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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. Aad, G.
    et al.
    Grahn, Karl-Johan
    KTH, School of Engineering Sciences (SCI), Physics, Particle and Astroparticle Physics.
    Lund-Jensen, Bengt
    KTH, School of Engineering Sciences (SCI), Physics, Particle and Astroparticle Physics.
    Strandberg, Jonas
    University of Chicago.
    Zwalinski, L.
    Lafaye, Remi
    KTH, School of Engineering Sciences (SCI), Physics, Particle and Astroparticle Physics.
    et, al
    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.

  • 3.
    Abbey-Lee, Robin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biology. Linköping University, Faculty of Science & Engineering. Max Planck Inst Ornithol, Germany.
    Dingemanse, Niels J.
    Ludwig Maximilians Univ Munchen, Germany.
    Adaptive individual variation in phenological responses to perceived predation levels2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1601Article in journal (Refereed)
    Abstract [en]

    The adaptive evolution of timing of breeding (a component of phenology) in response to environmental change requires individual variation in phenotypic plasticity for selection to act upon. A major question is what processes generate this variation. Here we apply multi-year manipulations of perceived predation levels (PPL) in an avian predator-prey system, identifying phenotypic plasticity in phenology as a key component of alternative behavioral strategies with equal fitness payoffs. We show that under low-PPL, faster (versus slower) exploring birds breed late (versus early); the pattern is reversed under high-PPL, with breeding synchrony decreasing in conjunction. Timing of breeding affects reproductive success, yet behavioral types have equal fitness. The existence of alternative behavioral strategies thus explains variation in phenology and plasticity in reproductive behavior, which has implications for evolution in response to anthropogenic change.

    Download full text (pdf)
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  • 4. Aben, Ralf C. H.
    et al.
    Barros, Nathan
    van Donk, Ellen
    Frenken, Thijs
    Hilt, Sabine
    Kazanjian, Garabet
    Lamers, Leon P. M.
    Peeters, Edwin T. H. M.
    Roelofs, Jan G. M.
    de Senerpont Domis, Lisette N.
    Stephan, Susanne
    Velthuis, Mandy
    Van de Waal, Dedmer B.
    Wik, Martin
    Thornton, Brett F.
    Wilkinson, Jeremy
    DelSontro, Tonya
    Kosten, Sarian
    Cross continental increase in methane ebullition under climate change2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, no 1Article in journal (Refereed)
    Abstract [en]

    Methane (CH4) strongly contributes to observed global warming. As natural CH4 emissions mainly originate from wet ecosystems, it is important to unravel how climate change may affect these emissions. This is especially true for ebullition (bubble flux from sediments), a pathway that has long been underestimated but generally dominates emissions. Here we show a remarkably strong relationship between CH4 ebullition and temperature across a wide range of freshwater ecosystems on different continents using multi-seasonal CH4 ebullition data from the literature. As these temperature–ebullition relationships may have been affected by seasonal variation in organic matter availability, we also conducted a controlled year-round mesocosm experiment. Here 4 °C warming led to 51% higher total annual CH4 ebullition, while diffusion was not affected. Our combined findings suggest that global warming will strongly enhance freshwater CH4 emissions through a disproportional increase in ebullition (6–20% per 1 °C increase), contributing to global warming.

  • 5. Aben, Ralf C. H.
    et al.
    Barros, Nathan
    van Donk, Ellen
    Frenken, Thijs
    Hilt, Sabine
    Kazanjian, Garabet
    Lamers, Leon P. M.
    Peeters, Edwin T. H. M.
    Roelofs, Jan G. M.
    de Senerpont Domis, Lisette N.
    Stephan, Susanne
    Velthuis, Mandy
    Van de Waal, Dedmer B.
    Wik, Martin
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Thornton, Brett F.
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Wilkinson, Jeremy
    DelSontro, Tonya
    Kosten, Sarian
    Cross continental increase in methane ebullition under climate change2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 1682Article in journal (Refereed)
    Abstract [en]

    Methane (CH4) strongly contributes to observed global warming. As natural CH4 emissions mainly originate from wet ecosystems, it is important to unravel how climate change may affect these emissions. This is especially true for ebullition (bubble flux from sediments), a pathway that has long been underestimated but generally dominates emissions. Here we show a remarkably strong relationship between CH4 ebullition and temperature across a wide range of freshwater ecosystems on different continents using multi-seasonal CH4 ebullition data from the literature. As these temperature-ebullition relationships may have been affected by seasonal variation in organic matter availability, we also conducted a controlled year-round mesocosm experiment. Here 4 degrees C warming led to 51% higher total annual CH4 ebullition, while diffusion was not affected. Our combined findings suggest that global warming will strongly enhance freshwater CH4 emissions through a disproportional increase in ebullition (6-20% per 1 degrees C increase), contributing to global warming.

  • 6.
    Abreu-Vieira, Gustavo
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fischer, Alexander W.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Hamburg, Germany.
    Mattsson, Charlotte
    de Jong, Jasper M. A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Ryden, Mikael
    Laurencikiene, Jurga
    Arner, Peter
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cidea improves the metabolic profile through expansion of adipose tissue2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7433Article in journal (Refereed)
    Abstract [en]

    In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.

  • 7. Adamczyk, Bartosz
    et al.
    Sietio, Outi-Maaria
    Strakoya, Petra
    Prommer, Judith
    Wild, Birgit
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. University of Vienna, Austria; University of Gothenburg, Sweden.
    Hagner, Marleena
    Pihlatie, Mari
    Fritze, Hannu
    Richter, Andreas
    Heinonsalo, Jussi
    Plant roots increase both decomposition and stable organic matter formation in boreal forest soil2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 3982Article in journal (Refereed)
    Abstract [en]

    Boreal forests are ecosystems with low nitrogen (N) availability that store globally significant amounts of carbon (C), mainly in plant biomass and soil organic matter (SOM). Although crucial for future climate change predictions, the mechanisms controlling boreal C and N pools are not well understood. Here, using a three-year field experiment, we compare SOM decomposition and stabilization in the presence of roots, with exclusion of roots but presence of fungal hyphae and with exclusion of both roots and fungal hyphae. Roots accelerate SOM decomposition compared to the root exclusion treatments, but also promote a different soil N economy with higher concentrations of organic soil N compared to inorganic soil N accompanied with the build-up of stable SOM-N. In contrast, root exclusion leads to an inorganic soil N economy (i.e., high level of inorganic N) with reduced stable SOM-N buildup. Based on our findings, we provide a framework on how plant roots affect SOM decomposition and stabilization.

  • 8. Aghion, S.
    et al.
    Ahlén, O.
    Amsler, C.
    Ariga, A.
    Ariga, T.
    Belov, A. S.
    Berggren, Karl
    Physics Department, European Organisation for Nuclear Research, Switzerland.
    Bonomi, G.
    Bräunig, P.
    Bremer, J.
    Brusa, R. S.
    Cabaret, L.
    Canali, C.
    Caravita, R.
    Castelli, F.
    Cerchiari, G.
    Cialdi, S.
    Comparat, D.
    Consolati, G.
    Derking, H.
    Di Domizio, S.
    Di Noto, L.
    Doser, M.
    Dudarev, A.
    Ereditato, A.
    Ferragut, R.
    Fontana, A.
    Genova, P.
    Giammarchi, M.
    Gligorova, A.
    Gninenko, S. N.
    Haider, S.
    Huse, T.
    Jordan, E.
    Jørgensen, L. V.
    Kaltenbacher, T.
    Kawada, J.
    Kellerbauer, A.
    Kimura, M.
    Knecht, A.
    Krasnický, D.
    Lagomarsino, V.
    Lehner, S.
    Magnani, A.
    Malbrunot, C.
    Mariazzi, S.
    Matveev, V. A.
    Moia, F.
    Nebbia, G.
    Nédélec, P.
    Oberthaler, M. K.
    Pacifico, N.
    Petràček, V.
    Pistillo, C.
    Prelz, F.
    Prevedelli, M.
    Regenfus, C.
    Riccardi, C.
    Røhne, O.
    Rotondi, A.
    Sandaker, H.
    Scampoli, P.
    Storey, J.
    Vasquez, M.A. Subieta
    Špaček, M.
    Testera, G.
    Vaccarone, R.
    Widmann, E.
    Zavatarelli, S.
    Zmeskal, J.
    A moiré deflectometer for antimatter2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, article id 2538Article in journal (Refereed)
    Abstract [en]

    The precise measurement of forces is one way to obtain deep insight into the fundamental interactions present in nature. In the context of neutral antimatter, the gravitational interaction is of high interest, potentially revealing new forces that violate the weak equivalence principle. Here we report on a successful extension of a tool from atom optics—the moiré deflectometer—for a measurement of the acceleration of slow antiprotons. The setup consists of two identical transmission gratings and a spatially resolving emulsion detector for antiproton annihilations. Absolute referencing of the observed antimatter pattern with a photon pattern experiencing no deflection allows the direct inference of forces present. The concept is also straightforwardly applicable to antihydrogen measurements as pursued by the AEgIS collaboration. The combination of these very different techniques from high energy and atomic physics opens a very promising route to the direct detection of the gravitational acceleration of neutral antimatter.

  • 9. Ahmadi, M.
    et al.
    Alves, B. X. R.
    Baker, C. J.
    Bertsche, W.
    Butler, E.
    Capra, A.
    Carruth, C.
    Cesar, C. L.
    Charlton, M.
    Cohen, S.
    Collister, R.
    Eriksson, S.
    Evans, A.
    Evetts, N.
    Fajans, J.
    Friesen, T.
    Fujiwara, M. C.
    Gill, D. R.
    Gutierrez, A.
    Hangst, J. S.
    Hardy, W. N.
    Hayden, M. E.
    Isaac, C. A.
    Ishida, A.
    Johnson, M. A.
    Jones, S. A.
    Jonsell, Svante
    Stockholm University, Faculty of Science, Department of Physics.
    Kurchaninov, L.
    Madsen, N.
    Mathers, M.
    Maxwell, D.
    McKenna, J. T. K.
    Menary, S.
    Michan, J. M.
    Momose, T.
    Munich, J. J.
    Nolan, P.
    Olchanski, K.
    Olin, A.
    Pusa, P.
    Rasmussen, C. Ø.
    Robicheaux, F.
    Sacramento, R. L.
    Sameed, M.
    Sarid, E.
    Silveira, D. M.
    Stracka, S.
    Stutter, G.
    So, C.
    Tharp, T. D.
    Thompson, J. E.
    Thompson, R. I.
    van der Werf, D. P.
    Wurtele, J. S.
    Antihydrogen accumulation for fundamental symmetry tests2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 681Article in journal (Refereed)
    Abstract [en]

    Antihydrogen, a positron bound to an antiproton, is the simplest anti-atom. Its structure and properties are expected to mirror those of the hydrogen atom. Prospects for precision comparisons of the two, as tests of fundamental symmetries, are driving a vibrant programme of research. In this regard, a limiting factor in most experiments is the availability of large numbers of cold ground state antihydrogen atoms. Here, we describe how an improved synthesis process results in a maximum rate of 10.5 +/- 0.6 atoms trapped and detected per cycle, corresponding to more than an order of magnitude improvement over previous work. Additionally, we demonstrate how detailed control of electron, positron and antiproton plasmas enables repeated formation and trapping of antihydrogen atoms, with the simultaneous retention of atoms produced in previous cycles. We report a record of 54 detected annihilation events from a single release of the trapped anti-atoms accumulated from five consecutive cycles.

  • 10. Ahola, Virpi
    et al.
    Lehtonen, Rainer
    Somervuo, Panu
    Salmela, Leena
    Koskinen, Patrik
    Rastas, Pasi
    Valimaki, Niko
    Paulin, Lars
    Kvist, Jouni
    Wahlberg, Niklas
    Tanskanen, Jaakko
    Hornett, Emily A.
    Ferguson, Laura C.
    Luo, Shiqi
    Cao, Zijuan
    de Jong, Maaike A.
    Duplouy, Anne
    Smolander, Olli-Pekka
    Vogel, Heiko
    McCoy, Rajiv C.
    Qian, Kui
    Chong, Wong Swee
    Zhang, Qin
    Ahmad, Freed
    Haukka, Jani K.
    Joshi, Aruj
    Salojarvi, Jarkko
    Wheat, Christopher W.
    Stockholm University, Faculty of Science, Department of Zoology.
    Grosse-Wilde, Ewald
    Hughes, Daniel
    Katainen, Riku
    Pitkanen, Esa
    Ylinen, Johannes
    Waterhouse, Robert M.
    Turunen, Mikko
    Vaharautio, Anna
    Ojanen, Sami P.
    Schulman, Alan H.
    Taipale, Minna
    Lawson, Daniel
    Ukkonen, Esko
    Makinen, Veli
    Goldsmith, Marian R.
    Holm, Liisa
    Auvinen, Petri
    Frilander, Mikko J.
    Hanski, Ilkka
    The Glanville fritillary genome retains an ancient karyotype and reveals selective chromosomal fusions in Lepidoptera2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 4737-Article in journal (Refereed)
    Abstract [en]

    Previous studies have reported that chromosome synteny in Lepidoptera has been well conserved, yet the number of haploid chromosomes varies widely from 5 to 223. Here we report the genome (393 Mb) of the Glanville fritillary butterfly (Melitaea cinxia; Nymphalidae), a widely recognized model species in metapopulation biology and eco-evolutionary research, which has the putative ancestral karyotype of n = 31. Using a phylogenetic analyses of Nymphalidae and of other Lepidoptera, combined with orthologue-level comparisons of chromosomes, we conclude that the ancestral lepidopteran karyotype has been n = 31 for at least 140 My. We show that fusion chromosomes have retained the ancestral chromosome segments and very few rearrangements have occurred across the fusion sites. The same, shortest ancestral chromosomes have independently participated in fusion events in species with smaller karyotypes. The short chromosomes have higher rearrangement rate than long ones. These characteristics highlight distinctive features of the evolutionary dynamics of butterflies and moths.

  • 11.
    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.

    Download full text (pdf)
    FULLTEXT01
  • 12. 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.

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  • 13.
    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.

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  • 14.
    Almstedt, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Elgendy, Ramy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Hekmati, Neda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Rosén, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Wärn, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Olsen, Thale Kristin
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden..
    Dyberg, Cecilia
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden..
    Doroszko, Milena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Larsson, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Arsenian Henriksson, Marie
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Påhlman, Sven
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Bexell, Daniel
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Department of Medicine, Integrated Cardio-Metabolic Centre Single Cell Facility, Karolinska Institutet, Stockholm, Sweden..
    Kogner, Per
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden..
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Integrative discovery of treatments for high-risk neuroblastoma.2020In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, no 1, article id 71Article in journal (Refereed)
    Abstract [en]

    Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

  • 15. Amole, C.
    et al.
    Ashkezari, M. D.
    Baquero-Ruiz, M.
    Bertsche, W.
    Butler, E.
    Capra, A.
    Cesar, C. L.
    Charlton, M.
    Eriksson, S.
    Fajans, J.
    Friesen, T.
    Fujiwara, M. C.
    Gill, D. R.
    Gutierrez, A.
    Hangst, J. S.
    Hardy, W. N.
    Hayden, M. E.
    Isaac, C. A.
    Jonsell, Svante
    Stockholm University, Faculty of Science, Department of Physics.
    Kurchaninov, L.
    Little, A.
    Madsen, N.
    McKenna, J. T. K.
    Menary, S.
    Napoli, S. C.
    Nolan, P.
    Olchanski, K.
    Olin, A.
    Povilus, A.
    Pusa, P.
    Rasmussen, C. O.
    Robicheaux, F.
    Sarid, E.
    Silveira, D. M.
    So, C.
    Tharp, T. D.
    Thompson, R. I.
    van der Werf, D. P.
    Vendeiro, Z.
    Wurtele, J. S.
    Zhmoginov, A. I.
    Charman, A. E.
    An experimental limit on the charge of antihydrogen2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 3955-Article in journal (Refereed)
    Abstract [en]

    The properties of antihydrogen are expected to be identical to those of hydrogen, and any differences would constitute a profound challenge to the fundamental theories of physics. The most commonly discussed antiatom- based tests of these theories are searches for antihydrogen- hydrogen spectral differences (tests of CPT (charge- parity- time) invariance) or gravitational differences (tests of the weak equivalence principle). Here we, the ALPHA Collaboration, report a different and somewhat unusual test of CPT and of quantum anomaly cancellation. A retrospective analysis of the influence of electric fields on antihydrogen atoms released from the ALPHA trap finds a mean axial deflection of 4.1 +/- 3.4mm for an average axial electric field of 0.51Vmm1. Combined with extensive numerical modelling, this measurement leads to a bound on the charge Qe of antihydrogen of Q (+/- 1.3 +/- 1.1 +/- 0.4)10 8. Here, e is the unit charge, and the errors are from statistics and systematic effects.

  • 16.
    Andersson, David
    et al.
    Stockholm University, Faculty of Science, Department of Physics. Norwegian University of Science and Technology (NTNU), Norway.
    de Wijn, Astrid S.
    Stockholm University, Faculty of Science, Department of Physics. Norwegian University of Science and Technology (NTNU), Norway.
    Understanding the friction of atomically thin layered materials2020In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, no 1, article id 420Article in journal (Refereed)
    Abstract [en]

    Friction is a ubiquitous phenomenon that greatly affects our everyday lives and is responsible for large amounts of energy loss in industrialised societies. Layered materials such as graphene have interesting frictional properties and are often used as (additives to) lubricants to reduce friction and protect against wear. Experimental Atomic Force Microscopy studies and detailed simulations have shown a number of intriguing effects such as frictional strengthening and dependence of friction on the number of layers covering a surface. Here, we propose a simple, fundamental, model for friction on thin sheets. We use our model to explain a variety of seemingly contradictory experimental as well as numerical results. This model can serve as a basis for understanding friction on thin sheets, and opens up new possibilities for ultimately controlling their friction and wear protection.

  • 17.
    Andersson Ersman, Peter
    et al.
    RISE Acreo, Sweden.
    Lassnig, Roman
    RISE Acreo, Sweden.
    Strandberg, Jan
    RISE Acreo, Sweden.
    Tu, Deyu
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Keshmiri, Vahid
    Linköping University, Department of Electrical Engineering, Information Coding. Linköping University, Faculty of Science & Engineering.
    Forchheimer, Robert
    Linköping University, Department of Electrical Engineering, Information Coding. Linköping University, Faculty of Science & Engineering.
    Fabiano, Simone
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Gustafsson, Goran
    RISE Acreo, Sweden.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    All-printed large-scale integrated circuits based on organic electrochemical transistors2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 5053Article in journal (Refereed)
    Abstract [en]

    The communication outposts of the emerging Internet of Things are embodied by ordinary items, which desirably include all-printed flexible sensors, actuators, displays and akin organic electronic interface devices in combination with silicon-based digital signal processing and communication technologies. However, hybrid integration of smart electronic labels is partly hampered due to a lack of technology that (de)multiplex signals between silicon chips and printed electronic devices. Here, we report all-printed 4-to-7 decoders and seven-bit shift registers, including over 100 organic electrochemical transistors each, thus minimizing the number of terminals required to drive monolithically integrated all-printed electrochromic displays. These relatively advanced circuits are enabled by a reduction of the transistor footprint, an effort which includes several further developments of materials and screen printing processes. Our findings demonstrate that digital circuits based on organic electrochemical transistors (OECTs) provide a unique bridge between all-printed organic electronics (OEs) and low-cost silicon chip technology for Internet of Things applications.

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  • 18.
    Andersson Ersman, Peter
    et al.
    RISE - Research Institutes of Sweden, ICT, Acreo.
    Lassnig, Roman
    RISE - Research Institutes of Sweden, ICT, Acreo.
    Strandberg, Jan
    RISE - Research Institutes of Sweden, ICT, Acreo.
    Tu, Deyu
    Linköping University, Sweden.
    Keshmiri, Vahid
    Linköping University, Sweden.
    Forchheimer, Robert
    Linköping University, Sweden.
    Fabiano, Simone
    Linköping University, Sweden.
    Gustafsson, Göran
    RISE - Research Institutes of Sweden, ICT, Acreo.
    Berggren, Magnus
    Linköping University, Sweden.
    All-printed large-scale integrated circuits based on organic electrochemical transistors2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, no 1, article id 5053Article in journal (Refereed)
    Abstract [en]

    The communication outposts of the emerging Internet of Things are embodied by ordinary items, which desirably include all-printed flexible sensors, actuators, displays and akin organic electronic interface devices in combination with silicon-based digital signal processing and communication technologies. However, hybrid integration of smart electronic labels is partly hampered due to a lack of technology that (de)multiplex signals between silicon chips and printed electronic devices. Here, we report all-printed 4-to-7 decoders and seven-bit shift registers, including over 100 organic electrochemical transistors each, thus minimizing the number of terminals required to drive monolithically integrated all-printed electrochromic displays. These relatively advanced circuits are enabled by a reduction of the transistor footprint, an effort which includes several further developments of materials and screen printing processes. Our findings demonstrate that digital circuits based on organic electrochemical transistors (OECTs) provide a unique bridge between all-printed organic electronics (OEs) and low-cost silicon chip technology for Internet of Things applications. © 2019, The Author(s).

  • 19. Andersson, Sandra
    et al.
    Sundberg, Marten
    Pristovsek, Nusa
    Ibrahim, Ahmed
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Natl Res Ctr, Egypt.
    Jonsson, Philip
    Katona, Borbala
    Clausson, Carl-Magnus
    Zieba, Agata
    Ramstrom, Margareta
    Soderberg, Ola
    Williams, Cecilia
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. Univ Houston, USA; Karolinska Inst, Sweden.
    Asplund, Anna
    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.

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  • 20.
    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.

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  • 21. Arabi, A.
    et al.
    Ullah, K.
    Branca, R. M. M.
    Johansson, J.
    Bandarra, D.
    Haneklaus, M.
    Fu, J.
    Ariës, I.
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics (closed 20130101). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Den Boer, M. L.
    Pokrovskaja, K.
    Grandér, D.
    Xiao, G.
    Rocha, S.
    Lehtiö, J.
    Sangfelt, O.
    Proteomic screen reveals Fbw7 as a modulator of the NF-kappa B pathway2012In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 3, p. 976-Article in journal (Refereed)
    Abstract [en]

    Fbw7 is a ubiquitin-ligase that targets several oncoproteins for proteolysis, but the full range of Fbw7 substrates is not known. Here we show that by performing quantitative proteomics combined with degron motif searches, we effectively screened for a more complete set of Fbw7 targets. We identify 89 putative Fbw7 substrates, including several disease-associated proteins. The transcription factor NF-κB2 (p100/p52) is one of the candidate Fbw7 substrates. We show that Fbw7 interacts with p100 via a conserved degron and that it promotes degradation of p100 in a GSK3 2 phosphorylation-dependent manner. Fbw7 inactivation increases p100 levels, which in the presence of NF-κB pathway stimuli, leads to increased p52 levels and activity. Accordingly, the apoptotic threshold can be increased by loss of Fbw7 in a p100-dependent manner. In conclusion, Fbw7-mediated destruction of p100 is a regulatory component restricting the response to NF-κB2 pathway stimulation.

  • 22. Aragão, Luiz E. O. C.
    et al.
    Anderson, Liana O.
    Fonseca, Marisa G.
    Rosan, Thais M.
    Vedovato, Laura B.
    Wagner, Fabien H.
    Silva, Camila V. J.
    Silva Junior, Celso H. L.
    Arai, Egidio
    Aguiar, Ana P.
    Stockholm University, Faculty of Science, Stockholm Resilience Centre. National Institute for Space Research, Brazil.
    Barlow, Jos
    Berenguer, Erika
    Deeter, Merritt N.
    Domingues, Lucas G.
    Gatti, Luciana
    Gloor, Manuel
    Malhi, Yadvinder
    Marengo, Jose A.
    Miller, John B.
    Phillips, Oliver L.
    Saatchi, Sassan
    21st Century drought-related fires counteract the decline of Amazon deforestation carbon emissions2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 536Article in journal (Refereed)
    Abstract [en]

    Tropical carbon emissions are largely derived from direct forest clearing processes. Yet, emissions from drought-induced forest fires are, usually, not included in national-level carbon emission inventories. Here we examine Brazilian Amazon drought impacts on fire incidence and associated forest fire carbon emissions over the period 2003-2015. We show that despite a 76% decline in deforestation rates over the past 13 years, fire incidence increased by 36% during the 2015 drought compared to the preceding 12 years. The 2015 drought had the largest ever ratio of active fire counts to deforestation, with active fires occurring over an area of 799,293 km(2). Gross emissions from forest fires (989 +/- 504 Tg CO2 year(-1)) alone are more than half as great as those from old-growth forest deforestation during drought years. We conclude that carbon emission inventories intended for accounting and developing policies need to take account of substantial forest fire emissions not associated to the deforestation process.

  • 23.
    Arheimer, Berit
    et al.
    SMHI, Research Department, Hydrology.
    Donnelly, Chantal
    SMHI, Research Department, Hydrology.
    Lindström, Göran
    SMHI, Research Department, Hydrology.
    Regulation of snow-fed rivers affects flow regimes more than climate change2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 62Article in journal (Refereed)
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  • 24. Artiglia, Luca
    et al.
    Edebeli, Jacinta
    Orlando, Fabrizio
    Chen, Shuzhen
    Lee, Ming-Tao
    Stockholm University, Faculty of Science, Department of Physics. Paul Scherrer Institut, Switzerland.
    Arroyo, Pablo Corral
    Gilgen, Anina
    Bartels-Rausch, Thorsten
    Kleibert, Armin
    Vazdar, Mario
    Carignano, Marcelo Andres
    Francisco, Joseph S.
    Shepson, Paul B.
    Gladich, Ivan
    Ammann, Markus
    A surface-stabilized ozonide triggers bromide oxidation at the aqueous solution-vapour interface2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 700Article in journal (Refereed)
    Abstract [en]

    Oxidation of bromide in aqueous environments initiates the formation of molecular halogen compounds, which is important for the global tropospheric ozone budget. In the aqueous bulk, oxidation of bromide by ozone involves a [Br center dot OOO-] complex as intermediate. Here we report liquid jet X-ray photoelectron spectroscopy measurements that provide direct experimental evidence for the ozonide and establish its propensity for the solution-vapour interface. Theoretical calculations support these findings, showing that water stabilizes the ozonide and lowers the energy of the transition state at neutral pH. Kinetic experiments confirm the dominance of the heterogeneous oxidation route established by this precursor at low, atmospherically relevant ozone concentrations. Taken together, our results provide a strong case of different reaction kinetics and mechanisms of reactions occurring at the aqueous phase-vapour interface compared with the bulk aqueous phase.

  • 25.
    Auffret, Alistair G.
    et al.
    Stockholm University, Faculty of Science, Department of Physical Geography. Swedish University of Agricultural Sciences, Sweden; University of York, UK.
    Kimberley, Adam
    Stockholm University, Faculty of Science, Department of Physical Geography.
    Plue, Jan
    Stockholm University, Faculty of Science, Department of Physical Geography. Södertörn University, Sweden.
    Waldén, Emelie
    Stockholm University, Faculty of Science, Department of Physical Geography.
    Super-regional land-use change and effects on the grassland specialist flora2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 3464Article in journal (Refereed)
    Abstract [en]

    Habitat loss through land-use change is the most pressing threat to biodiversity worldwide. European semi-natural grasslands have suffered an ongoing decline since the early twentieth century, but we have limited knowledge of how grassland loss has affected biodiversity across large spatial scales. We quantify land-use change over 50-70 years across a 175,000 km(2) super-region in southern Sweden, identifying a widespread loss of open cover and a homogenisation of landscape structure, although these patterns vary considerably depending on the historical composition of the landscape. Analysing species inventories from 46,796 semi-natural grasslands, our results indicate that habitat loss and degradation have resulted in a decline in grassland specialist plant species. Local factors are the best predictors of specialist richness, but the historical landscape predicts present-day richness better than the contemporary landscape. This supports the widespread existence of time-lagged biodiversity responses, indicating that further species losses could occur in the future.

  • 26.
    Auffret, Alistair G.
    et al.
    Swedish University of Agricultural Sciences / Stockholm University.
    Kimberley, Adam
    Stockholm University.
    Plue, Jan
    Södertörn University, School of Natural Sciences, Technology and Environmental Studies, Environmental Science. Stockholm University.
    Waldén, Emelie
    Stockholm University.
    Super-regional land-use change and effects on the grassland specialist flora2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 3464Article in journal (Refereed)
    Abstract [en]

    Habitat loss through land-use change is the most pressing threat to biodiversity worldwide. European semi-natural grasslands have suffered an ongoing decline since the early twentieth century, but we have limited knowledge of how grassland loss has affected biodiversity across large spatial scales. We quantify land-use change over 50-70 years across a 175,000 km(2) super-region in southern Sweden, identifying a widespread loss of open cover and a homogenisation of landscape structure, although these patterns vary considerably depending on the historical composition of the landscape. Analysing species inventories from 46,796 semi-natural grasslands, our results indicate that habitat loss and degradation have resulted in a decline in grassland specialist plant species. Local factors are the best predictors of specialist richness, but the historical landscape predicts present-day richness better than the contemporary landscape. This supports the widespread existence of time-lagged biodiversity responses, indicating that further species losses could occur in the future.

  • 27. Bagnoud, Alexandre
    et al.
    Chourey, Karuna
    Hettich, Robert L.
    de Bruijn, Ino
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Andersson, Anders F.
    Leupin, Olivier X.
    Schwyn, Bernhard
    Bernier-Latmani, Rizlan
    Reconstructing a hydrogen-driven microbial metabolic network in Opalinus Clay rock2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12770Article in journal (Refereed)
    Abstract [en]

    The Opalinus Clay formation will host geological nuclear waste repositories in Switzerland. It is expected that gas pressure will build-up due to hydrogen production from steel corrosion, jeopardizing the integrity of the engineered barriers. In an in situ experiment located in the Mont Terri Underground Rock Laboratory, we demonstrate that hydrogen is consumed by microorganisms, fuelling a microbial community. Metagenomic binning and metaproteomic analysis of this deep subsurface community reveals a carbon cycle driven by autotrophic hydrogen oxidizers belonging to novel genera. Necromass is then processed by fermenters, followed by complete oxidation to carbon dioxide by heterotrophic sulfate-reducing bacteria, which closes the cycle. This microbial metabolic web can be integrated in the design of geological repositories to reduce pressure build-up. This study shows that Opalinus Clay harbours the potential for chemolithoautotrophic-based system, and provides a model of microbial carbon cycle in deep subsurface environments where hydrogen and sulfate are present.

  • 28. 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.

  • 29. Baptista, Marisa A. P.
    et al.
    Keszei, Marton
    Oliveira, Mariana
    Sunahara, Karen K. S.
    Andersson, John
    Dahlberg, Carin I. M.
    Worth, Austen J.
    Lieden, Agne
    Kuo, I-Chun
    Wallin, Robert P. A.
    Snapper, Scott B.
    Eidsmo, Liv
    Scheynius, Annika
    Karlsson, Mikael C. I.
    Bouma, Gerben
    Burns, Siobhan O.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Thrasher, Adrian J.
    Nylén, Susanne
    Westerberg, Lisa S.
    Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12175Article in journal (Refereed)
    Abstract [en]

    Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.

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  • 30. Barfuss, Wolfram
    et al.
    Donges, Jonathan F.
    Stockholm University, Faculty of Science, Stockholm Resilience Centre. Potsdam Institute for Climate Impact Research, Germany.
    Lade, Steven J.
    Stockholm University, Faculty of Science, Stockholm Resilience Centre. The Australian National University, Australia.
    Kurths, Jürgen
    When optimization for governing human-environment tipping elements is neither sustainable nor safe2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2354Article in journal (Refereed)
    Abstract [en]

    Optimizing economic welfare in environmental governance has been criticized for delivering short-term gains at the expense of long-term environmental degradation. Different from economic optimization, the concepts of sustainability and the more recent safe operating space have been used to derive policies in environmental governance. However, a formal comparison between these three policy paradigms is still missing, leaving policy makers uncertain which paradigm to apply. Here, we develop a better understanding of their interrelationships, using a stylized model of human-environment tipping elements. We find that no paradigm guarantees fulfilling requirements imposed by another paradigm and derive simple heuristics for the conditions under which these trade-offs occur. We show that the absence of such a master paradigm is of special relevance for governing real-world tipping systems such as climate, fisheries, and farming, which may reside in a parameter regime where economic optimization is neither sustainable nor safe.

  • 31. Barnes, Michele L.
    et al.
    Bodin, Örjan
    Stockholm University, Faculty of Science, Stockholm Resilience Centre.
    McClanahan, Tim R.
    Kittinger, John N.
    Hoey, Andrew S.
    Gaoue, Orou G.
    Graham, Nicholas A. J.
    Social-ecological alignment and ecological conditions in coral reefs2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 2039Article in journal (Refereed)
    Abstract [en]

    Complex social-ecological interactions underpin many environmental problems. To help capture this complexity, we advance an interdisciplinary network modeling framework to identify important relationships between people and nature that can influence environmental conditions. Drawing on comprehensive social and ecological data from five coral reef fishing communities in Kenya; including interviews with 648 fishers, underwater visual census data of reef ecosystem condition, and time-series landings data; we show that positive ecological conditions are associated with 'social-ecological network closure' - i.e., fully linked and thus closed network structures between social actors and ecological resources. Our results suggest that when fishers facing common dilemmas form cooperative communication ties with direct resource competitors, they may achieve positive gains in reef fish biomass and functional richness. Our work provides key empirical insight to a growing body of research on social-ecological alignment, and helps to advance an integrative framework that can be applied empirically in different social-ecological contexts.

  • 32.
    Barrenäs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA.
    Raehtz, Kevin
    Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA USA;Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA.
    Xu, Cuiling
    Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA.
    Law, Lynn
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA.
    Green, Richard R.
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA.
    Silvestri, Guido
    Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA;Emory Univ, Yerkes Natl Primate Res Ctr, Div Microbiol & Immunol, Atlanta, GA 30322 USA.
    Bosinger, Steven E.
    Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA;Emory Univ, Yerkes Natl Primate Res Ctr, Div Microbiol & Immunol, Atlanta, GA 30322 USA.
    Nishida, Andrew
    Univ Washington, Dept Microbiol, Seattle, WA 98195 USA.
    Li, Qingsheng
    Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE USA.
    Lu, Wuxun
    Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE USA.
    Zhang, Jianshui
    Univ Nebraska, Sch Biol Sci, Nebraska Ctr Virol, Lincoln, NE USA.
    Thomas, Matthew J.
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA.
    Chang, Jean
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA.
    Smith, Elise
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA.
    Weiss, Jeffrey M.
    Univ Washington, Dept Microbiol, Seattle, WA 98195 USA.
    Dawoud, Reem A.
    Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA.
    Richter, George H.
    Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA.
    Trichel, Anita
    Univ Pittsburgh, Div Lab Anim Resources, Pittsburgh, PA USA.
    Ma, Dongzhu
    Univ Pittsburgh, Dept Orthoped Surg, Pittsburgh, PA USA.
    Peng, Xinxia
    North Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USA.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Apetrei, Cristian
    Univ Pittsburgh, Dept Med, Div Infect Dis, Pittsburgh, PA USA;Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA.
    Pandrea, Ivona
    Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA;Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA.
    Gale, Michael, Jr.
    Univ Washington, Dept Immunol, Seattle, WA 98195 USA;Univ Washington, Ctr Innate Immun & Immune Dis, Seattle, WA 98195 USA;Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA.
    Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 5101Article in journal (Refereed)
    Abstract [en]

    Natural hosts of simian immunodeficiency virus (SIV) avoid AIDS despite lifelong infection. Here, we examined how this outcome is achieved by comparing a natural SIV host, African green monkey (AGM) to an AIDS susceptible species, rhesus macaque (RM). To asses gene expression profiles from acutely SIV infected AGMs and RMs, we developed a systems biology approach termed Conserved Gene Signature Analysis (CGSA), which compared RNA sequencing data from rectal AGM and RM tissues to various other species. We found that AGMs rapidly activate, and then maintain, evolutionarily conserved regenerative wound healing mechanisms in mucosal tissue. The wound healing protein fibronectin shows distinct tissue distribution and abundance kinetics in AGMs. Furthermore, AGM monocytes exhibit an embryonic development and repair/regeneration signature featuring TGF-beta and concomitant reduced expression of inflammatory genes compared to RMs. This regenerative wound healing process likely preserves mucosal integrity and prevents inflammatory insults that underlie immune exhaustion in RMs.

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  • 33. Bartelt, Alexander
    et al.
    John, Clara
    Schaltenberg, Nicola
    Berbee, Jimmy F. P.
    Worthmann, Anna
    Cherradi, M. Lisa
    Schlein, Christian
    Piepenburg, Julia
    Boon, Mariette R.
    Rinninger, Franz
    Heine, Markus
    Toedter, Klaus
    Niemeier, Andreas
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
    Fischer, Markus
    Wijers, Sander L.
    Lichtenbelt, Wouter van Marken
    Scheja, Ludger
    Rensen, Patrick C. N.
    Heeren, Joerg
    Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 15010Article in journal (Refereed)
    Abstract [en]

    Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE(star)3-Leiden. CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.

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  • 34.
    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.

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  • 35. Bassett, Andrew R.
    et al.
    Azzam, Ghows
    Wheatley, Lucy
    Tibbit, Charlotte
    Rajakumar, Timothy
    McGowan, Simon
    Stanger, Nathan
    Ewels, Philip Andrew
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Taylor, Stephen
    Ponting, Chris P.
    Liu, Ji-Long
    Sauka-Spengler, Tatjana
    Fulga, Tudor A.
    Understanding functional miRNA-target interactions in vivo by site-specific genome engineering2014In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 5, p. 4640-Article in journal (Refereed)
    Abstract [en]

    MicroRNA (miRNA) target recognition is largely dictated by short 'seed' sequences, and single miRNAs therefore have the potential to regulate a large number of genes. Understanding the contribution of specific miRNA-target interactions to the regulation of biological processes in vivo remains challenging. Here we use transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technologies to interrogate the functional relevance of predicted miRNA response elements (MREs) to post-transcriptional silencing in zebrafish and Drosophila. We also demonstrate an effective strategy that uses CRISPR-mediated homology-directed repair with short oligonucleotide donors for the assessment of MRE activity in human cells. These methods facilitate analysis of the direct phenotypic consequences resulting from blocking specific miRNA-MRE interactions at any point during development.

  • 36.
    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.

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  • 37. Bañó-Polo, Manuel
    et al.
    Baeza-Delgado, Carlos
    Tamborero, Silvia
    Hazel, Anthony
    Grau, Brayan
    Nilsson, IngMarie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Whitley, Paul
    Gumbart, James C.
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Mingarro, Ismael
    Transmembrane but not soluble helices fold inside the ribosome tunnel2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 5246Article in journal (Refereed)
    Abstract [en]

    Integral membrane proteins are assembled into the ER membrane via a continuous ribosome-translocon channel. The hydrophobicity and thickness of the core of the membrane bilayer leads to the expectation that transmembrane (TM) segments minimize the cost of harbouring polar polypeptide backbones by adopting a regular pattern of hydrogen bonds to form a-helices before integration. Co-translational folding of nascent chains into an a-helical conformation in the ribosomal tunnel has been demonstrated previously, but the features governing this folding are not well understood. In particular, little is known about what features influence the propensity to acquire a-helical structure in the ribosome. Using in vitro translation of truncated nascent chains trapped within the ribosome tunnel and molecular dynamics simulations, we show that folding in the ribosome is attained for TM helices but not for soluble helices, presumably facilitating SRP (signal recognition particle) recognition and/or a favourable conformation for membrane integration upon translocon entry.

  • 38.
    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.

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  • 39.
    Belonoshko, Anatoly B.
    et al.
    Royal Inst Technol KTH, Sweden.
    Fu, Jie
    Ningbo Univ, Peoples R China.
    Bryk, Taras
    Natl Acad Sci Ukraine, Ukraine.
    Simak, Sergey
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, Faculty of Science & Engineering.
    Mattesini, Maurizio
    Univ Complutense Madrid, Spain; UCM, Spain.
    Low viscosity of the Earths inner core2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 2483Article in journal (Refereed)
    Abstract [en]

    The Earths solid inner core is a highly attenuating medium. It consists mainly of iron. The high attenuation of sound wave propagation in the inner core is at odds with the widely accepted paradigm of hexagonal close-packed phase stability under inner core conditions, because sound waves propagate through the hexagonal iron without energy dissipation. Here we show by first-principles molecular dynamics that the body-centered cubic phase of iron, recently demonstrated to be thermodynamically stable under the inner core conditions, is considerably less elastic than the hexagonal phase. Being a crystalline phase, the body-centered cubic phase of iron possesses the viscosity close to that of a liquid iron. The high attenuation of sound in the inner core is due to the unique diffusion characteristic of the body-centered cubic phase. The low viscosity of iron in the inner core enables the convection and resolves a number of controversies.

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  • 40.
    Belonoshko, Anatoly
    et al.
    KTH, School of Engineering Sciences (SCI), Physics, Condensed Matter Theory.
    Fu, Jie
    Ningbo Univ, Dept Phys, Fac Sci, Ningbo 315211, Zhejiang, Peoples R China..
    Bryk, Taras
    Natl Acad Sci Ukraine, Inst Condensed Matter Phys, UA-79011 Lvov, Ukraine..
    Simak, Sergei, I
    Linkoping Univ, Dept Phys Chem & Biol IFM, SE-58183 Linkoping, Sweden..
    Mattesini, Maurizio
    Univ Complutense Madrid, Dept Earths Phys & Astrophys, E-28040 Madrid, Spain.;UCM, CSIC, Fac Ciencias Fis, Inst Geociencias, Plaza Ciencias 1, Madrid 28040, Spain..
    Low viscosity of the Earth's inner core2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 2483Article in journal (Refereed)
    Abstract [en]

    The Earth's solid inner core is a highly attenuating medium. It consists mainly of iron. The high attenuation of sound wave propagation in the inner core is at odds with the widely accepted paradigm of hexagonal close-packed phase stability under inner core conditions, because sound waves propagate through the hexagonal iron without energy dissipation. Here we show by first-principles molecular dynamics that the body-centered cubic phase of iron, recently demonstrated to be thermodynamically stable under the inner core conditions, is considerably less elastic than the hexagonal phase. Being a crystalline phase, the body-centered cubic phase of iron possesses the viscosity close to that of a liquid iron. The high attenuation of sound in the inner core is due to the unique diffusion characteristic of the body-centered cubic phase. The low viscosity of iron in the inner core enables the convection and resolves a number of controversies.

  • 41. Belotelov, V. I.
    et al.
    Kreilkamp, L. E.
    Akimov, I. A.
    Kalish, A. N.
    Bykov, D. A.
    Kasture, S.
    Yallapragada, V. J.
    Gopal, Achanta Venu
    Grishin, Alexander M.
    KTH, School of Information and Communication Technology (ICT), Integrated Devices and Circuits.
    Khartsev, Sergiy I.
    KTH, School of Information and Communication Technology (ICT), Integrated Devices and Circuits.
    Nur-E-Alam, M.
    Vasiliev, M.
    Doskolovich, L. L.
    Yakovlev, D. R.
    Alameh, K.
    Zvezdin, A. K.
    Bayer, M.
    Plasmon-mediated magneto-optical transparency2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 2128-Article in journal (Refereed)
    Abstract [en]

    Magnetic field control of light is among the most intriguing methods for modulation of light intensity and polarization on sub-nanosecond timescales. The implementation in nanostructured hybrid materials provides a remarkable increase of magneto-optical effects. However, so far only the enhancement of already known effects has been demonstrated in such materials. Here we postulate a novel magneto-optical phenomenon that originates solely from suitably designed nanostructured metal-dielectric material, the so-called magneto-plasmonic crystal. In this material, an incident light excites coupled plasmonic oscillations and a waveguide mode. An in-plane magnetic field allows excitation of an orthogonally polarized waveguide mode that modifies optical spectrum of the magneto-plasmonic crystal and increases its transparency. The experimentally achieved light intensity modulation reaches 24%. As the effect can potentially exceed 100%, it may have great importance for applied nanophotonics. Further, the effect allows manipulating and exciting waveguide modes by a magnetic field and light of proper polarization.

  • 42. Bergkvist, Johanna
    et al.
    Klawonn, Isabell
    Whitehouse, Martin J.
    Swedish Museum of Natural History, Department of Geology.
    Lavik, Gaute
    Brüchert, Volker
    Ploug, Helle
    Turbulence simultaneously stimulates small- and large-scale CO2 sequestration by chain-forming diatoms in the sea2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1Article in journal (Refereed)
    Abstract [en]

    Chain-forming diatoms are key CO2-fixing organisms in the ocean. Under turbulent conditions they form fast-sinking aggregates that are exported from the upper sunlit ocean to the ocean interior. A decade-old paradigm states that primary production in chain-forming diatoms is stimulated by turbulence. Yet, direct measurements of cell-specific primary production in individual field populations of chain-forming diatoms are poorly documented. Here we measured cell-specific carbon, nitrate and ammonium assimilation in two field populations of chain-forming diatoms (Skeletonema and Chaetoceros) at low-nutrient concentrations under still conditions and turbulent shear using secondary ion mass spectrometry combined with stable isotopic tracers and compared our data with those predicted by mass transfer theory. Turbulent shear significantly increases cell-specific C assimilation compared to still conditions in the cells/chains that also form fast-sinking, aggregates rich in carbon and ammonium. Thus, turbulence simultaneously stimulates small-scale biological CO2 assimilation and large-scale biogeochemical C and N cycles in the ocean.

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  • 43. Bergkvist, Johanna
    et al.
    Klawonn, Isabell
    Stockholm University, Faculty of Science, Department of Ecology, Environment and Plant Sciences.
    Whitehouse, Martin J.
    Stockholm University, Faculty of Science, Department of Geological Sciences. Swedish Museum of Natural History, Sweden.
    Lavik, Gaute
    Brüchert, Volker
    Stockholm University, Faculty of Science, Department of Geological Sciences.
    Ploug, Helle
    Turbulence simultaneously stimulates small-and large-scale CO2 sequestration by chain-forming diatoms in the sea2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 3046Article in journal (Refereed)
    Abstract [en]

    Chain-forming diatoms are key CO2-fixing organisms in the ocean. Under turbulent conditions they form fast-sinking aggregates that are exported from the upper sunlit ocean to the ocean interior. A decade-old paradigm states that primary production in chain-forming diatoms is stimulated by turbulence. Yet, direct measurements of cell-specific primary production in individual field populations of chain-forming diatoms are poorly documented. Here we measured cell-specific carbon, nitrate and ammonium assimilation in two field populations of chain-forming diatoms (Skeletonema and Chaetoceros) at low-nutrient concentrations under still conditions and turbulent shear using secondary ion mass spectrometry combined with stable isotopic tracers and compared our data with those predicted by mass transfer theory. Turbulent shear significantly increases cell-specific C assimilation compared to still conditions in the cells/chains that also form fast-sinking, aggregates rich in carbon and ammonium. Thus, turbulence simultaneously stimulates small-scale biological CO2 assimilation and large-scale biogeochemical C and N cycles in the ocean.

  • 44. Berglund, Emelie
    et al.
    Maaskola, Jonas
    Schultz, Niklas
    Friedrich, Stefanie
    Marklund, Maja
    Bergenstråhle, Joseph
    Tarish, Firas
    Tanoglidi, Anna
    Vickovic, Sanja
    Larsson, Ludvig
    Salmeń, Fredrik
    Ogris, Christoph
    Wallenborg, Karolina
    Lagergren, Jens
    Sonnhammer, Erik
    Helleday, Thomas
    Lundeberg, Joakim
    Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1Article 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 micro- environment. 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.

  • 45.
    Berglund, Emelie
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Maaskola, Jonas
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Schultz, Niklas
    Friedrich, Stefanie
    Marklund, Maja
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Bergenstrahle, Joseph
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Tarish, Firas
    Tanoglidi, Anna
    Vickovic, Sanja
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Larsson, Ludvig
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology.
    Salmén, Fredrik
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Ogris, Christoph
    Wallenborg, Karolina
    Lagergren, Jens
    KTH, School of Electrical Engineering and Computer Science (EECS), Computational Science and Technology (CST).
    Ståhl, Patrik
    Sonnhammer, Erik
    Helleday, Thomas
    Lundeberg, Joakim
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    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.

  • 46.
    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.

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  • 47. Berglund, Emelie
    et al.
    Maaskola, Jonas
    Schultz, Niklas
    Friedrich, Stefanie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Marklund, Maja
    Bergenstråhle, Joseph
    Tarish, Firas
    Tanoglidi, Anna
    Vickovic, Sanja
    Larsson, Ludvig
    Salmén, Fredrik
    Ogris, Christoph
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wallenborg, Karolina
    Lagergren, Jens
    Ståhl, Patrik
    Sonnhammer, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Helleday, Thomas
    Lundeberg, Joakim
    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.

  • 48.
    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.

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  • 49.
    Berntsson, Ronnie P. A.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Peng, Lisheng
    Dong, Min
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Structure of dual receptor binding to botulinum neurotoxin B2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 2058-Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins are highly toxic, and bind two receptors to achieve their high affinity and specificity for neurons. Here we present the first structure of a botulinum neurotoxin bound to both its receptors. We determine the 2.3-angstrom structure of a ternary complex of botulinum neurotoxin type B bound to both its protein receptor synaptotagmin II and its ganglioside receptor GD1a. We show that there is no direct contact between the two receptors, and that the binding affinity towards synaptotagmin II is not influenced by the presence of GD1a. The interactions of botulinum neurotoxin type B with the sialic acid 5 moiety of GD1a are important for the ganglioside selectivity. The structure demonstrates that the protein receptor and the ganglioside receptor occupy nearby but separate binding sites, thus providing two independent anchoring points.

  • 50.
    Bian, Qingzhen
    et al.
    Linkoping Univ, Dept Phys Chem & Biol IFM, S-58183 Linkoping, Sweden..
    Ma, Fei
    Lund Univ, Div Chem Phys, S-22100 Lund, Sweden..
    Chen, Shula
    Linkoping Univ, Dept Phys Chem & Biol IFM, S-58183 Linkoping, Sweden..
    Wei, Qi
    Univ Macau, Inst Appl Phys & Mat Engn, Macau, Peoples R China..
    Su, Xiaojun
    Lund Univ, Div Chem Phys, S-22100 Lund, Sweden..
    Buyanova, Irina A.
    Linkoping Univ, Dept Phys Chem & Biol IFM, S-58183 Linkoping, Sweden..
    Chen, Weimin M.
    Linkoping Univ, Dept Phys Chem & Biol IFM, S-58183 Linkoping, Sweden..
    Ponseca, Carlito S.
    Linkoping Univ, Dept Phys Chem & Biol IFM, S-58183 Linkoping, Sweden..
    Linares, Mathieu
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Karki, Khadga J.
    Lund Univ, Div Chem Phys, S-22100 Lund, Sweden..
    Yartsev, Arkady
    Lund Univ, Div Chem Phys, S-22100 Lund, Sweden..
    Inganas, Olle
    Linkoping Univ, Dept Phys Chem & Biol IFM, S-58183 Linkoping, Sweden..
    Vibronic coherence contributes to photocurrent generation in organic semiconductor heterojunction diodes2020In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, no 1, article id 617Article in journal (Refereed)
    Abstract [en]

    Charge separation dynamics after the absorption of a photon is a fundamental process relevant both for photosynthetic reaction centers and artificial solar conversion devices. It has been proposed that quantum coherence plays a role in the formation of charge carriers in organic photovoltaics, but experimental proofs have been lacking. Here we report experimental evidence of coherence in the charge separation process in organic donor/acceptor heterojunctions, in the form of low frequency oscillatory signature in the kinetics of the transient absorption and nonlinear two-dimensional photocurrent spectroscopy. The coherence plays a decisive role in the initial 200 femtoseconds as we observe distinct experimental signatures of coherent photocurrent generation. This coherent process breaks the energy barrier limitation for charge formation, thus competing with excitation energy transfer. The physics may inspire the design of new photovoltaic materials with high device performance, which explore the quantum effects in the next-generation optoelectronic applications.

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