form proteolytically active flagella. Originating by a metallopeptidase insertion into the central flagellin hypervariable region, this flagellin family has expanded to at least 74 bacterial species. In the pathogen, Clostridium haemolyticum, metallopeptidase-containing flagellin (which we termed flagellinolysin) is the second most abundant protein in the flagella and is localized to the extracellular flagellar surface. Purified flagellar filaments and recombinant flagellin exhibit proteolytic activity, cleaving nearly 1000 different peptides. With similar to 20,000 flagellin copies per similar to 10-mu m flagella this assembles the largest proteolytic complex known. Flagellum-mediated extracellular proteolysis expands our understanding of the functional plasticity of bacterial flagella, revealing this family as enzymatic biopolymers that mediate interactions with diverse peptide substrates.

  • 32.
    Edfors, Fredrik
    et al.
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Hober, Andreas
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Linderbäck, Klas
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Maddalo, Gianluca
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Azimi, Alireza
    Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, SE-17177 Stockholm, Sweden.
    Sivertsson, Åsa
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Tegel, Hanna
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Szigyarto, Cristina Al-Khalili
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    von Feilitzen, Kalle
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Oksvold, Per
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Forsström, Björn
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden;KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden;Tech Univ Denmark, Novo Nordisk Fdn Ctr Biosustainabil, DK-2970 Horsholm, Denmark.
    Enhanced validation of antibodies for research applications2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 4130Article in journal (Refereed)
    Abstract [en]

    There is a need for standardized validation methods for antibody specificity and selectivity. Recently, five alternative validation pillars were proposed to explore the specificity of research antibodies using methods with no need for prior knowledge about the protein target. Here, we show that these principles can be used in a streamlined manner for enhanced validation of research antibodies in Western blot applications. More than 6,000 antibodies were validated with at least one of these strategies involving orthogonal methods, genetic knockdown, recombinant expression, independent antibodies, and capture mass spectrometry analysis. The results show a path forward for efforts to validate antibodies in an application-specific manner suitable for both providers and users.

  • 33.
    Egea-Jimenez, Antonio Luis
    et al.
    Aix Marseille Univ, Inst Paoli Calmettes, INSERM, CRCM,U1068,CNRS UMR7258, F-13009 Marseille, France; Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Gallardo, Rodrigo
    Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium;Katholieke Univ Leuven, Dept Mol Cellular & Mol Med, VIB, VIB Switch Lab, B-3000 Leuven, Belgium.
    Garcia-Pino, Abel
    Vrije Univ Brussel, Struct Biol Brussels, Dept Biotechnol DBIT, Pl Laan 2, B-1050 Brussels, Belgium; VIB, Mol Recognit Unit, Struct Biol Res Ctr, Pl Laan 2, B-1050 Brussels, Belgium; Univ Libre Bruxelles, Biol Struct & Biophys, CP300,Rue Prof Jeener & Brachet 12, B-6041 Gosselies, Belgium.
    Ivarsson, Ylva
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Wawrzyniak, Anna Maria
    Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Kashyap, Rudra
    Aix Marseille Univ, Inst Paoli Calmettes, INSERM, CRCM,U1068,CNRS UMR7258, F-13009 Marseille, France; Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Loris, Remy
    Vrije Univ Brussel, Struct Biol Brussels, Dept Biotechnol DBIT, Pl Laan 2, B-1050 Brussels, Belgium; VIB, Mol Recognit Unit, Struct Biol Res Ctr, Pl Laan 2, B-1050 Brussels, Belgium.
    Schymkowitz, Joost
    Katholieke Univ Leuven, Dept Mol Cellular & Mol Med, VIB, VIB Switch Lab, B-3000 Leuven, Belgium.
    Rousseau, Frederic
    Katholieke Univ Leuven, Dept Mol Cellular & Mol Med, VIB, VIB Switch Lab, B-3000 Leuven, Belgium.
    Zimmermann, Pascale
    Aix Marseille Univ, Inst Paoli Calmettes, INSERM, CRCM,U1068,CNRS UMR7258, F-13009 Marseille, France; Katholieke Univ Leuven, Dept Human Genet, ON1 Herestr 49,Box 602, B-3000 Leuven, Belgium.
    Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12101Article in journal (Refereed)
    Abstract [en]

    PDZ domain-containing proteins work as intracellular scaffolds to control spatio-temporal aspects of cell signalling. This function is supported by the ability of their PDZ domains to bind other proteins such as receptors, but also phosphoinositide lipids important for membrane trafficking. Here we report a crystal structure of the syntenin PDZ tandem in complex with the carboxy-terminal fragment of Frizzled 7 and phosphatidylinositol 4,5-bisphosphate (PIP2). The crystal structure reveals a tripartite interaction formed via the second PDZ domain of syntenin. Biophysical and biochemical experiments establish co-operative binding of the tripartite complex and identify residues crucial for membrane PIP2-specific recognition. Experiments with cells support the importance of the syntenin-PIP2 interaction for plasma membrane targeting of Frizzled 7 and c-jun phosphorylation. This study contributes to our understanding of the biology of PDZ proteins as key players in membrane compartmentalization and dynamics.

  • 34.
    Elewa, Ahmed
    et al.
    Karolinska Institute, Department of Cell and Molecular Biology.
    Wang, Heng
    Huazhong Agricultural University, College of Animal Science and Technology.
    Talavera-López, Carlos
    Karolinska Institute, Department of Cell and Molecular Biology; Francis Crick Institute.
    Joven, Alberto
    Karolinska Institute, Department of Cell and Molecular Biology.
    Brito, Goncalo
    Karolinska Institute, Department of Cell and Molecular Biology.
    Kumar, Anoop
    Karolinska Institute, Department of Cell and Molecular Biology.
    Hameed, L. Shahul
    Karolinska Institute, Department of Cell and Molecular Biology.
    Penrad-Mobayed, May
    CNRS, Institut Jacques Monod; University Paris-Diderot.
    Yao, Zeyu
    Karolinska Institute, Department of Cell and Molecular Biology.
    Zamani, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Dept Med Biochem & Microbiol, SE-75123 Uppsala, Sweden..
    Abbas, Yamen
    Harvard University, Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute.
    Abdullayev, Ilgar
    Karolinska Institute, Department of Cell and Molecular Biology; Ludwig Institute for Cancer Research.
    Sandberg, Rickard
    Karolinska Institute, Department of Cell and Molecular Biology; Ludwig Institute for Cancer Research.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Björn
    Karolinska Institute, Department of Cell and Molecular Biology.
    Simon, Andras
    Karolinska Institute, Department of Cell and Molecular Biology.
    Reading and editing the Pleurodeles waltl genome reveals novel features of tetrapod regeneration2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 2286Article in journal (Refereed)
    Abstract [en]

    Salamanders exhibit an extraordinary ability among vertebrates to regenerate complex body parts. However, scarce genomic resources have limited our understanding of regeneration in adult salamanders. Here, we present the ~20 Gb genome and transcriptome of the Iberian ribbed newt Pleurodeles waltl, a tractable species suitable for laboratory research. We find that embryonic stem cell-specific miRNAs mir-93b and mir-427/430/302, as well as Harbinger DNA transposons carrying the Myb-like proto-oncogene have expanded dramatically in the Pleurodeleswaltl genome and are co-expressed during limb regeneration. Moreover, we find that a family of salamander methyltransferases is expressed specifically in adult appendages. Using CRISPR/Cas9 technology to perturb transcription factors, we demonstrate that, unlike the axolotl, Pax3 is present and necessary for development and that contrary to mammals, muscle regeneration is normal without functional Pax7 gene. Our data provide a foundation for comparative genomic studies that generate models for the uneven distribution of regenerative capacities among vertebrates.

  • 35.
    Enroth, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bosdotter Enroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strong effects of genetic and lifestyle factors on biomarker variation and use of personalized cutoffs2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 4684-Article in journal (Refereed)
    Abstract [en]

    Ideal biomarkers used for disease diagnosis should display deviating levels in affected individuals only and be robust to factors unrelated to the disease. Here we show the impact of genetic, clinical and lifestyle factors on circulating levels of 92 protein biomarkers for cancer and inflammation, using a population-based cohort of 1,005 individuals. For 75% of the biomarkers, the levels are significantly heritable and genome-wide association studies identifies 16 novel loci and replicate 2 previously known loci with strong effects on one or several of the biomarkers with P-values down to 4.4 × 10−58. Integrative analysis attributes as much as 56.3% of the observed variance to non-disease factors. We propose that information on the biomarker-specific profile of major genetic, clinical and lifestyle factors should be used to establish personalized clinical cutoffs, and that this would increase the sensitivity of using biomarkers for prediction of clinical end points.

  • 36.
    Fan, Ke
    et al.
    KTH Royal Inst Technol, Dept Chem, Organ Chem, S-10044 Stockholm, Sweden.;Wuhan Univ Technol, State Key Lab Adv Technol Mat Synth & Proc, Wuhan 430070, Peoples R China..
    Chen, Hong
    KTH Royal Inst Technol, Dept Chem, Organ Chem, S-10044 Stockholm, Sweden..
    Ji, Yongfei
    KTH Royal Inst Technol, Sch Biotechnol, Div Theoret Chem & Biol, SE-10691 Stockholm, Sweden..
    Huang, Hui
    KTH Royal Inst Technol, Dept Chem Surface & Corros Sci, SE-10044 Stockholm, Sweden..
    Claesson, Per Martin
    KTH Royal Inst Technol, Dept Chem Surface & Corros Sci, SE-10044 Stockholm, Sweden..
    Daniel, Quentin
    KTH Royal Inst Technol, Dept Chem, Organ Chem, S-10044 Stockholm, Sweden..
    Philippe, Bertrand
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Rensmo, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Li, Fusheng
    KTH Royal Inst Technol, Dept Chem, Organ Chem, S-10044 Stockholm, Sweden..
    Luo, Yi
    KTH Royal Inst Technol, Sch Biotechnol, Div Theoret Chem & Biol, SE-10691 Stockholm, Sweden..
    Sun, Licheng
    KTH Royal Inst Technol, Dept Chem, Organ Chem, S-10044 Stockholm, Sweden.;Dalian Univ Technol, DUT KTH Joint Educ & Res Ctr Mol Devices, State Key Lab Fine Chem, Dalian 116024, Peoples R China..
    Nickel-vanadium monolayer double hydroxide for efficient electrochemical water oxidation2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11981Article in journal (Refereed)
    Abstract [en]

    Highly active and low-cost electrocatalysts for water oxidation are required due to the demands on sustainable solar fuels; however, developing highly efficient catalysts to meet industrial requirements remains a challenge. Herein, we report a monolayer of nickel-vanadium-layered double hydroxide that shows a current density of 27 mA cm(-2) (57 mA cm(-2) after ohmic-drop correction) at an overpotential of 350 mV for water oxidation. Such performance is comparable to those of the best-performing nickel-iron-layered double hydroxides for water oxidation in alkaline media. Mechanistic studies indicate that the nickel-vanadium-layered double hydroxides can provide high intrinsic catalytic activity, mainly due to enhanced conductivity, facile electron transfer and abundant active sites. This work may expand the scope of cost-effective electrocatalysts for water splitting.

  • 37.
    Faranda, Davide
    et al.
    Univ Paris Saclay, UVSQ, CNRS, LSCE,IPSL,CEA,CEA Saclay Orme Merisiers,UMR 8212, F-91191 Gif Sur Yvette, France;London Math Lab, 8 Margravine Gardens, London W68RH, England.
    Alvarez-Castro, M. Carmen
    Univ Paris Saclay, UVSQ, CNRS, LSCE,IPSL,CEA,CEA Saclay Orme Merisiers,UMR 8212, F-91191 Gif Sur Yvette, France;Ctr Euromediterraneo Cambiamenti Climat, Climate Simulat & Predict Div, I-40127 Bologna, Italy.
    Messori, Gabriele
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL. Univ Paris Saclay, UVSQ, CNRS, LSCE,IPSL,CEA,CEA Saclay Orme Merisiers,UMR 8212, F-91191 Gif Sur Yvette, France;Stockholm Univ, Dept Meteorol, S-10691 Stockholm, Sweden;Bolin Ctr Climate Res, S-10691 Stockholm, Sweden.
    Rodrigues, David
    Univ Paris Saclay, UVSQ, CNRS, LSCE,IPSL,CEA,CEA Saclay Orme Merisiers,UMR 8212, F-91191 Gif Sur Yvette, France.
    Yiou, Pascal
    Univ Paris Saclay, UVSQ, CNRS, LSCE,IPSL,CEA,CEA Saclay Orme Merisiers,UMR 8212, F-91191 Gif Sur Yvette, France.
    The hammam effect or how a warm ocean enhances large scale atmospheric predictability2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1316Article in journal (Refereed)
    Abstract [en]

    The atmosphere's chaotic nature limits its short-term predictability. Furthermore, there is little knowledge on how the difficulty of forecasting weather may be affected by anthropogenic climate change. Here, we address this question by employing metrics issued from dynamical systems theory to describe the atmospheric circulation and infer the dynamical properties of the climate system. Specifically, we evaluate the changes in the sub-seasonal predictability of the large-scale atmospheric circulation over the North Atlantic for the historical period and under anthropogenic forcing, using centennial reanalyses and CMIP5 simulations. For the future period, most datasets point to an increase in the atmosphere's predictability. AMIP simulations with 4K warmer oceans and 4 x atmospheric CO2 concentrations highlight the prominent role of a warmer ocean in driving this increase. We term this the hammam effect. Such effect is linked to enhanced zonal atmospheric patterns, which are more predictable than meridional configurations.

  • 38. Ferreira, Silvia A
    et al.
    Motwani, Meghna S
    Faull, Peter A
    Seymour, Alexis J
    Yu, Tracy T L
    Enayati, Marjan
    Taheem, Dheraj K
    Salzlechner, Christoph
    Haghighi, Tabasom
    Kania, Ewa M
    Oommen, Oommen P
    Ahmed, Tarek
    Loaiza, Sandra
    Parzych, Katarzyna
    Dazzi, Francesco
    Varghese, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Festy, Frederic
    Grigoriadis, Agamemnon E
    Auner, Holger W
    Snijders, Ambrosius P
    Bozec, Laurent
    Gentleman, Eileen
    Bi-directional cell-pericellular matrix interactions direct stem cell fate2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 4049Article in journal (Refereed)
    Abstract [en]

    Modifiable hydrogels have revealed tremendous insight into how physical characteristics of cells' 3D environment drive stem cell lineage specification. However, in native tissues, cells do not passively receive signals from their niche. Instead they actively probe and modify their pericellular space to suit their needs, yet the dynamics of cells' reciprocal interactions with their pericellular environment when encapsulated within hydrogels remains relatively unexplored. Here, we show that human bone marrow stromal cells (hMSC) encapsulated within hyaluronic acid-based hydrogels modify their surroundings by synthesizing, secreting and arranging proteins pericellularly or by degrading the hydrogel. hMSC's interactions with this local environment have a role in regulating hMSC fate, with a secreted proteinaceous pericellular matrix associated with adipogenesis, and degradation with osteogenesis. Our observations suggest that hMSC participate in a bi-directional interplay between the properties of their 3D milieu and their own secreted pericellular matrix, and that this combination of interactions drives fate.

  • 39.
    Foote, Andrew D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, Oster Volgade 5-7, DK-1350 Copenhagen K, Denmark.;Univ Bern, Inst Ecol & Evolut, Computat & Mol Populat Genet Lab, Baltzerstr 6, CH-3012 Bern, Switzerland..
    Vijay, Nagarjun
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Avila-Arcos, Maria C.
    Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, Oster Volgade 5-7, DK-1350 Copenhagen K, Denmark.;Stanford Univ, Dept Genet, Stanford, CA 94305 USA..
    Baird, Robin W.
    Cascadia Res, 4th Ave, Olympia, WA 98501 USA..
    Durban, John W.
    NOAA, Marine Mammal & Turtle Div, Southwest Fisheries Sci Ctr, Natl Marine Fisheries Serv, 8901 La Jolla Shores Dr, La Jolla, CA 92037 USA..
    Fumagalli, Matteo
    UCL, UCL Genet Inst, Dept Genet Evolut & Environm, London WC1E 6BT, England..
    Gibbs, Richard A.
    Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA..
    Hanson, M. Bradley
    NOAA, NW Fisheries Sci Ctr, Natl Marine Fisheries Serv, 2725 Montlake Blvd East, Seattle, WA 98112 USA..
    Korneliussen, Thorfinn S.
    Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, Oster Volgade 5-7, DK-1350 Copenhagen K, Denmark..
    Martin, Michael D.
    Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, Oster Volgade 5-7, DK-1350 Copenhagen K, Denmark..
    Robertson, Kelly M.
    NOAA, Marine Mammal & Turtle Div, Southwest Fisheries Sci Ctr, Natl Marine Fisheries Serv, 8901 La Jolla Shores Dr, La Jolla, CA 92037 USA..
    Sousa, Vitor C.
    Univ Bern, Inst Ecol & Evolut, Computat & Mol Populat Genet Lab, Baltzerstr 6, CH-3012 Bern, Switzerland..
    Vieira, Filipe G.
    Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, Oster Volgade 5-7, DK-1350 Copenhagen K, Denmark..
    Vinar, Tomas
    Comenius Univ, Fac Math Phys & Informat, Bratislava 84248, Slovakia..
    Wade, Paul
    NOAA, Natl Marine Mammal Lab, Alaska Fisheries Sci Ctr, Natl Marine Fisheries Serv, 7600 Sand Point Way NE, Seattle, WA 98115 USA..
    Worley, Kim C.
    Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA..
    Excoffier, Laurent
    Univ Bern, Inst Ecol & Evolut, Computat & Mol Populat Genet Lab, Baltzerstr 6, CH-3012 Bern, Switzerland..
    Morin, Phillip A.
    NOAA, Marine Mammal & Turtle Div, Southwest Fisheries Sci Ctr, Natl Marine Fisheries Serv, 8901 La Jolla Shores Dr, La Jolla, CA 92037 USA..
    Gilbert, M. Thomas P.
    Univ Copenhagen, Nat Hist Museum Denmark, Ctr GeoGenet, Oster Volgade 5-7, DK-1350 Copenhagen K, Denmark.;Curtin Univ, Dept Environm & Agr, Trace & Environm DNA Lab, Perth, WA 6102, Australia..
    Wolf, Jochen B. W.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Munich, Dept Biol 2, Sect Evolutionary Biol, Grosshaderner Str 2, D-82152 Planegg Martinsried, Germany..
    Genome-culture coevolution promotes rapid divergence of killer whale ecotypes2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11693Article in journal (Refereed)
    Abstract [en]

    Analysing population genomic data from killer whale ecotypes, which we estimate have globally radiated within less than 250,000 years, we show that genetic structuring including the segregation of potentially functional alleles is associated with socially inherited ecological niche. Reconstruction of ancestral demographic history revealed bottlenecks during founder events, likely promoting ecological divergence and genetic drift resulting in a wide range of genome-wide differentiation between pairs of allopatric and sympatric ecotypes. Functional enrichment analyses provided evidence for regional genomic divergence associated with habitat, dietary preferences and post-zygotic reproductive isolation. Our findings are consistent with expansion of small founder groups into novel niches by an initial plastic behavioural response, perpetuated by social learning imposing an altered natural selection regime. The study constitutes an important step towards an understanding of the complex interaction between demographic history, culture, ecological adaptation and evolution at the genomic level.

  • 40.
    Franceschini, Nora
    et al.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27516 USA.
    Giambartolomei, Claudia
    Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA.
    de Vries, Paul S.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA.
    Finan, Chris
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA.
    Huntley, Rachael P.
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Lovering, Ruth C.
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Tajuddin, Salman M.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Winkler, Thomas W.
    Univ Regensburg, Dept Genet Epidemiol, D-93053 Regensburg, Germany.
    Graff, Misa
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27516 USA.
    Kavousi, Maryam
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands.
    Dale, Caroline
    UCL, Inst Hlth Informat, London WC1E 6BT, England.
    Smith, Albert V.
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland;Univ Iceland, IS-101 Reykjavik, Iceland.
    Hofer, Edith
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria;Med Univ Graz, Inst Med Informat Stat & Documentat, A-8036 Graz, Austria.
    van Leeuwen, Elisabeth M.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands.
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-3015 Groningen, Netherlands.
    Lu, Lingyi
    Wake Forest Univ, Bowman Gray Sch Med, Dept Biostatist Sci, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA.
    Scholz, Markus
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany.
    Sargurupremraj, Muralidharan
    Univ Bordeaux, INSERM, CHU Bordeaux, Bordeaux Populat Hlth Res Ctr,UMR 1219, F-33000 Bordeaux, France.
    Pitkanen, Niina
    Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland.
    Franzen, Oscar
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA;Clin Gene Networks AB, S-10462 Stockholm, Sweden.
    Joshi, Peter K.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
    Noordam, Raymond
    Leiden Univ, Med Ctr, Sect Gerontol & Geriatr, Dept Internal Med, NL-2300 RC Leiden, Netherlands.
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland.
    Hwang, Shih-Jen
    NHLBI, Populat Sci Branch, Div Intramural Res, NIH, Framingham, MA 01702 USA;NHLBI, Intramural Res Program, Framingham Heart Study, Framingham, MA 01702 USA.
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
    Schminke, Ulf
    Univ Med Greifswald, Dept Neurol, D-17475 Greifswald, Germany.
    Palmas, Walter
    Columbia Univ, Dept Med, New York, NY 10032 USA.
    Isaacs, Aaron
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Maastricht Univ, CARIM Sch Cardiovasc Dis, Maastricht Ctr Syst Biol MaCSBio, Dept Biochem, NL-6229 Maastricht, Netherlands.
    Correa, Adolfo
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
    Zonderman, Alan B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany.
    Cox, Amanda J.
    Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC 25157 USA;Griffith Univ, Menzies Hlth Inst Queensland, Southport, Qld 4222, Australia.
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Med Ctr Rotterdam, Erasmus Med Ctr, Dept Internal Med, NL-3015 Rotterdam, Netherlands.
    Wong, Andrew
    UCL, MRC Unit Lifelong Hlth & Ageing, London WC1E 6BT, England.
    Smit, Andries J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Med, NL-2300 Groningen, Netherlands.
    Newman, Anne B.
    Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA;Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15213 USA.
    Britton, Annie
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.
    Ruusalepp, Arno
    Clin Gene Networks AB, S-10462 Stockholm, Sweden;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, EE-51010 Tartu, Estonia;Tartu Univ Hosp, Dept Cardiac Surg, EE-51010 Tartu, Estonia.
    Sennblad, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, S-17177 Stockholm, Sweden.
    Hedblad, Bo
    Lund Univ, Dept Clin Sci Malmo, SE-20502 Malmo, Sweden.
    Pasaniuc, Bogdan
    Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA;Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA.
    Penninx, Brenda W.
    Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res & Neurosci Campus Amste, Department Psychiat, NL-1081 HL Amsterdam, Netherlands.
    Langefeld, Carl D.
    Wake Forest Univ, Bowman Gray Sch Med, Dept Biostatist Sci, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA.
    Wassel, Christina L.
    Premier Inc, Appl Sci, Charlotte, NC 28277 USA.
    Tzourio, Christophe
    Univ Bordeaux, INSERM, CHU Bordeaux, Bordeaux Populat Hlth Res Ctr,UMR 1219, F-33000 Bordeaux, France.
    Fava, Cristiano
    Lund Univ, Dept Clin Sci Malmo, SE-20502 Malmo, Sweden;Univ Verona, Dept Med, I-37134 Verona, Italy.
    Baldassarre, Damiano
    Univ Milan, Dept Med Biotechnol & Translat Med, I-20133 Milan, Italy;IRCCS, Ctr Cardiol Monzino, I-20138 Milan, Italy.
    O'Leary, Daniel H.
    Tufts Univ, Sch Med, St Elizabeths Med Ctr, Boston, MA 02135 USA.
    Teupser, Daniel
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany;LMU, Univ Hosp Munich, Inst Lab Med, D-80539 Munich, Germany.
    Kuh, Diana
    UCL, MRC Unit Lifelong Hlth & Ageing, London WC1E 6BT, England.
    Tremoli, Elena
    IRCCS, Ctr Cardiol Monzino, I-20138 Milan, Italy;Univ Milan, Dipartimento Sci Farmacol Biomol, I-20133 Milan, Italy.
    Mannarino, Elmo
    Univ Perugia, Internal Med Angiol & Arteriosclerosis Dis, Dept Clin & Expt Med, I-06123 Perugia, Italy.
    Grossi, Enzo
    Ctr Diagnost Italiano, I-20147 Milan, Italy.
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
    Schadt, Eric E.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA;Clin Gene Networks AB, S-10462 Stockholm, Sweden.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA 94309 USA;Stanford Univ, Stanford Cardiovasc Inst, G1120, Stanford, CA USA.
    Veglia, Fabrizio
    IRCCS, Ctr Cardiol Monzino, I-20138 Milan, Italy.
    Rivadeneira, Fernando
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Med Ctr Rotterdam, Erasmus Med Ctr, Dept Internal Med, NL-3015 Rotterdam, Netherlands.
    Beutner, Frank
    Heart Ctr Leipzig, D-04103 Leipzig, Germany.
    Chauhan, Ganesh
    Univ Bordeaux, INSERM, CHU Bordeaux, Bordeaux Populat Hlth Res Ctr,UMR 1219, F-33000 Bordeaux, France;Indian Inst Sci, Ctr Brain Res, Bangalore 560012, Karnataka, India.
    Heiss, Gerardo
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27516 USA.
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, NL-3015 Groningen, Netherlands.
    Campbell, Harry
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
    Voelzke, Henry
    Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany;DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany.
    Markus, Hugh S.
    Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge CB2 0QQ, England.
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9JZ, Midlothian, Scotland.
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands.
    de Graaf, Jacqueline
    Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 GA Nijmegen, Netherlands.
    Price, Jacqueline
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
    Pott, Janne
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany.
    Hopewell, Jemma C.
    Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford OX3 7LF, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford OX3 7LF, England.
    Liang, Jingjing
    Case Western Reserve Univ, Sch Med, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA.
    Thiery, Joachim
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany;Univ Leipzig, Inst Lab Med, D-04109 Leipzig, Germany.
    Engmann, Jorgen
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, S-17177 Stockholm, Sweden.
    Rice, Kenneth
    Univ Washington, Dept Biostat, Seattle, WA 98105 USA.
    Taylor, Kent D.
    Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA.
    Dhana, Klodian
    Rush Univ, Med Ctr, Dept Internal Med, Chicago, IL 60612 USA.
    Kiemeney, Lambertus A. L. M.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 GA Nijmegen, Netherlands.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Raffield, Laura M.
    Univ N Carolina, Dept Genet, Chapel Hill, NC 27516 USA.
    Launer, Lenore J.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Holdt, Lesca M.
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany;LMU, Univ Hosp Munich, Inst Lab Med, D-80539 Munich, Germany.
    Doer, Marcus
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany;Univ Med Greifswald, Dept Internal Med B, D-17475 Greifswald, Germany.
    Dichgans, Martin
    LMU, Univ Hosp, Inst Stroke & Dementia Res ISD, D-80539 Munich, Germany;Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany.
    Traylor, Matthew
    Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge CB2 0QQ, England.
    Sitzer, Matthias
    Goethe Univ Frankfurt, Ctr Neurol & Neurosurg, Dept Neurol, D-60323 Frankfurt, Germany.
    Kumari, Meena
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England;Essex Univ, Inst Social & Econ Res, Colchester CO4 3SQ, Essex, England.
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England.
    Nalls, Mike A.
    NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA;Data Tecn Int, Glen Echo, MD 20812 USA.
    Melander, Olle
    Lund Univ, Dept Clin Sci Malmo, SE-20502 Malmo, Sweden.
    Raitakari, Olli
    Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20520 Turku, Finland;Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku 20521, Finland.
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Bern, ISPM, CH-3012 Bern, Switzerland.
    Rueda-Ochoa, Oscar L.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Ind Santander, Sch Med, Electrocardiog Res Grp, Santander 680003, Colombia.
    Roussos, Panos
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA;Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA;James J Peters VA Med Ctr, MIRECC, Bronx, NY 10468 USA.
    Whincup, Peter H.
    St Georges Univ London, Populat Hlth Res Inst, London SW17 0RE, England.
    Amouyel, Philippe
    INSERM, U1167, F-59000 Lille, France;Inst Pasteur, U1167, F-59000 Lille, France;Univ Lille, U1167, RID AGE, F-59000 Lille, France;CHU Lille, U1167, F-59000 Lille, France.
    Giral, Philippe
    Sorbonne Univ, Pitie Salpetriere Hosp, Cardiovasc Prevent Unit, F-75013 Paris, France.
    Anugu, Pramod
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA.
    Wong, Quenna
    Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA.
    Malik, Rainer
    LMU, Univ Hosp, Inst Stroke & Dementia Res ISD, D-80539 Munich, Germany.
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio 70100, Finland;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland.
    Burkhardt, Ralph
    Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany;Univ Leipzig, Inst Lab Med, D-04109 Leipzig, Germany;Univ Hosp Regensburg, Inst Clin Chem & Lab Med, D-93053 Regensburg, Germany.
    Hardy, Rebecca
    UCL, MRC Unit Lifelong Hlth & Ageing, London WC1E 6BT, England.
    Schmidt, Reinhold
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, A-8036 Graz, Austria.
    de Mutsert, Renee
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 Leiden, Netherlands.
    Morris, Richard W.
    Univ Bristol, Bristol Med Sch, Dept Populat Hlth Sci, Bristol BS8 1QU, Avon, England.
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, S-17177 Stockholm, Sweden;Univ Glasgow, Inst Hlth & Wellbeing, Mental Hlth & Wellbeing, Glasgow G12 0XH, Lanark, Scotland.
    Wannamethee, S. Goya
    UCL, Dept Primary Care & Populat Hlth, London WC1E 6BT, England.
    Hagg, Sara
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden.
    Shah, Sonia
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    McLachlan, Stela
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland.
    Trompet, Stella
    Leiden Univ, Med Ctr, Sect Gerontol & Geriatr, Dept Internal Med, NL-2300 RC Leiden, Netherlands;Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RC Leiden, Netherlands.
    Seshadri, Sudha
    Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA.
    Kurl, Sudhir
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, FI-70210 Kuopio, Finland.
    Heckbert, Susan R.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98101 USA;Kaiser Permanente Washington Hlth Res Inst, Seattle, WA 98101 USA.
    Ring, Susan
    Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol BS8 1QU, Avon, England;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 1TH, Avon, England.
    Harris, Tamara B.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere 33014, Finland;Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland.
    Galesloot, Tessel E.
    Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 GA Nijmegen, Netherlands.
    Shah, Tina
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Dept Cardiol, S-17177 Stockholm, Sweden.
    Plagnol, Vincent
    UCL, Genet Inst, London WC1E 6BT, England.
    Rosamond, Wayne D.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27516 USA.
    Post, Wendy
    Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA;Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD 21205 USA.
    Zhu, Xiaofeng
    Case Western Reserve Univ, Sch Med, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA.
    Zhang, Xiaoling
    NHLBI, Intramural Res Program, Framingham Heart Study, Framingham, MA 01702 USA;Boston Univ, Sch Med, Sect Biomed Genet, Boston, MA 02215 USA.
    Guo, Xiuqing
    Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA;Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Dept Pediat, Med Ctr, Torrance, CA 90502 USA.
    Saba, Yasaman
    Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, A-8010 Graz, Austria.
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Imperial Coll London, Dept Epidemiol & Biostat, London SW7 2AZ, England.
    Seldenrijk, Adrie
    Univ Amsterdam, Med Ctr, Dept Psychiat, GGZ inGeest & Amsterdam Publ Hlth Res Inst, NL-1081 HV Amsterdam, Netherlands.
    Morrison, Alanna C.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Human Genet Ctr, Houston, TX 77030 USA.
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, S-17177 Stockholm, Sweden.
    Psaty, Bruce M.
    Kaiser Permanente Washington Hlth Res Inst, Seattle, WA 98101 USA;Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA;Univ Washington, Dept Med, Seattle, WA 98195 USA;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.
    van Duijn, Cornelia M.
    Erasmus MC, Dept Epidemiol, NL-3015 Rotterdam, Netherlands;Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford OX3 7LF, England;Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit, Oxford OX3 7LF, England.
    Lawlor, Deborah A.
    Univ Bristol, Bristol Med Sch, Populat Hlth Sci, Bristol BS8 1QU, Avon, England;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 1TH, Avon, England.
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2333 Leiden, Netherlands;Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, NL-2333 ZA Leiden, Netherlands.
    Bowden, Donald W.
    Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Gen, 300 S Hawthorne Rd, Winston Salem, NC 27157 USA.
    Schmidt, Helena
    Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, A-8010 Graz, Austria.
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH8 9AG, Midlothian, Scotland;Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland.
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA.
    Rotter, Jerome I.
    Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Med Ctr, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA;Univ Calif Los Angeles, Los Angeles Biomed Res Inst Harbor, Dept Pediat, Med Ctr, Torrance, CA 90502 USA.
    Wardlaw, Joanna M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland;Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh EH16 4SB, Midlothian, Scotland;Univ Edinburgh, UK Dementia Res Inst, Edinburgh EH16 4SB, Midlothian, Scotland.
    Deanfield, John
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Halcox, Julian
    Swansea Univ, Med Sch, Swansea SA2 8PP, W Glam, Wales.
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere 33014, Finland;Univ Tampere, Sch Med, Dept Clin Chem, Tampere 33014, Finland.
    Loeffler, Markus
    Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany;Univ Leipzig, LIFE Res Ctr Civilizat Dis, D-04107 Leipzig, Germany.
    Evans, Michele K.
    NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA.
    Debette, Stephanie
    Univ Bordeaux, INSERM, CHU Bordeaux, Bordeaux Populat Hlth Res Ctr,UMR 1219, F-33000 Bordeaux, France.
    Humphries, Steve E.
    UCL, Inst Cardiovasc Sci, Crt Cardiovasc Genet, London WC1E 6BT, England.
    Voelker, Uwe
    DZHK German Ctr Cardiovasc Res, Partner Site Greifswald, D-17475 Greifswald, Germany;Univ Med Greifswald, Interfac Inst Genet & Funct Gen, D-17475 Greifswald, Germany.
    Gudnason, Vilmundur
    Iceland Heart Assoc, IS-201 Kopavogur, Iceland;Univ Iceland, IS-101 Reykjavik, Iceland.
    Hingorani, Aroon D.
    UCL, Inst Cardiovasc Sci, London WC1 6BT, England.
    Bjorkegren, Johan L. M.
    Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA;Clin Gene Networks AB, S-10462 Stockholm, Sweden;Univ Tartu, Inst Biomed & Translat Med, Dept Pathophysiol, EE-51010 Tartu, Estonia;Karolinska Univ Sjukhuset, Karolinska Inst, Dept Med, Integrated Cardio Metab Ctr, SE-14157 Huddinge, Sweden.
    Casas, Juan P.
    UCL, Inst Hlth Informat, London WC1E 6BT, England.
    O'Donnell, Christopher J.
    NHLBI, Intramural Adm Management Branch, NIH, Bldg 10, Bethesda, MD 20892 USA;Boston Vet Adm Healthcare, Cardiol Sect, Boston, MA 02130 USA;Harvard Med Sch, Boston, MA 02115 USA.
    GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 5141Article in journal (Refereed)
    Abstract [en]

    Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

  • 41.
    Franchini, Paolo
    et al.
    Univ Konstanz, Dept Biol, Lehrstuhl Zool & Evolut Biol, Univ Str 10, D-78457 Constance, Germany.
    Jones, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Konstanz, Dept Biol, Lehrstuhl Zool & Evolut Biol, Univ Str 10, D-78457 Constance, Germany.
    Xiong, Peiwen
    Univ Konstanz, Dept Biol, Lehrstuhl Zool & Evolut Biol, Univ Str 10, D-78457 Constance, Germany.
    Kneitz, Susanne
    Univ Wurzburg, Biozentrum, Physiol Chem, D-97074 Wurzburg, Germany.
    Gompert, Zachariah
    Utah State Univ, Dept Biol, Logan, UT 84322 USA.
    Warren, Wesley C.
    Washington Univ, Sch Med, McDonnell Genome Inst, St Louis, MO 63108 USA.
    Walter, Ronald B.
    Texas State Univ, Dept Chem & Biochem, Xiphophorus Genet Stock Ctr, San Marcos, TX 78666 USA.
    Meyer, Axel
    Univ Konstanz, Dept Biol, Lehrstuhl Zool & Evolut Biol, Univ Str 10, D-78457 Constance, Germany;Harvard Univ, Radcliffe Inst Adv Study, 9 Garden St, Cambridge, MA 02139 USA.
    Schartl, Manfred
    Univ Wurzburg, Biozentrum, Physiol Chem, D-97074 Wurzburg, Germany;Univ Clin Wurzburg, Comprehens Canc Ctr, Josef Schneider Str 6, D-97074 Wurzburg, Germany;Texas A&M Univ, Hagler Inst Adv Study, College Stn, TX 77843 USA;Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA.
    Long-term experimental hybridisation results in the evolution of a new sex chromosome in swordtail fish2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 5136Article in journal (Refereed)
    Abstract [en]

    The remarkable diversity of sex determination mechanisms known in fish may be fuelled by exceptionally high rates of sex chromosome turnovers or transitions. However, the evolutionary causes and genomic mechanisms underlying this variation and instability are yet to be understood. Here we report on an over 30-year evolutionary experiment in which we tested the genomic consequences of hybridisation and selection between two Xiphophorus fish species with different sex chromosome systems. We find that introgression and imposing selection for pigmentation phenotypes results in the retention of an unexpectedly large maternally derived genomic region. During the hybridisation process, the sex-determining region of the X chromosome from one parental species was translocated to an autosome in the hybrids leading to the evolution of a new sex chromosome. Our results highlight the complexity of factors contributing to patterns observed in hybrid genomes, and we experimentally demonstrate that hybridisation can catalyze rapid evolution of a new sex chromosome.

  • 42.
    Franco, Irene
    et al.
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Johansson, Anna C. V.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Olsson, Karl
    Karolinska Inst, Dept Lab Med, Div Clin Physiol, S-14186 Huddinge, Sweden..
    Vrtacnik, Peter
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Lundin, Par
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden.;Stockholm Univ, DBB, Sci Life Lab, S-10691 Stockholm, Sweden..
    Helgadottir, Hafdis T.
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Larsson, Malin
    Linkoping Univ, Dept Phys Chem & Biol, Sci Life Lab, S-58183 Linkoping, Sweden..
    Revechon, Gwladys
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Bosia, Carla
    IIGM, I-10126 Turin, Italy.;Politecn Torino, Dept Appl Sci & Technol, I-10129 Turin, Italy..
    Pagnani, Andrea
    IIGM, I-10126 Turin, Italy.;Politecn Torino, Dept Appl Sci & Technol, I-10129 Turin, Italy..
    Provero, Paolo
    Mol Biotechnol Ctr, Dept Mol Biotechnol & Hlth Sci, I-10126 Turin, Italy.;Ist Sci San Raffaele, Ctr Translat Genom & Bioinformat, I-20132 Milan, Italy..
    Gustafsson, Thomas
    Fischer, Helene
    Eriksson, Maria
    Karolinska Inst, Ctr Innovat Med, Dept Biosci & Nutr, S-14157 Huddinge, Sweden..
    Somatic mutagenesis in satellite cells associates with human skeletal muscle aging2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 800Article in journal (Refereed)
    Abstract [en]

    Human aging is associated with a decline in skeletal muscle (SkM) function and a reduction in the number and activity of satellite cells (SCs), the resident stem cells. To study the connection between SC aging and muscle impairment, we analyze the whole genome of single SC clones of the leg muscle vastus lateralis from healthy individuals of different ages (21-78 years). We find an accumulation rate of 13 somatic mutations per genome per year, consistent with proliferation of SCs in the healthy adult muscle. SkM-expressed genes are protected from mutations, but aging results in an increase in mutations in exons and promoters, targeting genes involved in SC activity and muscle function. In agreement with SC mutations affecting the whole tissue, we detect a missense mutation in a SC propagating to the muscle. Our results suggest somatic mutagenesis in SCs as a driving force in the age-related decline of SkM function.

  • 43.
    Frietsch, B.
    et al.
    Free Univ Berlin, Fachbereich Phys, D-14195 Berlin, Germany.;Max Born Inst, D-12489 Berlin, Germany..
    Bowlan, J.
    Free Univ Berlin, Fachbereich Phys, D-14195 Berlin, Germany.;Max Born Inst, D-12489 Berlin, Germany..
    Carley, R.
    Free Univ Berlin, Fachbereich Phys, D-14195 Berlin, Germany.;Max Born Inst, D-12489 Berlin, Germany..
    Teichmann, M.
    Free Univ Berlin, Fachbereich Phys, D-14195 Berlin, Germany.;Max Born Inst, D-12489 Berlin, Germany..
    Wienholdt, S.
    Univ Konstanz, Fachbereich Phys, D-78457 Constance, Germany..
    Hinzke, D.
    Univ Konstanz, Fachbereich Phys, D-78457 Constance, Germany..
    Nowak, U.
    Univ Konstanz, Fachbereich Phys, D-78457 Constance, Germany..
    Carva, Karel
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. Charles Univ Prague, Fac Math & Phys, DCMP, CZ-12116 Prague 2, Czech Republic..
    Oppeneer, Peter M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Weinelt, M.
    Free Univ Berlin, Fachbereich Phys, D-14195 Berlin, Germany..
    Disparate ultrafast dynamics of itinerant and localized magnetic moments in gadolinium metal2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 8262Article in journal (Refereed)
    Abstract [en]

    The Heisenberg-Dirac intra-atomic exchange coupling is responsible for the formation of the atomic spin moment and thus the strongest interaction in magnetism. Therefore, it is generally assumed that intra-atomic exchange leads to a quasi-instantaneous aligning process in the magnetic moment dynamics of spins in separate, on-site atomic orbitals. Following ultrashort optical excitation of gadolinium metal, we concurrently record in photoemission the 4f magnetic linear dichroism and 5d exchange splitting. Their dynamics differ by one order of magnitude, with decay constants of 14 versus 0.8 ps, respectively. Spin dynamics simulations based on an orbital-resolved Heisenberg Hamiltonian combined with first-principles calculations explain the particular dynamics of 5d and 4f spin moments well, and corroborate that the 5d exchange splitting traces closely the 5d spin-moment dynamics. Thus gadolinium shows disparate dynamics of the localized 4f and the itinerant 5d spin moments, demonstrating a breakdown of their intra-atomic exchange alignment on a picosecond timescale.

  • 44.
    Frye, Maike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Taddei, Andrea
    Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England..
    Dierkes, Cathrin
    Max Planck Inst Mol Biomed, D-48149 Munster, Germany..
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fielden, Matthew
    Albanova Univ Ctr, KTH Royal Inst Technol, Dept Appl Phys, S-10691 Stockholm, Sweden..
    Ortsäter, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Kazenwadel, Jan
    Univ South Australia, Ctr Canc Biol, Adelaide, SA 5000, Australia.;SA Pathol, Adelaide, SA 5000, Australia..
    Calado, Dinis P.
    Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England..
    Ostergaard, Pia
    St Georges Univ London, Mol & Clin Sci Inst, Lymphovasc Res Unit, London SW17 0RE, England..
    Salminen, Marjo
    Univ Helsinki, Dept Vet Biosci, Helsinki 00014, Finland..
    He, Liqun
    Tianjin Med Univ, Gen Hosp, Minist Educ & Tianjin City, Tianjin Neurol Inst,Dept Neurosurg,Key Lab Post, Tianjin 300052, Peoples R China..
    Harvey, Natasha L.
    Univ South Australia, Ctr Canc Biol, Adelaide, SA 5000, Australia.;SA Pathol, Adelaide, SA 5000, Australia..
    Kiefer, Friedemann
    Max Planck Inst Mol Biomed, D-48149 Munster, Germany.;Univ Munster, EIMI, D-48149 Munster, Germany..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1511Article in journal (Refereed)
    Abstract [en]

    Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.

  • 45.
    Fu, Ziao
    et al.
    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
    Indrisiunaite, Gabriele
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Kaledhonkar, Sandip
    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
    Shah, Binita
    Department of Biological Sciences, Barnard College, New York, USA.
    Sun, Ming
    Department of Biological Sciences, Colmbia University, New York, USA.
    Chen, Bo
    Department of Biological Sciences, Colmbia University, New York, USA.
    Grassucci, Robert A.
    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, USA.
    Ehrenberg, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Frank, Joachim
    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, USA; Department of Biological Sciences, Colmbia University, New York, USA.
    The structural basis for release-factor activation during translation termination revealed by time-resolved cryogenic electron microscopy2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 2579Article in journal (Refereed)
    Abstract [en]

    When the ribosome encounters a stop codon, it recruits a release factor (RF) to hydrolyze the ester bond between the peptide chain and tRNA. RFs have structural motifs that recognize stop codons in the decoding center and a GGQ motif for induction of hydrolysis in the peptidyl transfer center 70 Å away. Surprisingly, free RF2 is compact, with only 20 Å between its codon-reading and GGQ motifs. Cryo-EM showed that ribosome-bound RFs have extended structures, suggesting that RFs are compact when entering the ribosome and then extend their structures upon stop codon recognition. Here we use time-resolved cryo-EM to visualize transient compact forms of RF1 and RF2 at 3.5 and 4 Å resolution, respectively, in the codon-recognizing ribosome complex on the native pathway. About 25% of complexes have RFs in the compact state at 24 ms reaction time, and within 60 ms virtually all ribosome-bound RFs are transformed to their extended forms.

  • 46.
    Gandasi, Nikhil R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Contact-induced clustering of syntaxin and munc18 docks secretory granules at the exocytosis site2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, article id 3914Article in journal (Refereed)
    Abstract [en]

    Docking of secretory vesicles at the plasma membrane is a poorly understood prerequisite for exocytosis. Current models propose raft-like clusters containing syntaxin as docking receptor, but direct evidence for this is lacking. Here we provide quantitative measurements of several exocytosis proteins (syntaxin, SNAP25, munc18, munc13 and rab3) at the insulin granule release site and show that docking coincides with rapid de novo formation of syntaxin1/munc18 clusters at the nascent docking site. Formation of such clusters prevents undocking and is not observed during failed docking attempts. Overexpression of syntaxins' N-terminal Habc-domain competitively interferes with both cluster formation and successful docking. SNAP25 and munc13 are recruited to the docking site more than a minute later, consistent with munc13's reported role in granule priming rather than docking. We conclude that secretory vesicles dock by inducing syntaxin1/munc18 clustering in the target membrane, and find no evidence for preformed docking receptors.

  • 47.
    Giampietro, Costanza
    et al.
    FIRC Inst Mol Oncol, I-20139 Milan, Italy.;Univ Milan, Dept Biosci, I-20133 Milan, Italy..
    Deflorian, Gianluca
    FIRC Inst Mol Oncol, I-20139 Milan, Italy..
    Gallo, Stefania
    CNR, Ist Genet Mol, I-27100 Pavia, Italy.;IUSS Ist Univ Super, I-27100 Pavia, Italy..
    Di Matteo, Anna
    CNR, Ist Genet Mol, I-27100 Pavia, Italy.;Lazzaro Spallanzani Univ Pavia, Dipartimento Biol & Biotecnol, I-27100 Pavia, Italy..
    Pradella, Davide
    CNR, Ist Genet Mol, I-27100 Pavia, Italy.;Lazzaro Spallanzani Univ Pavia, Dipartimento Biol & Biotecnol, I-27100 Pavia, Italy..
    Bonomi, Serena
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    Belloni, Elisa
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    Nyqvist, Daniel
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17177 Stockholm, Sweden..
    Quaranta, Valeria
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    Confalonieri, Stefano
    FIRC Inst Mol Oncol, I-20139 Milan, Italy.;Ist Europeo Oncol, Dipartimento Oncol Sperimentale, I-20141 Milan, Italy..
    Bertalot, Giovanni
    Ist Europeo Oncol, Dipartimento Oncol Sperimentale, I-20141 Milan, Italy..
    Orsenigo, Fabrizio
    FIRC Inst Mol Oncol, I-20139 Milan, Italy..
    Pisati, Federica
    FIRC Inst Mol Oncol, I-20139 Milan, Italy..
    Ferrero, Elisabetta
    Ist Sci San Raffaele, Dept Oncol, I-20132 Milan, Italy..
    Biamonti, Giuseppe
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    Fredrickx, Evelien
    Ist Sci San Raffaele, Div Neurosci, I-20132 Milan, Italy.;Ist Sci San Raffaele, INSPE, I-20132 Milan, Italy..
    Taveggia, Carla
    Ist Sci San Raffaele, Div Neurosci, I-20132 Milan, Italy.;Ist Sci San Raffaele, INSPE, I-20132 Milan, Italy..
    Wyatt, Chris D. R.
    Ctr Genom Regulat CRG, EMBL CRG Res Unit Syst Biol, Barcelona 08003, Spain.;Univ Pompeu Fabra UPF, Barcelona 08003, Spain..
    Irimia, Manuel
    Ctr Genom Regulat CRG, EMBL CRG Res Unit Syst Biol, Barcelona 08003, Spain.;Univ Pompeu Fabra UPF, Barcelona 08003, Spain..
    Di Fiore, Pier Paolo
    FIRC Inst Mol Oncol, I-20139 Milan, Italy.;Ist Europeo Oncol, Dipartimento Oncol Sperimentale, I-20141 Milan, Italy.;Univ Milan, Dipartimento Sci Salute, I-20122 Milan, Italy..
    Blencowe, Benjamin J.
    Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada..
    Dejana, Elisabetta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. FIRC Inst Mol Oncol, I-20139 Milan, Italy.;Univ Milan, Dept Biosci, I-20133 Milan, Italy..
    Ghigna, Claudia
    CNR, Ist Genet Mol, I-27100 Pavia, Italy..
    The alternative splicing factor Nova2 regulates vascular development and lumen formation2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 8479Article in journal (Refereed)
    Abstract [en]

    Vascular lumen formation is a fundamental step during angiogenesis; yet, the molecular mechanisms underlying this process are poorly understood. Recent studies have shown that neural and vascular systems share common anatomical, functional and molecular similarities. Here we show that the organization of endothelial lumen is controlled at the post-transcriptional level by the alternative splicing (AS) regulator Nova2, which was previously considered to be neural cell-specific. Nova2 is expressed during angiogenesis and its depletion disrupts vascular lumen formation in vivo. Similarly, Nova2 depletion in cultured endothelial cells (ECs) impairs the apical distribution and the downstream signalling of the Par polarity complex, resulting in altered EC polarity, a process required for vascular lumen formation. These defects are linked to AS changes of Nova2 target exons affecting the Par complex and its regulators. Collectively, our results reveal that Nova2 functions as an AS regulator in angiogenesis and is a novel member of the 'angioneurins' family.

  • 48.
    Girovsky, Jan
    et al.
    Paul Scherrer Inst, Lab Micro & Nanotechnol, CH-5232 Villigen, Switzerland.;Delft Univ Technol, Kavli Inst Nanosci, Dept Quantum Nanosci, Lorentzweg 1, NL-2628 CJ Delft, Netherlands..
    Nowakowski, Jan
    Paul Scherrer Inst, Lab Micro & Nanotechnol, CH-5232 Villigen, Switzerland..
    Ali, Md. Ehesan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. Inst Nano Sci & Technol, Phase 10,Sect 64, Mohali 160062, Punjab, India..
    Baljozovic, Milos
    Paul Scherrer Inst, Lab Micro & Nanotechnol, CH-5232 Villigen, Switzerland..
    Rossmann, Harald R.
    Paul Scherrer Inst, Lab Micro & Nanotechnol, CH-5232 Villigen, Switzerland..
    Nijs, Thomas
    Univ Basel, Dept Phys, CH-4056 Basel, Switzerland..
    Aeby, Elise A.
    Univ Basel, Dept Phys, CH-4056 Basel, Switzerland..
    Nowakowska, Sylwia
    Univ Basel, Dept Phys, CH-4056 Basel, Switzerland..
    Siewert, Dorota
    Univ Basel, Dept Phys, CH-4056 Basel, Switzerland..
    Srivastava, Gitika
    Paul Scherrer Inst, Lab Micro & Nanotechnol, CH-5232 Villigen, Switzerland.;Swiss Fed Labs Mat Sci & Technol, Nanoscale Mat Sci, Empa, CH-8600 Dubendorf, Switzerland..
    Wäckerlin, Christian
    Ecole Polytech Fed Lausanne, Inst Phys IPHYS, CH-1015 Lausanne, Switzerland.;Swiss Fed Labs Mat Sci & Technol, Nanoscale Mat Sci, Empa, CH-8600 Dubendorf, Switzerland..
    Dreiser, Jan
    Paul Scherrer Inst, Swiss Light Source, CH-5232 Villigen, Switzerland..
    Decurtins, Silvio
    Univ Bern, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern, Switzerland..
    Liu, Shi-Xia
    Univ Bern, Dept Chem & Biochem, Freiestr 3, CH-3012 Bern, Switzerland..
    Oppeneer, Peter M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. Uppsala Univ, Dept Phys & Astron, Box 516, S-75120 Uppsala, Sweden..
    Jung, Thomas A.
    Paul Scherrer Inst, Lab Micro & Nanotechnol, CH-5232 Villigen, Switzerland..
    Ballav, Nirmalya
    IISER, Dept Chem, Pune 411008, Maharashtra, India..
    Long-range ferrimagnetic order in a two-dimensional supramolecular Kondo lattice2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15388Article in journal (Refereed)
    Abstract [en]

    Realization of long-range magnetic order in surface-supported two-dimensional systems has been challenging, mainly due to the competition between fundamental magnetic interactions as the short-range Kondo effect and spin-stabilizing magnetic exchange interactions. Spin-bearing molecules on conducting substrates represent a rich platform to investigate the interplay of these fundamental magnetic interactions. Here we demonstrate the direct observation of long-range ferrimagnetic order emerging in a two-dimensional supramolecular Kondo lattice. The lattice consists of paramagnetic hexadeca-fluorinated iron phthalocyanine (FeFPc) and manganese phthalocyanine (MnPc) molecules co-assembled into a checkerboard pattern on single-crystalline Au(111) substrates. Remarkably, the remanent magnetic moments are oriented in the out-of-plane direction with significant contribution from orbital moments. First-principles calculations reveal that the FeFPc-MnPc antiferromagnetic nearest-neighbour coupling is mediated by the Ruderman-Kittel-Kasuya-Yosida exchange interaction via the Au substrate electronic states. Our findings suggest the use of molecular frameworks to engineer novel low-dimensional magnetically ordered materials and their application in molecular quantum devices.

  • 49.
    Grönlund, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Analysis and Applied Mathematics.
    Lötstedt, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Delay-induced anomalous fluctuations in intracellular regulation2011In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 2, p. 419:1-7Article in journal (Refereed)
  • 50.
    Grönlund, Andreas
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lötstedt, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transcription factor binding kinetics constrain noise suppression via negative feedback2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 1864:1-5Article in journal (Refereed)
12345 1 - 50 of 222
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