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  • 51.
    Brænne, Ingrid
    et al.
    University of Lübeck, Institute for Cardiogeneticss; DZHK (German Research Center for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel; University Heart Center Lübeck.
    Willenborg, Christina
    University of Lübeck, Institute for Cardiogeneticss.
    Tragante, Vinicius
    University Medical Center Utrecht, Division Heart and Lungs, Department of Cardiology.
    Kessler, Thorsten
    Technische Universität München, Deutsches Herzzentrum München.
    Zeng, Lingyao
    Technische Universität München, Deutsche s Herzzentrum München.
    Reiz, Benedikt
    University of Lübeck, Institute for Cardiogeneticss; DZHK (German Research Center for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel; University Heart Center Lübeck.
    Kleinecke, Mariana
    University of Lübeck, Institute for Cardiogeneticss; DZHK (German Research Center for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel; University Heart Center Lübeck.
    von Ameln, Simon
    Technische Universität München, Deutsches Herzzentrum München.
    Willer, Cristen J.
    University of Michigan, Dept of Biostatistics.
    Laakso, Markku
    University of Eastern Finland and Kuopio University Hospital, Internal Medicine, Institute of Clinical Medicine.
    Wild, Philipp S.
    University Medical Center Mainz, Preventive Cardiology and Preventive Medicine; University Medical Center Mainz, Center for Thrombosis and Hemostasis; DZHK (German Center for Cardiovascular Research), Partner Site RhineMain.
    Zeller, Tanja
    DZHK (German Research Center for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel; University Heart Center Hamburg-Eppendorf, Department of General and Interventional Cardiology .
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Franks, Paul W.
    Lund University, Skåne University Hospital Malmö, Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit .
    Salomaa, Veikko
    THL-National Institute for Health and Welfare, POB 30, Mannerheimintie 166, FI-00271, Helsinki.
    Dehghan, Abbas
    Erasmus University Medical Center, Department of Epidemiology.
    Meitinger, Thomas
    Erasmus University Medical Center, Department of Epidemiology; German Research Center for Environmental Health, Helmholtz Zentrum München, Institute of Human Genetics; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance; Technische Universität München, Institute of Human Genetics.
    Samani, Nilesh J.
    University of Leicester, Deparment of Cardiovascular Sciences; Glenfield Hospital, NIHR Leicester Cardiovascular Biomedical Research Unit.
    Asselbergs, Folkert W.
    University Medical Center Utrecht, Division Heart and Lungs, Department of Cardiology; University College London, Faculty of Population Health Science, Institute of Cardiovascular Science .
    Erdmann, Jeanette
    University of Lübeck, Institute for Cardiogeneticss; DZHK (German Research Center for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel; University Heart Center Lübeck.
    Schunkert, Heribert
    Technische Universität München, Deutsches Herzzentrum München; German Research Center for Environmental Health, Helmholtz Zentrum München, Institute of Human Genetics.
    A genomic exploration identifies mechanisms that may explain adverse cardiovascular effects of COX-2 inhibitors2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 10252Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 x 10(-5) (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.

  • 52.
    Buck, Moritz
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Nilsson, Louise K. J.
    Swedish Univ Agr Sci SLU, Dept Ecol, S-75007 Uppsala, Sweden..
    Brunius, Carl
    Swedish Univ Agr Sci SLU, Dept Food Sci, S-75007 Uppsala, Sweden..
    Dabire, Roch K.
    Inst Rech Sci Sante, Ctr Muraz, O1 BP 390, Bobo Dioulasso 01, Burkina Faso..
    Hopkins, Richard
    Swedish Univ Agr Sci SLU, Dept Ecol, S-75007 Uppsala, Sweden.;Univ Greenwich, Nat Resources Inst, Cent Ave, Chatham ME4 4TB, Kent, England..
    Terenius, Olle
    Swedish Univ Agr Sci SLU, Dept Ecol, S-75007 Uppsala, Sweden..
    Bacterial associations reveal spatial population dynamics in Anopheles gambiae mosquitoes2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22806Article in journal (Refereed)
    Abstract [en]

    The intolerable burden of malaria has for too long plagued humanity and the prospect of eradicating malaria is an optimistic, but reachable, target in the 21st century. However, extensive knowledge is needed about the spatial structure of mosquito populations in order to develop effective interventions against malaria transmission. We hypothesized that the microbiota associated with a mosquito reflects acquisition of bacteria in different environments. By analyzing the whole-body bacterial flora of An. gambiae mosquitoes from Burkina Faso by 16 S amplicon sequencing, we found that the different environments gave each mosquito a specific bacterial profile. In addition, the bacterial profiles provided precise and predicting information on the spatial dynamics of the mosquito population as a whole and showed that the mosquitoes formed clear local populations within a meta-population network. We believe that using microbiotas as proxies for population structures will greatly aid improving the performance of vector interventions around the world.

  • 53.
    Buck, Moritz
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Nilsson, Louise K. J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Swedish Univ Agr Sci SLU, Dept Ecol, S-75007 Uppsala, Sweden..
    Brunius, Carl
    Swedish Univ Agr Sci SLU, Dept Food Sci, S-75007 Uppsala, Sweden..
    Dabire, Roch K.
    Inst Rech Sci Sante, Ctr Muraz, O1 BP 390, Bobo Dioulasso 01, Burkina Faso..
    Hopkins, Richard
    Swedish Univ Agr Sci SLU, Dept Ecol, S-75007 Uppsala, Sweden.;Univ Greenwich, Nat Resources Inst, Cent Ave, Chatham ME4 4TB, Kent, England..
    Terenius, Olle
    Swedish Univ Agr Sci SLU, Dept Ecol, S-75007 Uppsala, Sweden..
    Bacterial associations reveal spatial population dynamics in Anopheles gambiae mosquitoes2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22806Article in journal (Refereed)
    Abstract [en]

    The intolerable burden of malaria has for too long plagued humanity and the prospect of eradicating malaria is an optimistic, but reachable, target in the 21st century. However, extensive knowledge is needed about the spatial structure of mosquito populations in order to develop effective interventions against malaria transmission. We hypothesized that the microbiota associated with a mosquito reflects acquisition of bacteria in different environments. By analyzing the whole-body bacterial flora of An. gambiae mosquitoes from Burkina Faso by 16 S amplicon sequencing, we found that the different environments gave each mosquito a specific bacterial profile. In addition, the bacterial profiles provided precise and predicting information on the spatial dynamics of the mosquito population as a whole and showed that the mosquitoes formed clear local populations within a meta-population network. We believe that using microbiotas as proxies for population structures will greatly aid improving the performance of vector interventions around the world.

  • 54.
    Budd, David A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Troll, Valentin R.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics. Ist Nazl Geofis & Vulcanol, Rome, Italy.
    Deegan, Frances M.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics. Swedish Museum Nat Hist, Dept Geosci, Stockholm, Sweden.
    Jolis, Ester
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Smith, Victoria
    Research Laboratory for Archaeology and the History of Art, University of Oxford, Oxford, UK.
    Whitehouse, Martin
    Department of Geosciences, Swedish Museum of Natural History, Stockholm, Sweden.
    Harris, Chris
    Department of Geological Sciences, University of Cape Town, South Africa.
    Freda, Carmela
    Istituto Nazionale di Geofisica e Vulcanologia, Rome, Italy.
    Hilton, David
    Scripps Institution of Oceanography, University of California, San Diego, USA.
    Halldórsson, Sæmundur
    Scripps Institution of Oceanography, University of California, San Diego, USA; Univ Iceland, Inst Earth Sci, Reykjavik, Iceland.
    Bindeman, Ilya
    Department of Geological Sciences, University of Oregon, Oregon, USA.
    Magma reservoir dynamics at Toba caldera, Indonesia, recorded by oxygen isotope zoning in quartz2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 40624Article in journal (Refereed)
    Abstract [en]

    Quartz is a common phase in high-silica igneous rocks and is resistant to post-eruptive alteration, thus offering a reliable record of magmatic processes in silicic magma systems. Here we employ the 75 ka Toba super-eruption as a case study to show that quartz can resolve late-stage temporal changes in magmatic δ18O values. Overall, Toba quartz crystals exhibit comparatively high δ18O values, up to 10.2‰, due to magma residence within, and assimilation of, local granite basement. However, some 40% of the analysed quartz crystals display a decrease in δ18O values in outermost growth zones compared to their cores, with values as low as 6.7‰ (maximum ∆core−rim = 1.8‰). These lower values are consistent with the limited zircon record available for Toba, and the crystallisation history of Toba quartz traces an influx of a low-δ18O component into the magma reservoir just prior to eruption. Here we argue that this late-stage low-δ18O component is derived from hydrothermally-altered roof material. Our study demonstrates that quartz isotope stratigraphy can resolve magmatic events that may remain undetected by whole-rock or zircon isotope studies, and that assimilation of altered roof material may represent a viable eruption trigger in large Toba-style magmatic systems.

  • 55.
    Buntin, Sebastian
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Geophysics.
    Malehmir, Alireza
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Geophysics.
    Koyi, Hemin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Högdahl, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Malinowski, Michal
    Polish Acad Sci, Inst Geophys, Warsaw, Poland.
    Larsson, Sven Ake
    Gothenburg Univ, Earth Sci Ctr, Dept Geol, Gothenburg, Sweden.
    Thybo, Hans
    Istanbul Tech Univ, Eurasia Inst Earth Sci, Istanbul, Turkey.
    Juhlin, Christopher
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Geophysics.
    Korja, Annakaisa
    Univ Helsinki, Inst Seismol, Helsinki, Finland.
    Gorszczyk, Andrzej
    Polish Acad Sci, Inst Geophys, Warsaw, Poland.
    Emplacement and 3D geometry of crustal-scale saucer-shaped intrusions in the Fennoscandian Shield2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 10498Article in journal (Refereed)
    Abstract [en]

    Saucer-shaped intrusions of tens of meters to tens of kilometres across have been observed both from surface geological mapping and geophysical observations. However, there is only one location where they have been reported to extend c. 100 km laterally, and emplaced both in a sedimentary basin and the crystalline basement down to 12 km depth. The legacy BABEL offshore seismic data, acquired over the central Fennoscandian Shield in 1989, have been recovered and reprocessed with the main goal of focusing on this series of globally unique crustal-scale saucer-shaped intrusions present onshore and offshore below the Bothnian Sea. The intrusions (c. 1.25 Ga), emplaced in an extensional setting, are observed within both sedimentary rocks (<1.5 Ga) and in the crystalline basement (>1.5 Ga). They have oval shapes with diameters ranging 30-100 km. The reprocessed seismic data provide evidence of up-doming of the lower crust (representing the melt reservoir) below the intrusions that, in turn, are observed at different depths in addition to a steep seismically transparent zone interpreted to be a discordant feeder dyke system. Relative age constraints and correlation with onshore saucer-shaped intrusions of different size suggest that they are internally connected and fed by each other from deeper to shallower levels. We argue for a nested emplacement mechanism and against a controlling role by the overlying sedimentary basin as the saucer-shaped intrusions are emplaced in both the sedimentary rocks as well as in the underlying crystalline basement. The interplay between magma pressure and overburden pressure, as well as the, at the time, ambient stress regime, are responsible for their extensive extent and rather constant thicknesses (c. 100-300 m). Saucer-shaped intrusions may therefore be present elsewhere in the crystalline basement to the same extent as observed in this study some of which are a significant source of raw materials.

  • 56.
    Burchardt, Steffi
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Solid Earth Geology.
    Troll, Valentin R.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Solid Earth Geology.
    Mathieu, Lucie
    Emeleus, Henry C.
    Donaldson, Colin H.
    Ardnamurchan 3D cone-sheet architecture explained by a single elongate magma chamber2013In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3, p. 2891-Article in journal (Refereed)
    Abstract [en]

    The Palaeogene Ardnamurchan central igneous complex, NW Scotland, was a defining place for the development of the classic concepts of cone-sheet and ring-dyke emplacement and has thus fundamentally influenced our thinking on subvolcanic structures. We have used the available structural information on Ardnamurchan to project the underlying three-dimensional (3D) cone-sheet structure. Here we show that a single elongate magma chamber likely acted as the source of the cone-sheet swarm(s) instead of the traditionally accepted model of three successive centres. This proposal is supported by the ridge-like morphology of the Ardnamurchan volcano and is consistent with the depth and elongation of the gravity anomaly underlying the peninsula. Our model challenges the traditional model of cone-sheet emplacement at Ardnamurchan that involves successive but independent centres in favour of a more dynamical one that involves a single, but elongate and progressively evolving magma chamber system.

  • 57.
    Burchardt, Steffi
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Troll, Valentin R.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Schmeling, Harro
    Goethe Univ Frankfurt, Fac Earth Sci, Altenhoferallee 1, D-60438 Frankfurt, Germany..
    Koyi, Hemin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Blythe, Lara
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Solid Earth Geology.
    Erupted frothy xenoliths may explain lack of country-rock fragments in plutons2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 34566Article in journal (Refereed)
    Abstract [en]

    Magmatic stoping is discussed to be a main mechanism of magma emplacement. As a consequence of stoping, abundant country-rock fragments should occur within, and at the bottom of, magma reservoirs as "xenolith graveyards", or become assimilated. However, the common absence of sufficient amounts of both xenoliths and crustal contamination have led to intense controversy about the efficiency of stoping. Here, we present new evidence that may explain the absence of abundant country-rock fragments in plutons. We report on vesiculated crustal xenoliths in volcanic rocks that experienced devolatilisation during heating and partial melting when entrained in magma. We hypothesise that the consequential inflation and density decrease of the xenoliths allowed them to rise and become erupted instead of being preserved in the plutonic record. Our thermomechanical simulations of this process demonstrate that early-stage xenolith sinking can be followed by the rise of a heated, partially-molten xenolith towards the top of the reservoir. There, remnants may disintegrate and mix with resident magma or erupt. Shallow-crustal plutons emplaced into hydrous country rocks may therefore not necessarily contain evidence of the true amount of magmatic stoping during their emplacement. Further studies are needed to quantify the importance of frothy xenolith in removing stoped material.

  • 58.
    Burgos-Parra, E.
    et al.
    Univ Exeter, Coll Engn Math & Phys Sci, Exeter EX4 4QL, Devon, England.
    Bukin, N.
    Univ Exeter, Coll Engn Math & Phys Sci, Exeter EX4 4QL, Devon, England.
    Sani, S.
    KTH Royal Inst Technol, Sch Engn Sci, Dept Mat & Nanophys, Kista, Sweden.
    Figueroa, A. I.
    Diamond Light Source, Magnet Spect Grp, Didcot, Oxon, England.
    Beutier, G.
    Univ Grenoble Alpes, CNRS, Genoble INP, SIMaP, Grenoble, France.
    Dupraz, M.
    Univ Grenoble Alpes, CNRS, Genoble INP, SIMaP, Grenoble, France.
    Chung, Sunjae
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy. Univ Gothenburg, Dept Phys, Gothenburg, Sweden; KTH Royal Inst Technol, Sch Engn Sci, Dept Mat & Nanophys, Kista, Sweden.
    Duerrenfeld, P.
    Univ Gothenburg, Dept Phys, Gothenburg, Sweden.
    Le, Q. Tuan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy. Univ Gothenburg, Dept Phys, Gothenburg, Sweden.
    Mohseni, S. M.
    Shahid Beheshti Univ, Fac Phys, Tehran, Iran.
    Houshang, A.
    NanOsc AB, Electrum 205, Kista, Sweden; Univ Gothenburg, Dept Phys, Gothenburg, Sweden.
    Cavill, S. A.
    Univ York, Dept Phys, York, N Yorkshire, England.
    Hicken, R. J.
    Univ Exeter, Coll Engn Math & Phys Sci, Exeter EX4 4QL, Devon, England.
    Akerman, J.
    NanOsc AB, Electrum 205, Kista, Sweden; Univ Gothenburg, Dept Phys, Gothenburg, Sweden; KTH Royal Inst Technol, Sch Engn Sci, Dept Mat & Nanophys, Kista, Sweden.
    van der Laan, G.
    Diamond Light Source, Magnet Spect Grp, Didcot, Oxon, England.
    Ogrin, F. Y.
    Univ Exeter, Coll Engn Math & Phys Sci, Exeter EX4 4QL, Devon, England.
    Investigation of magnetic droplet solitons using x-ray holography with extended references2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 11533Article in journal (Refereed)
    Abstract [en]

    A dissipative magnetic soliton, or magnetic droplet, is a structure that has been predicted to exist within a thin magnetic layer when non-linearity is balanced by dispersion, and a driving force counteracts the inherent damping of the spin precession. Such a soliton can be formed beneath a nano-contact (NC) that delivers a large spin-polarized current density into a magnetic layer with perpendicular magnetic anisotropy. Although the existence of droplets has been confirmed from electrical measurements and by micromagnetic simulations, only a few attempts have been made to directly observe the magnetic landscape that sustains these structures, and then only for a restricted set of experimental parameter values. In this work we use and x-ray holography technique HERALDO, to image the magnetic structure of the [ Co/ Ni] x4 multilayer within a NC orthogonal pseudo spin-valve, for different range of magnetic fields and injected electric currents. The magnetic configuration imaged at -33 mA and 0.3 T for devices with 90 nm NC diameter reveals a structure that is within the range of current where the droplet soliton exist based on our electrical measurements and have it is consistent with the expected size of the droplet (similar to 100 nm diameter) and its spatial position within the sample. We also report the magnetisation configurations observed at lower DC currents in the presence of fields (0-50 mT), where it is expected to observe regimes of the unstable droplet formation.

  • 59.
    Buzzi, Michele
    et al.
    Paul Scherrer Inst, CH-5232 Villigen, Switzerland..
    Makita, Mikako
    Paul Scherrer Inst, CH-5232 Villigen, Switzerland..
    Howald, Ludovic
    Paul Scherrer Inst, CH-5232 Villigen, Switzerland..
    Kleibert, Armin
    Paul Scherrer Inst, CH-5232 Villigen, Switzerland..
    Vodungbo, Boris
    Ecole Polytech, CNRS, UMR 7639, Lab Opt Appl,ENSTA ParisTech, Chemin Huniere, F-91761 Palaiseau, France.;UPMC Univ Paris 06, Sorbonne Univ, CNRS, LCPMR, F-75005 Paris, France..
    Maldonado, Pablo
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Raabe, Jörg
    Paul Scherrer Inst, CH-5232 Villigen, Switzerland..
    Jaouen, Nicolas
    Synchrotron SOLEIL, BP 48, F-91192 Gif Sur Yvette, France..
    Redlin, Harald
    DESY, HASYLAB, Notkestr 85, D-22607 Hamburg, Germany..
    Tiedtke, Kai
    DESY, HASYLAB, Notkestr 85, D-22607 Hamburg, Germany..
    Oppeneer, Peter M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    David, Christian
    Paul Scherrer Inst, CH-5232 Villigen, Switzerland..
    Nolting, Frithjof
    Paul Scherrer Inst, CH-5232 Villigen, Switzerland..
    Luning, Jan
    UPMC Univ Paris 06, Sorbonne Univ, CNRS, LCPMR, F-75005 Paris, France.;Synchrotron SOLEIL, BP 48, F-91192 Gif Sur Yvette, France..
    Single-shot Monitoring of Ultrafast Processes via X-ray Streaking at a Free Electron Laser2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 7253Article in journal (Refereed)
    Abstract [en]

    The advent of x-ray free electron lasers has extended the unique capabilities of resonant x-ray spectroscopy techniques to ultrafast time scales. Here, we report on a novel experimental method that allows retrieving with a single x-ray pulse the time evolution of an ultrafast process, not only at a few discrete time delays, but continuously over an extended time window. We used a single x-ray pulse to resolve the laser-induced ultrafast demagnetisation dynamics in a thin cobalt film over a time window of about 1.6 ps with an excellent signal to noise ratio. From one representative single shot measurement we extract a spin relaxation time of (130 +/- 30) fs with an average value, based on 193 single shot events of (113 +/- 20) fs. These results are limited by the achieved experimental time resolution of 120 fs, and both values are in excellent agreement with previous results and theoretical modelling. More generally, this new experimental approach to ultrafast x-ray spectroscopy paves the way to the study of non-repetitive processes that cannot be investigated using traditional repetitive pump-probe schemes.

  • 60.
    Bychkov, Dmitrii
    et al.
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland..
    Linder, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland..
    Turkki, Riku
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland..
    Nordling, Stig
    Univ Helsinki, Dept Pathol, Med, Helsinki, Finland..
    Kovanen, Panu E.
    Univ Helsinki, Dept Pathol, Helsinki, Finland.;Helsinki Univ Hosp, HUSLAB, Helsinki, Finland..
    Verrill, Clare
    Univ Oxford, Nuffield Dept Surg Sci, NIHR Oxford Biomed Res Ctr, Oxford, England..
    Walliander, Margarita
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland..
    Lundin, Mikael
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland..
    Haglund, Caj
    Univ Helsinki, Dept Surg, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Translat Canc Biol, Helsinki, Finland..
    Lundin, Johan
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki Inst Life Sci HiLIFE, Helsinki, Finland.;Karolinska Inst, Dept Publ Hlth Sci, Global Hlth IHCAR, Stockholm, Sweden..
    Deep learning based tissue analysis predicts outcome in colorectal cancer2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 3395Article in journal (Refereed)
    Abstract [en]

    Image-based machine learning and deep learning in particular has recently shown expert-level accuracy in medical image classification. In this study, we combine convolutional and recurrent architectures to train a deep network to predict colorectal cancer outcome based on images of tumour tissue samples. The novelty of our approach is that we directly predict patient outcome, without any intermediate tissue classification. We evaluate a set of digitized haematoxylin-eosin-stained tumour tissue microarray (TMA) samples from 420 colorectal cancer patients with clinicopathological and outcome data available. The results show that deep learning-based outcome prediction with only small tissue areas as input outperforms (hazard ratio 2.3; CI 95% 1.79-3.03; AUC 0.69) visual histological assessment performed by human experts on both TMA spot (HR 1.67; CI 95% 1.28-2.19; AUC 0.58) and whole-slide level (HR 1.65; CI 95% 1.30-2.15; AUC 0.57) in the stratification into low-and high-risk patients. Our results suggest that state-of-the-art deep learning techniques can extract more prognostic information from the tissue morphology of colorectal cancer than an experienced human observer.

  • 61.
    Bysani, Madhusudhan
    et al.
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Agren, Rasmus
    Chalmers Univ Technol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol & Biol Engn, Gothenburg, Sweden.
    Davegardh, Cajsa
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Volkov, Petr
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Ronn, Tina
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Unneberg, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bacos, Karl
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Ling, Charlotte
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    ATAC-seq reveals alterations in open chromatin in pancreatic islets from subjects with type 2 diabetes2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7785Article in journal (Refereed)
    Abstract [en]

    Impaired insulin secretion from pancreatic islets is a hallmark of type 2 diabetes (T2D). Altered chromatin structure may contribute to the disease. We therefore studied the impact of T2D on open chromatin in human pancreatic islets. We used assay for transposase-accessible chromatin using sequencing (ATAC-seq) to profile open chromatin in islets from T2D and non-diabetic donors. We identified 57,105 and 53,284 ATAC-seq peaks representing open chromatin regions in islets of nondiabetic and diabetic donors, respectively. The majority of ATAC-seq peaks mapped near transcription start sites. Additionally, peaks were enriched in enhancer regions and in regions where islet-specific transcription factors (TFs), e.g. FOXA2, MAFB, NKX2.2, NKX6.1 and PDX1, bind. Islet ATAC-seq peaks overlap with 13 SNPs associated with T2D (e.g. rs7903146, rs2237897, rs757209, rs11708067 and rs878521 near TCF7L2, KCNQ1, HNF1B, ADCY5 and GCK, respectively) and with additional 67 SNPs in LD with known T2D SNPs (e.g. SNPs annotated to GIPR, KCNJ11, GLIS3, IGF2BP2, FTO and PPARG). There was enrichment of open chromatin regions near highly expressed genes in human islets. Moreover, 1,078 open chromatin peaks, annotated to 898 genes, differed in prevalence between diabetic and non-diabetic islet donors. Some of these peaks are annotated to candidate genes for T2D and islet dysfunction (e.g. HHEX, HMGA2, GLIS3, MTNR1B and PARK2) and some overlap with SNPs associated with T2D (e.g. rs3821943 near WFS1 and rs508419 near ANK1). Enhancer regions and motifs specific to key TFs including BACH2, FOXO1, FOXA2, NEUROD1, MAFA and PDX1 were enriched in differential islet ATAC-seq peaks of T2D versus non-diabetic donors. Our study provides new understanding into how T2D alters the chromatin landscape, and thereby accessibility for TFs and gene expression, in human pancreatic islets.

  • 62.
    Cai, Ruibo
    et al.
    Beijing Forestry Univ, Coll Nat Conservat, Beijing, Peoples R China..
    Shafer, Aaron B. A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Laguardia, Alice
    Beijing Forestry Univ, Coll Nat Conservat, Beijing, Peoples R China..
    Lin, Zhenzhen
    Chinese Acad Sci, Inst Zool, Key Lab Anim Ecol & Conservat Biol, Beijing, Peoples R China..
    Liu, Shuqiang
    Beijing Forestry Univ, Coll Nat Conservat, Beijing, Peoples R China..
    Hu, Defu
    Beijing Forestry Univ, Coll Nat Conservat, Beijing, Peoples R China..
    Recombination and selection in the major histocompatibility complex of the endangered forest musk deer (Moschus berezovskii)2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 17285Article in journal (Refereed)
    Abstract [en]

    The forest musk deer (Moschus berezovskii) is a high elevation species distributed across western China and northern Vietnam. Once abundant, habitat loss and poaching has led to a dramatic decrease in population numbers prompting the IUCN to list the species as endangered. Here, we characterized the genetic diversity of a Major Histocompatibility Complex (MHC) locus and teased apart driving factors shaping its variation. Seven DRB exon 2 alleles were identified among a group of randomly sampled forest musk deer from a captive population in the Sichuan province of China. Compared to other endangered or captive ungulates, forest musk deer have relatively low levels of MHC genetic diversity. Non-synonymous substitutions primarily occurred in the putative peptide-binding region (PBR), with analyses suggesting that recombination and selection has shaped the genetic diversity across the locus. Specifically, inter-allelic recombination generated novel allelic combinations, with evidence for both positive selection acting on the PBR and negative selection on the non-PBR. An improved understanding of functional genetic variability of the MHC will facilitate better design and management of captive breeding programs for this endangered species.

  • 63.
    Campeau, Audrey
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Wallin, Marcus
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Giesler, Reiner
    Climate Impacts Research Centre, Department of Ecology and Environmental Science, Umeå University, Abisko, Sweden.
    Löfgren, Stefan
    Department of Aquatic Sciences and Assessment, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Mörth, Carl-Magnus
    Geology and Geochemistry, Stockholm University, Stockholm, Sweden.
    Schiff, Sherry
    Department of Earth and Environmental Sciences, University of Waterloo, Waterloo, Ontario, Canada.
    Venkiteswaran, Jason
    Department of Geography and Environmental Studies, Wilfrid Laurier University, Waterloo, Ontario, Canada.
    Bishop, Kevin
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL. Department of Aquatic Sciences and Assessment, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Multiple sources and sinks of dissolved inorganic carbon across Swedish streams, refocusing the lens of stable C isotopes2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 9158Article in journal (Refereed)
    Abstract [en]

    It is well established that stream dissolved inorganic carbon (DIC) fluxes play a central role in the global C cycle, yet the sources of stream DIC remain to a large extent unresolved. Here, we explore large-scale patterns in delta C-13-DIC from streams across Sweden to separate and further quantify the sources and sinks of stream DIC. We found that stream DIC is governed by a variety of sources and sinks including biogenic and geogenic sources, CO2 evasion, as well as in-stream processes. Although soil respiration was the main source of DIC across all streams, a geogenic DIC influence was identified in the northernmost region. All streams were affected by various degrees of atmospheric CO2 evasion, but residual variance in delta C-13-DIC also indicated a significant influence of in-stream metabolism and anaerobic processes. Due to those multiple sources and sinks, we emphasize that simply quantifying aquatic DIC fluxes will not be sufficient to characterise their role in the global C cycle.

  • 64.
    Cappel, Ute B.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics. Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England.;Univ London Imperial Coll Sci Technol & Med, Dept Phys, London SW7 2AZ, England..
    Moia, Davide
    Univ London Imperial Coll Sci Technol & Med, Dept Phys, London SW7 2AZ, England..
    Bruno, Annalisa
    Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England.;Italian Natl Agcy New Technol Energy & Sustainabl, Naples, Italy.;Energy Res Inst NTU ERI N, Res Techno Plaza,X Frontier Block,Level 5, Singapore 637553, Singapore..
    Vaissier, Valerie
    MIT, Dept Chem, 77 Massachusetts Ave, Cambridge, MA 02139 USA..
    Haque, Saif A.
    Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England..
    Barnes, Piers R. F.
    Univ London Imperial Coll Sci Technol & Med, Dept Phys, London SW7 2AZ, England..
    Evidence for photo-induced charge separation between dye molecules adsorbed to aluminium oxide surfaces2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 21276Article in journal (Refereed)
    Abstract [en]

    Excited state dynamics and photo-induced charge transfer of dye molecules have been widely studied due to their relevance for organic and dye-sensitised solar cells. Herein, we present a femtosecond transient absorption spectroscopy study of the indolene dye D131 when adsorbed to inert Al2O3 substrates for different surface concentration of the dye. Surprisingly, we find that at high surface concentrations, the first singlet excited state of the dye is converted into a new state with an efficiency of about 80%. We assign the absorption features of this state to the oxidised dye and discuss the possibility of photo-induced charge separation between neighboring dye molecules. Our study is the first to show that this process can be highly efficient without the use of donor and acceptor molecules of different chemical structures.

  • 65.
    Cardias, R.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. Fed Univ Para, Fac Fis, Belem, PA, Brazil.
    Szilva, Attila
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Bergman, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Di Marco, Igor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Katsnelson, M. I.
    Radboud Univ Nijmegen, Inst Mol & Mat, Heijendaalseweg 135, NL-6525 AJ Nijmegen, Netherlands.;Ural Fed Univ, Theoret Phys & Appl Math Dept, Mira Str 19, Ekaterinburg 620002, Russia..
    Lichtenstein, A. I.
    Ural Fed Univ, Theoret Phys & Appl Math Dept, Mira Str 19, Ekaterinburg 620002, Russia.;Univ Hamburg, Inst Theoret Phys, Jungiusstrasse 9, D-20355 Hamburg, Germany..
    Nordström, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Klautau, A. B.
    Fed Univ Para, Fac Fis, Belem, PA, Brazil..
    Eriksson, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Kvashnin, Yaroslav O.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    The Bethe-Slater curve revisited; new insights from electronic structure theory2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 4058Article in journal (Refereed)
    Abstract [en]

    The Bethe-Slater (BS) curve describes the relation between the exchange coupling and interatomic distance. Based on a simple argument of orbital overlaps, it successfully predicts the transition from antiferromagnetism to ferromagnetism, when traversing the 3d series. In a previous article [Phys. Rev. Lett. 116, 217202 (2016)] we reported that the dominant nearestneighbour (NN) interaction for 3d metals in the bcc structure indeed follows the BS curve, but the trends through the series showed a richer underlying physics than was initially assumed. The orbital decomposition of the inter-site exchange couplings revealed that various orbitals contribute to the exchange interactions in a highly non-trivial and sometimes competitive way. In this communication we perform a deeper analysis by comparing 3d metals in the bcc and fcc structures. We find that there is no coupling between the E-g orbitals of one atom and T-2g orbitals of its NNs, for both cubic phases. We demonstrate that these couplings are forbidden by symmetry and formulate a general rule allowing to predict when a similar situation is going to happen. In gamma-Fe, as in alpha-Fe, we find a strong competition in the symmetry-resolved orbital contributions and analyse the differences between the high-spin and low-spin solutions.

  • 66.
    Carlsson Almlöf, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sylwan, Lina
    Karolinska Inst, Dept Biosci & Nutr, Sci Life Lab SciLifeLab, Solna, Sweden..
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Padyukov, Leonid
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Bengtsson, Christine
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Jonsen, Andreas
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Dahlqvist, Solbritt Rantapaa
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Sjowall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, AIR Rheumatol, Linkoping, Sweden..
    Bengtsson, Anders A.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Novel risk genes for systemic lupus erythematosus predicted by random forest classification2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6236Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

  • 67.
    Carthy, Jon M.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Imperial Coll London, Fac Med, Div Brain Sci, London, England..
    Stoeter, Martin
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Bellomo, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Vanlandewijck, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Angelos
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moren, Anita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Kardassis, Dimitris
    Univ Crete, Sch Med, Dept Biochem, Iraklion 71003, Crete, Greece..
    Gahman, Timothy C.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Shiau, Andrew K.
    Ludwig Inst Canc Res, Small Mol Discovery Program, La Jolla, CA 92093 USA..
    Bickle, Marc
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Zerial, Marino
    Max Planck Inst Mol Cell Biol & Genet, Dresden, Germany..
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 29868Article in journal (Refereed)
    Abstract [en]

    Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition. In addition to TGF-beta receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked alpha-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-beta-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-beta-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer.

  • 68. Carthy, Jonathon
    Bellomo, Claudia ()
    Vanlandewijck, Michael ()
    Heldin, Angelos ()
    Moren, Anita ()
    Kardassis, Dimitri ()
    Gahman, Timothy ()
    Shiau, Andrew ()
    Bickle, Marc ()
    Zerial, Marino ()
    Heldin, Carl-Henrik ()
    Moustakas, Aristidis ()
    Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myo broblast di erentiation2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Refereed)
  • 69.
    Cat, Aurelie Nguyen Dinh
    et al.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Callera, Glaucia E.
    Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Friederich, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.
    Sanchez, Ana
    Univ Complutense, Fac Farm, Dept Fisiol, Madrid, Spain..
    Dulak-Lis, Maria Gabriela
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Tsiropoulou, Sofia
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    Montezano, Augusto C.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland..
    He, Ying
    Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Briones, Ana M.
    Univ Autonoma Madrid, CIBER Enfermedades Cardiovasc, Sch Med, Dept Pharmacol, Madrid, Spain..
    Jaisser, Frederic
    Ctr Rech Cordeliers, INSERM Team 1 1138, Paris, France..
    Touyz, Rhian M.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Glasgow, Lanark, Scotland.;Univ Ottawa, Ottawa Hosp, Res Inst, Kidney Res Ctr, Ottawa, ON, Canada..
    Vascular dysfunction in obese diabetic db/db mice involves the interplay between aldosterone/mineralocorticoid receptor and Rho kinase signaling2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 2952Article in journal (Refereed)
    Abstract [en]

    Activation of aldosterone/mineralocorticoid receptors (MR) has been implicated in vascular dysfunction of diabetes. Underlying mechanisms are elusive. Therefore, we investigated the role of Rho kinase (ROCK) in aldosterone/MR signaling and vascular dysfunction in a model of diabetes. Diabetic obese mice (db/db) and control counterparts (db/+) were treated with MR antagonist (MRA, potassium canrenoate, 30 mg/kg/day, 4 weeks) or ROCK inhibitor, fasudil (30 mg/kg/day, 3 weeks). Plasma aldosterone was increased in db/db versus db/+. This was associated with enhanced vascular MR signaling. Norepinephrine (NE)-induced contraction was increased in arteries from db/db mice. These responses were attenuated in mice treated with canrenoate or fasudil. Db/db mice displayed hypertrophic remodeling and increased arterial stiffness, improved by MR blockade. Vascular calcium sensitivity was similar between depolarized arteries from db/+ and db/db. Vascular hypercontractility in db/db mice was associated with increased myosin light chain phosphorylation and reduced expression of PKG-1 alpha. Vascular RhoA/ROCK signaling and expression of pro-inflammatory and pro-fibrotic markers were exaggerated in db/db mice, effects that were attenuated by MRA. Fasudil, but not MRA, improved vascular insulin sensitivity in db/db mice, evidenced by normalization of Irs1 phosphorylation. Our data identify novel pathways involving MR-RhoA/ROCK-PKG-1 that underlie vascular dysfunction and injury in diabetic mice.

  • 70.
    Cavalli, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baltzer, Nicholas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Umer, Husen Muhammad
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Grau, Jan
    Martin Luther Univ Halle Wittenberg, Inst Comp Sci, Halle, Germany.
    Lemnian, Ioana
    Martin Luther Univ Halle Wittenberg, Inst Comp Sci, Halle, Germany.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallerman, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Spalinskas, Rapolas
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden.
    Sahlen, Pelin
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden.
    Grosse, Ivo
    Martin Luther Univ Halle Wittenberg, Inst Comp Sci, Halle, Germany;German Ctr Integrat Biodivers Res iDiv, Leipzig, Germany.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Allele specific chromatin signals, 3D interactions, and motif predictions for immune and B cell related diseases2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 2695Article in journal (Refereed)
    Abstract [en]

    Several Genome Wide Association Studies (GWAS) have reported variants associated to immune diseases. However, the identified variants are rarely the drivers of the associations and the molecular mechanisms behind the genetic contributions remain poorly understood. ChIP-seq data for TFs and histone modifications provide snapshots of protein-DNA interactions allowing the identification of heterozygous SNPs showing significant allele specific signals (AS-SNPs). AS-SNPs can change a TF binding site resulting in altered gene regulation and are primary candidates to explain associations observed in GWAS and expression studies. We identified 17,293 unique AS-SNPs across 7 lymphoblastoid cell lines. In this set of cell lines we interrogated 85% of common genetic variants in the population for potential regulatory effect and we identified 237 AS-SNPs associated to immune GWAS traits and 714 to gene expression in B cells. To elucidate possible regulatory mechanisms we integrated long-range 3D interactions data to identify putative target genes and motif predictions to identify TFs whose binding may be affected by AS-SNPs yielding a collection of 173 AS-SNPs associated to gene expression and 60 to B cell related traits. We present a systems strategy to find functional gene regulatory variants, the TFs that bind differentially between alleles and novel strategies to detect the regulated genes.

  • 71.
    Chang, Bo
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Shah, Ali
    Aalto University.
    Zhou, Quan
    Aalto University.
    Ras, Robin
    Aalto University.
    Hjort, Klas
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Microsystems Technology.
    Self-transport and self-alignment of microchips using microscopic rain2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 14966Article in journal (Refereed)
    Abstract [en]

    Alignment of microchips with receptors is an important process step in the construction of integrated micro- and nanosystems for emerging technologies, and facilitating alignment by spontaneous self-assembly processes is highly desired. Previously, capillary self-alignment of microchips driven by surface tension effects on patterned surfaces has been reported, where it was essential for microchips to have sufficient overlap with receptor sites. Here we demonstrate for the first time capillary self-transport and self-alignment of microchips, where microchips are initially placed outside the corresponding receptor sites and can be self-transported by capillary force to the receptor sites followed by self-alignment. The surface consists of hydrophilic silicon receptor sites surrounded by superhydrophobic black silicon. Rain-induced microscopic droplets are used to form the meniscus for the self-transport and self-alignment. The boundary conditions for the self-transport have been explored by modeling and confirmed experimentally. The maximum permitted gap between a microchip and a receptor site is determined by the volume of the liquid and by the wetting contrast between receptor site and substrate. Microscopic rain applied on hydrophilic-superhydrophobic patterned surfaces greatly improves the capability, reliability and error-tolerance of the process, avoiding the need for accurate initial placement of microchips, and thereby greatly simplifying the alignment process.

  • 72.
    Chen, Siyi
    et al.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, 1E Kent Ridge Rd,NUHS Tower Block,Level 10, Singapore 119228, Singapore..
    Larsson, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore..
    Robinson, Robert C.
    ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 138673, Singapore.;Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore.;Nanyang Technol Univ, NTU Inst Struct Biol, 59 Nanyang Dr, Singapore 636921, Singapore..
    Chen, Swaine L.
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, 1E Kent Ridge Rd,NUHS Tower Block,Level 10, Singapore 119228, Singapore.;Genome Inst Singapore, GERMS, 60 Biopolis St,Genome 02-01, Singapore 138672, Singapore.;Genome Inst Singapore, Infect Dis Grp, 60 Biopolis St,Genome 02-01, Singapore 138672, Singapore..
    Direct and convenient measurement of plasmid stability in lab and clinical isolates of E-coli2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 4788Article in journal (Refereed)
    Abstract [en]

    Plasmids are important mobile elements in bacteria, contributing to evolution, virulence, and antibiotic resistance. Natural plasmids are generally large and maintained at low copy number and thus prone to be lost. Therefore, dedicated plasmid maintenance systems have evolved, leading to plasmid loss rates as low as 1 per 107 divisions. These low rates complicate studies of plasmid loss, as traditional techniques for measuring plasmid loss are laborious and not quantitative. To overcome these limitations, we leveraged a stringent negative selection system to develop a method for performing direct, quantitative measurements of plasmid loss in E. coli. We applied our method to gain mechanistic insights into a heterologously reconstituted segregation system in lab strains and clinical isolates of E. coli. We also performed direct stability studies of a currently circulating resistance plasmid in a clinical isolate, strain EC958, which is a member of the rapidly expanding global ST131 E. coli clone. Our results establish the foundational assays required to screen for small molecules targeting plasmid stability, which could complement current strategies for reducing the spread of antibiotic resistance, complementing other strategies for treating antibiotic resistant bacteria.

  • 73.
    Cheng, Xinlai
    et al.
    Institut für Pharmazie und Molekulare Biotechnologie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
    Peuckert, Christiane
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Wölfl, Stefan
    Institut für Pharmazie und Molekulare Biotechnologie, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
    Essential role of mitochondrial Stat3 in p38MAPK mediated apoptosis under oxidative stress2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 15388Article in journal (Refereed)
    Abstract [en]

    Stat3 is an oncogene, frequently associated with malignant transformation. A body of evidence implicates that phospho-Stat3(Y705) contributes to its nucleic translocation, while phospho-Stat3(S727) leads to the accumulation in mitochondria. Both are of importance for tumor cell proliferation. In comparison to well-characterized signaling pathways interplaying with Stat3(Y705), little is known about Stat3(S727). In this work, we studied the influence of Stat3 deficiency on the viability of cells exposed to H2O2 or hypoxia using siRNA and CRISPR/Cas9 genome-editing. We found dysregulation of mitochondrial activity, which was associated with excessive ROS formation and reduced mitochondrial membrane potential, and observed a synergistic effect for oxidative stress-mediated apoptosis in Stat3-KD cells or cells carrying Stat3(Y705F), but not Stat3(S727D), suggesting the importance of functional mitochondrial Stat3 in this context. We also found that ROS-mediated activation of ASK1/p38(MAPK) was involved and adding antioxidants, p38(MAPK) inhibitor, or genetic repression of ASK1 could easily rescue the cellular damage. Our finding reveals a new role of mitochondrial Stat3 in preventing ASK1/p38(MAPK)-mediated apoptosis, wich further support the notion that selective inhibition mitochondrial Stat3 could provide a primsing target for chemotherapy.

  • 74. Chi Fru, Ernest
    et al.
    Arvestål, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Palaeobiology.
    Callac, Nolwenn
    El Albani, Abderrazak
    Kilias, Stephanos
    Argyraki, Ariadne
    Jakobsson, Martin
    Arsenic stress after the Proterozoic glaciations2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 17789Article in journal (Refereed)
    Abstract [en]

    Protection against arsenic damage in organisms positioned deep in the tree of life points to early evolutionary sensitization. Here, marine sedimentary records reveal a Proterozoic arsenic concentration patterned to glacial-interglacial ages. The low glacial and high interglacial sedimentary arsenic concentrations, suggest deteriorating habitable marine conditions may have coincided with atmospheric oxygen decline after ~2.1 billion years ago. A similar intensification of near continental margin sedimentary arsenic levels after the Cryogenian glaciations is also associated with amplified continental weathering. However, interpreted atmospheric oxygen increase at this time, suggests that the marine biosphere had widely adapted to the reorganization of global marine elemental cycles by glaciations. Such a glacially induced biogeochemical bridge would have produced physiologically robust communities that enabled increased oxygenation of the ocean-atmosphere system and the radiation of the complex Ediacaran-Cambrian life.

  • 75.
    Chiavaroli, Valentina
    et al.
    Liggins Institute, University of Auckland, Auckland, New Zealand.
    Cutfield, Wayne S
    Liggins Institute, University of Auckland, Auckland, New Zealand.
    Derraik, José G. B.
    Liggins Institute, University of Auckland, Auckland, New Zealand.
    Pan, Zengxiang
    Liggins Institute, University of Auckland, Auckland, New Zealand.
    Ngo, Sherry
    Liggins Institute, University of Auckland, Auckland, New Zealand.
    Sheppard, Allan
    Liggins Institute, University of Auckland, Auckland, New Zealand.
    Craigie, Susan
    Liggins Institute, University of Auckland, Auckland, New Zealand.
    Stone, Peter
    Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
    Sadler, Lynn
    National Women's Health, Auckland District Health Board, Auckland, New Zealand.
    Ahlsson, Fredrik
    Liggins Institute, University of Auckland, New Zealand.
    Infants born large-for-gestational-age display slower growth in early infancy, but no epigenetic changes at birth2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 14540Article in journal (Refereed)
    Abstract [en]

    We evaluated the growth patterns of infants born large-for-gestational-age (LGA) from birth to age 1 year compared to those born appropriate-for-gestational-age (AGA). In addition, we investigated possible epigenetic changes associated with being born LGA. Seventy-one newborns were classified by birth weight as AGA (10(th)-90(th) percentile; n = 42) or LGA (>90(th) percentile; n = 29). Post-natal follow-up until age 1 year was performed with clinical assessments at 3, 6, and 12 months. Genome-wide DNA methylation was analysed on umbilical tissue in 19 AGA and 27 LGA infants. At birth, LGA infants had greater weight (p < 0.0001), length (p < 0.0001), ponderal index (p = 0.020), as well as greater head (p < 0.0001), chest (p = 0.044), and abdominal (p = 0.007) circumferences than AGA newborns. LGA infants were still larger at the age of 3 months, but by age 6 months there were no more differences between groups, due to higher length and weight increments in AGA infants between 0 and 6 months (p < 0.0001 and p = 0.002, respectively). Genome-wide analysis showed no epigenetic differences between LGA and AGA infants. Overall, LGA infants had slower growth in early infancy, being anthropometrically similar to AGA infants by 6 months of age. In addition, differences between AGA and LGA newborns were not associated with epigenetic changes.

  • 76.
    Chiavaroli, Valentina
    et al.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Hopkins, Sarah A.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Derraik, Jose G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, A Better Start Natl Sci Challenge, Auckland, New Zealand.
    Biggs, Janene B.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Rodrigues, Raquel O.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Brennan, Christine H.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Seneviratne, Sumudu N.
    Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Colombo, Dept Paediat, Fac Med, Colombo, Sri Lanka.
    Higgins, Chelsea
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Baldi, James C.
    Univ Otago, Dunedin Sch Med, Dept Med, Dunedin, New Zealand.
    McCowan, Lesley M. E.
    Univ Auckland, Dept Obstet & Gynaecol, Fac Med & Hlth Sci, Auckland, New Zealand.
    Cutfield, Wayne S.
    Univ Auckland, Liggins Inst, Auckland, New Zealand;Univ Auckland, A Better Start Natl Sci Challenge, Auckland, New Zealand.
    Hofman, Paul L.
    Univ Auckland, Liggins Inst, Auckland, New Zealand.
    Exercise in pregnancy: 1-year and 7-year follow-ups of mothers and offspring after a randomized controlled trial2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12915Article in journal (Refereed)
    Abstract [en]

    There are limited data on long-term outcomes of mothers or their offspring following exercise interventions during pregnancy. We assessed long-term effects of an exercise intervention (home-based stationary cycling) between 20-36 weeks of gestation on anthropometry and body composition in mothers and offspring after 1 and 7 years. 84 women were randomised to intervention or usual activity, with follow-up data available for 61 mother-child pairs (38 exercisers) at 1 year and 57 (33 exercisers) at 7 years. At 1 year, there were no observed differences in measured outcomes between mothers and offspring in the two groups. At the 7-year follow-up, mothers were mostly similar, except that exercisers had lower systolic blood pressure (-6.2 mmHg; p = 0.049). However, offspring of mothers who exercised during pregnancy had increased total body fat (+3.2%; p = 0.034) and greater abdominal (+4.1% android fat; p = 0.040) and gynoid (+3.5% gynoid fat; p = 0.042) adiposity compared with controls. Exercise interventions beginning during pregnancy may be beneficial to long-term maternal health. However, the initiation of exercise during pregnancy amongst sedentary mothers may be associated with adverse effects in the offspring during childhood. Larger follow-up studies are required to investigate long-term effects of exercise in pregnancy.

  • 77. Choudhury, D.
    et al.
    Pal, B.
    Sharma, A.
    Bhat, S. V.
    Sarma, Dipankar Das
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Magnetization in electron- and Mn- doped SrTiO32013In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3, p. 1433-Article in journal (Refereed)
    Abstract [en]

    Mn- doped SrTiO3.0, when synthesized free of impurities, is a paramagnetic insulator with interesting dielectric properties. Since delocalized charge carriers are known to promote ferromagnetism in a large number of systems via diverse mechanisms, we have looked for the possibility of any intrinsic, spontaneous magnetization by simultaneous doping of Mn ions and electrons into SrTiO3 via oxygen vacancies, thereby forming SrTi1-xMnxO3-delta, to the extent of making the doped system metallic. We find an absence of any enhancement of the magnetization in the metallic sample when compared with a similarly prepared Mn doped, however, insulating sample. Our results, thus, are not in agreement with a recent observation of a weak ferromagnetism in metallic Mn doped SrTiO3 system.

  • 78.
    Clausson, Carl-Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Ishaq, Omer
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Klaesson, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kühnemund, Malte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Grannas, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Koos, Björn
    Qian, Xiaoyan
    Ranefall, Petter
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Krzywkowski, Tomasz
    Brismar, Hjalmar
    Nilsson, Mats
    Wählby, Carolina
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Compaction of rolling circle amplification products increases signal integrity and signal–to–noise ratio2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 12317:1-10, article id 12317Article in journal (Refereed)
  • 79. Cojoc, Gheorghe
    et al.
    Florescu, Ana-Maria
    Krull, Alexander
    Klemm, Anna H
    Pavin, Nenad
    Jülicher, Frank
    Tolić, Iva M
    Paired arrangement of kinetochores together with microtubule pivoting and dynamics drive kinetochore capture in meiosis I.2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25736Article in journal (Refereed)
    Abstract [en]

    Kinetochores are protein complexes on the chromosomes, whose function as linkers between spindle microtubules and chromosomes is crucial for proper cell division. The mechanisms that facilitate kinetochore capture by microtubules are still unclear. In the present study, we combine experiments and theory to explore the mechanisms of kinetochore capture at the onset of meiosis I in fission yeast. We show that kinetochores on homologous chromosomes move together, microtubules are dynamic and pivot around the spindle pole, and the average capture time is 3-4 minutes. Our theory describes paired kinetochores on homologous chromosomes as a single object, as well as angular movement of microtubules and their dynamics. For the experimentally measured parameters, the model reproduces the measured capture kinetics and shows that the paired configuration of kinetochores accelerates capture, whereas microtubule pivoting and dynamics have a smaller contribution. Kinetochore pairing may be a general feature that increases capture efficiency in meiotic cells.

  • 80.
    Conradson, Steven D.
    et al.
    Synchrotron Soleil, Orme Merisiers St Aubin, F-91192 Gif Sur Yvette, France..
    Gilbertson, Steven M.
    Los Alamos Natl Lab, Los Alamos, NM 87545 USA..
    Daifuku, Stephanie L.
    Univ Rochester, Dept Chem, Rochester, NY 14627 USA..
    Kehl, Jeffrey A.
    Univ Rochester, Dept Chem, Rochester, NY 14627 USA..
    Durakiewicz, Tomasz
    Los Alamos Natl Lab, Los Alamos, NM 87545 USA..
    Andersson, David A.
    Los Alamos Natl Lab, Los Alamos, NM 87545 USA..
    Bishop, Alan R.
    Los Alamos Natl Lab, Los Alamos, NM 87545 USA..
    Byler, Darrin D.
    Los Alamos Natl Lab, Los Alamos, NM 87545 USA..
    Maldonado, Pablo
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Oppeneer, Peter M.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Valdez, James A.
    Los Alamos Natl Lab, Los Alamos, NM 87545 USA..
    Neidig, Michael L.
    Univ Rochester, Dept Chem, Rochester, NY 14627 USA..
    Rodriguez, George
    Los Alamos Natl Lab, Los Alamos, NM 87545 USA..
    Possible Demonstration of a Polaronic Bose-Einstein(-Mott) Condensate in UO2(+x) by Ultrafast THz Spectroscopy and Microwave Dissipation2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15278Article in journal (Refereed)
    Abstract [en]

    Bose-Einstein condensates (BECs) composed of polarons would be an advance because they would combine coherently charge, spin, and a crystal lattice. Following our earlier report of unique structural and spectroscopic properties, we now identify potentially definitive evidence for polaronic BECs in photo-and chemically doped UO2(+x) on the basis of exceptional coherence in the ultrafast time dependent terahertz absorption and microwave spectroscopy results that show collective behavior including dissipation patterns whose precedents are condensate vortex and defect disorder and condensate excitations. That some of these signatures of coherence in an atom-based system extend to ambient temperature suggests a novel mechanism that could be a synchronized, dynamical, disproportionation excitation, possibly via the solid state analog of a Feshbach resonance that promotes the coherence. Such a mechanism would demonstrate that the use of ultra-low temperatures to establish the BEC energy distribution is a convenience rather than a necessity, with the actual requirement for the particles being in the same state that is not necessarily the ground state attainable by other means. A macroscopic quantum object created by chemical doping that can persist to ambient temperature and resides in a bulk solid would be revolutionary in a number of scientific and technological fields.

  • 81. Costa, MS
    Afonso, TB
    Freitas, S
    Preto, M
    Lopes, Viviana
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Vasconcelos, V
    Magalhães, C
    Leão, PN
    The conifer biomarkers dehydroabietic and abietic acids are widespread in Cyanobacteria2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 23436Article in journal (Refereed)
    Abstract [en]

    Terpenes, a large family of natural products with important applications, are commonly associated with plants and fungi. The diterpenoids dehydroabietic and abietic acids are defense metabolites abundant in resin, and are used as biomarkers for conifer plants. We report here for the first time that the two diterpenoid acids are produced by members of several genera of cyanobacteria. Dehydroabietic acid was isolated from two cyanobacterial strains and its identity was confirmed spectroscopically. One or both of the diterpenoids were detected in the cells of phylogenetically diverse cyanobacteria belonging to four cyanobacterial 'botanical orders', from marine, estuarine and inland environments. Dehydroabietic acid was additionally found in culture supernatants. We investigated the natural role of the two resin acids in cyanobacteriausing ecologically-relevant bioassays and found that the compounds inhibited the growth of a small coccoid cyanobacterium. The unexpected discovery of dehydroabietic and abietic acids in a wide range of cyanobacteria has implications for their use as plant biomarkers.

  • 82.
    Couto, Rafael C.
    et al.
    Royal Inst Technol, Sch Biotechnol, Theoret Chem & Biol, S-10691 Stockholm, Sweden.;Univ Fed Goias, Inst Quim, Campus Samambaia,CP 131, BR-74001970 Goiania, Go, Brazil..
    Guarise, Marco
    Lab Nacl Luz Sincrotron, BR-10000 Campinas, Brazil.;Univ Paris 06, Univ Paris 04, Lab Chim Phys Matiere & Rayonnement, UMR7614, F-75005 Paris, France..
    Nicolaou, Alessandro
    Synchrotron SOLEIL, BP 48, F-91192 Gif Sur Yvette, France..
    Jaouen, Nicolas
    Synchrotron SOLEIL, BP 48, F-91192 Gif Sur Yvette, France..
    Chiuzbaian, Gheorghe S.
    Univ Paris 06, Univ Paris 04, Lab Chim Phys Matiere & Rayonnement, UMR7614, F-75005 Paris, France..
    Luening, Jan
    Univ Paris 06, Univ Paris 04, Lab Chim Phys Matiere & Rayonnement, UMR7614, F-75005 Paris, France..
    Ekholm, Victor
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Rubensson, Jan-Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Sathe, Conny
    Lund Univ, MAX Lab 4, Box 118, S-22100 Lund, Sweden..
    Hennies, Franz
    Lund Univ, MAX Lab 4, Box 118, S-22100 Lund, Sweden..
    Kimberg, Victor
    Royal Inst Technol, Sch Biotechnol, Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Guimaraes, Freddy F.
    Univ Fed Goias, Inst Quim, Campus Samambaia,CP 131, BR-74001970 Goiania, Go, Brazil..
    Agren, Hans
    Royal Inst Technol, Sch Biotechnol, Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Gel'mukhanov, Faris
    Royal Inst Technol, Sch Biotechnol, Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Journel, Loic
    Univ Paris 06, Univ Paris 04, Lab Chim Phys Matiere & Rayonnement, UMR7614, F-75005 Paris, France..
    Simon, Marc
    Univ Paris 06, Univ Paris 04, Lab Chim Phys Matiere & Rayonnement, UMR7614, F-75005 Paris, France..
    Anomalously strong two-electron one-photon X-ray decay transitions in CO caused by avoided crossing2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 20947Article in journal (Refereed)
    Abstract [en]

    The unique opportunity to study and control electron-nuclear quantum dynamics in coupled potentials offered by the resonant inelastic X-ray scattering (RIXS) technique is utilized to unravel an anomalously strong two-electron one-photon transition from core-excited to Rydberg final states in the CO molecule. High-resolution RIXS measurements of CO in the energy region of 12-14 eV are presented and analyzed by means of quantum simulations using the wave packet propagation formalism and ab initio calculations of potential energy curves and transition dipole moments. The very good overall agreement between the experimental results and the theoretical predictions allows an in-depth interpretation of the salient spectral features in terms of Coulomb mixing of "dark" with "bright" final states leading to an effective two-electron one-photon transition. The present work illustrates that the improved spectral resolution of RIXS spectra achievable today may call for more advanced theories than what has been used in the past.

  • 83.
    Dabrowski, Michal J.
    et al.
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Draminski, Michal
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Diamanti, Klev
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Stepniak, Karolina
    Nencki Inst Expt Biol, Warsaw, Poland..
    Mozolewska, Magdalena A.
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Teisseyre, Pawel
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Koronacki, Jacek
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Kaminska, Bozena
    Nencki Inst Expt Biol, Warsaw, Poland..
    Wojtas, Bartosz
    Nencki Inst Expt Biol, Warsaw, Poland..
    Unveiling new interdependencies between significant DNA methylation sites, gene expression profiles and glioma patients survival2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4390Article in journal (Refereed)
    Abstract [en]

    In order to find clinically useful prognostic markers for glioma patients' survival, we employed Monte Carlo Feature Selection and Interdependencies Discovery (MCFS-ID) algorithm on DNA methylation (HumanMethylation450 platform) and RNA-seq datasets from The Cancer Genome Atlas (TCGA) for 88 patients observed until death. The input features were ranked according to their importance in predicting patients' longer (400+ days) or shorter (<= 400 days) survival without prior classification of the patients. Interestingly, out of the 65 most important features found, 63 are methylation sites, and only two mRNAs. Moreover, 61 out of the 63 methylation sites are among those detected by the 450 k array technology, while being absent in the HumanMethylation27. The most important methylation feature (cg15072976) overlaps with the RE1 Silencing Transcription Factor (REST) binding site, and was confirmed to intersect with the REST binding motif in human U87 glioma cells. Six additional methylation sites from the top 63 overlap with REST sites. We found that the methylation status of the cg15072976 site affects transcription factor binding in U87 cells in gel shift assay. The cg15072976 methylation status discriminates <= 400 and 400+ patients in an independent dataset from TCGA and shows positive association with survival time as evidenced by Kaplan-Meier plots.

  • 84.
    Das, Sarbashis
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frisk, Christoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Maria J.
    Karolinska Univ Hosp, Dept Clin Physiol, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden.
    Walentinsson, Anna
    AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab Dis, S-43183 Gothenburg, Sweden.
    Corbascio, Matthias
    Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Dept Thorac Surg, S-17176 Stockholm, Sweden.
    Hage, Camilla
    Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Heart & VascularTheme, S-17176 Stockholm, Sweden.
    Kumar, Chanchal
    AstraZeneca, IMED Biotech Unit, Translat Sci Cardiovasc Renal & Metab Dis, S-43183 Gothenburg, Sweden;Karolinska Inst, ICMC, Dept Med, S-14157 Huddinge, Sweden.
    Asp, Michaela
    Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden.
    Lundeberg, Joakim
    Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden.
    Maret, Eva
    Karolinska Univ Hosp, Dept Clin Physiol, S-17176 Stockholm, Sweden;Karolinska Inst, Dept Mol Med & Surg, S-17177 Stockholm, Sweden.
    Persson, Hans
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, S-18288 Stockholm, Sweden;Danderyd Hosp, Dept Cardiol, S-18288 Stockholm, Sweden.
    Linde, Cecilia
    Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden;Karolinska Univ Hosp, Heart & VascularTheme, S-17176 Stockholm, Sweden.
    Persson, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, S-17177 Stockholm, Sweden.
    Transcriptomics of cardiac biopsies reveals differences in patients with or without diagnostic parameters for heart failure with preserved ejection fraction2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3179Article in journal (Refereed)
    Abstract [en]

    Heart failure affects 2-3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics would show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction >= 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group.

  • 85.
    Das, Sarbashis
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Pettersson, B. M. Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Behra, Phani Rama Krishna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Mallick, Amrita
    Univ Louisiana, Dept Biol, Lafayette, LA USA.
    Cheramie, Martin
    Univ Louisiana, Dept Biol, Lafayette, LA USA.
    Ramesh, Malavika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Shirreff, Lisa
    Univ Louisiana, Dept Biol, Lafayette, LA USA.
    DuCote, Tanner
    Univ Louisiana, Dept Biol, Lafayette, LA USA.
    Dasgupta, Santanu
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Ennis, Don G.
    Univ Louisiana, Dept Biol, Lafayette, LA USA.
    Kirsebom, Leif
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Extensive genomic diversity among Mycobacterium marinum strains revealed by whole genome sequencing2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12040Article in journal (Refereed)
    Abstract [en]

    Mycobacterium marinum is the causative agent for the tuberculosis-like disease mycobacteriosis in fish and skin lesions in humans. Ubiquitous in its geographical distribution, M. marinum is known to occupy diverse fish as hosts. However, information about its genomic diversity is limited. Here, we provide the genome sequences for 15 M. marinum strains isolated from infected humans and fish. Comparative genomic analysis of these and four available genomes of the M. marinum strains M, E11, MB2 and Europe reveal high genomic diversity among the strains, leading to the conclusion that M. marinum should be divided into two different clusters, the "M"- and the "Aronson"-type. We suggest that these two clusters should be considered to represent two M. marinum subspecies. Our data also show that the M. marinum pan-genome for both groups is open and expanding and we provide data showing high number of mutational hotspots in M. marinum relative to other mycobacteria such as Mycobacterium tuberculosis. This high genomic diversity might be related to the ability of M. marinum to occupy different ecological niches.

  • 86.
    de Boeck, Miriam
    et al.
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Gemon Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Cui, Chao
    Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Gemon Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Mulder, Aat A.
    Leiden Univ, Med Ctr, Electron Microscopy Sect, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands..
    Jost, Carolina R.
    Leiden Univ, Med Ctr, Electron Microscopy Sect, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands..
    Ikeno, Souichi
    Showa Pharmaceut Univ, Lab Biochem, Tokyo 1948543, Japan..
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine. Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands.;Leiden Univ, Med Ctr, Canc Gemon Ctr Netherlands, NL-2300 RC Leiden, Netherlands..
    Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 24968Article in journal (Refereed)
    Abstract [en]

    The transforming growth factor-beta (TGF-beta) family is known to play critical roles in cancer progression. While the dual role of TGF-beta is well described, the function of bone morphogenetic proteins (BMPs) is unclear. In this study, we established the involvement of Smad6, a BMP-specific inhibitory Smad, in breast cancer cell invasion. We show that stable overexpression of Smad6 in breast cancer MCF10A M2 cells inhibits BMP signalling, thereby mitigating BMP6-induced suppression of mesenchymal marker expression. Using a zebrafish xenograft model, we demonstrate that overexpression of Smad6 potentiates invasion of MCF10A M2 cells and enhances the aggressiveness of breast cancer MDA-MB-231 cells in vivo, whereas a reversed phenotype is observed after Smad6 knockdown. Interestingly, BMP6 pre-treatment of MDA-MB-231 cells induced cluster formation at the invasive site in the zebrafish. BMP6 also stimulated cluster formation of MDA-MB-231 cells co-cultured on Human Microvascular Endothelial Cells (HMEC)-1 in vitro. Electron microscopy illustrated an induction of cell-cell contact by BMP6. The clinical relevance of our findings is highlighted by a correlation of high Smad6 expression with poor distant metastasis free survival in ER-negative cancer patients. Collectively, our data strongly indicates the involvement of Smad6 and BMP signalling in breast cancer cell invasion in vivo.

  • 87.
    de Kock, Neil
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Acharya, Santosh R.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala Univ, Dept Chem, Biomed Ctr, Analyt Chem, Box 599, S-75124 Uppsala, Sweden.
    A Novel Targeted Analysis of Peripheral Steroids by Ultra-Performance Supercritical Fluid Chromatography Hyphenated to Tandem Mass Spectrometry2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16993Article in journal (Refereed)
    Abstract [en]

    Ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS) is an alternative method for steroid analysis. Continuous development of analytical methodologies for steroid profiling is of major importance in the clinical environment to provide useful and more comprehensive data. The aim of this study was to identify and quantify a large number of endogenous steroids from the four major classes (estrogens, androgens, progestogens and corticosteroids) simultaneously within a short analytical time. This novel UPSFC-MS/MS method with electrospray in positive ionisation (ESI+) mode is robust, selective and present sufficiently high sensitivity to profile nineteen steroids in 50 mu L human plasma. Under optimised conditions, nineteen different steroids were separated with high efficiency in the multiple reaction monitoring (MRM) mode. The linearity of the method was good with correlation coefficients (R-2) in the range of 0.9983-0.9999 and with calibration range from 0.05-500 ng/mL in human plasma. The intraday and interday precision of the method, as RSD, was less than 15%. The accuracy of the nineteen analytes varied between 80 to 116%. Finally, the novel method was successfully applied for the determination of nineteen steroids within 5 minutes providing the possibility to use it for research as well as routine healthcare practice.

  • 88.
    Deegan, Frances
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics. Swedish Museum Nat Hist, Dept Geosci, SE-10405 Stockholm, Sweden..
    Troll, Valentin R.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics. Istituto Nazionale di Geofisica e Vulcanologia (INGV), I-00143 Rome, Italy..
    Whitehouse, Martin J.
    Swedish Museum Nat Hist, Dept Geosci, SE-10405 Stockholm, Sweden..
    Jolis, Ester M.
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Mineralogy Petrology and Tectonics.
    Freda, Carmela
    Istituto Nazionale di Geofisica e Vulcanologia (INGV), I-00143 Rome, Italy..
    Boron isotope fractionation in magma via crustal carbonate dissolution2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 30774Article in journal (Refereed)
    Abstract [en]

    Carbon dioxide released by arc volcanoes is widely considered to originate from the mantle and from subducted sediments. Fluids released from upper arc carbonates, however, have recently been proposed to help modulate arc CO2 fluxes. Here we use boron as a tracer, which substitutes for carbon in limestone, to further investigate crustal carbonate degassing in volcanic arcs. We performed laboratory experiments replicating limestone assimilation into magma at crustal pressure-temperature conditions and analysed boron isotope ratios in the resulting experimental glasses. Limestone dissolution and assimilation generates CaO-enriched glass near the reaction site and a CO2-dominated vapour phase. The CaO-rich glasses have extremely low delta B-11 values down to -41.5%, reflecting preferential partitioning of B-10 into the assimilating melt. Loss of B-11 from the reaction site occurs via the CO2 vapour phase generated during carbonate dissolution, which transports B-11 away from the reaction site as a boron-rich fluid phase. Our results demonstrate the efficacy of boron isotope fractionation during crustal carbonate assimilation and suggest that low delta B-11 melt values in arc magmas could flag shallow-level additions to the subduction cycle.

  • 89.
    Delgado-Vega, Angélica M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Martinez-Bueno, Manuel
    Univ Granada, Pfizer, Andalusian Govt Ctr Genom & Oncol Res GENYO, Granada, Spain.
    Oparina, Nina Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Inst Environm Med, Solna, Sweden.
    Herraez, David Lopez
    UFZ Helmholtz Ctr Environm Res, Dept Effect Directed Anal, Leipzig, Germany.
    Kristjansdottir, Helga
    Landspitalinn, Unit Rheumatol, Reykjavik, Iceland.
    Steinsson, Kristjan
    Landspitalinn, Unit Rheumatol, Reykjavik, Iceland.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alarcon-Riquelme, Marta E.
    Univ Granada, Pfizer, Andalusian Govt Ctr Genom & Oncol Res GENYO, Granada, Spain;Karolinska Inst, Inst Environm Med, Solna, Sweden.
    Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8775Article in journal (Refereed)
    Abstract [en]

    In an effort to identify rare alleles associated with SLE, we have performed whole exome sequencing of the most distantly related affected individuals from two large Icelandic multicase SLE families followed by Ta targeted genotyping of additional relatives. We identified multiple rare likely pathogenic variants in nineteen genes co-segregating with the disease through multiple generations. Gene co-expression and protein-protein interaction analysis identified a network of highly connected genes comprising several loci previously implicated in autoimmune diseases. These genes were significantly enriched for immune system development, lymphocyte activation, DNA repair, and V(D) J gene recombination GO-categories. Furthermore, we found evidence of aggregate association and enrichment of rare variants at the FAM71E1/EMC10 locus in an independent set of 4,254 European SLE-cases and 4,349 controls. Our study presents evidence supporting that multiple rare likely pathogenic variants, in newly identified genes involved in known disease pathogenic pathways, segregate with SLE at the familial and population level.

  • 90.
    Derraik, Jose G. B.
    et al.
    Univ Auckland, Liggins Inst, Auckland 1, New Zealand..
    Ahlsson, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Diderholm, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Lundgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Obesity rates in two generations of Swedish women entering pregnancy, and associated obesity risk among adult daughters2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 16692Article in journal (Refereed)
    Abstract [en]

    We examined changes in obesity rates in two generations of Swedish women entering pregnancy, and assessed the effects of maternal body mass index (BMI) on the risk of overweight or obesity among adult daughters. This study covered an intergenerational retrospective cohort of 26,561 Swedish mothers and their 26,561 first-born daughters. There was a 4-fold increase in obesity rates, which rose from 3.1% among women entering pregnancy in 1982-1988 to 12.3% among their daughters in 2000-2008 (p < 0.0001) when entering pregnancy. The greater the maternal BMI, the greater the odds of overweight and/or obesity among daughters. Underweight mothers had half the odds of having an overweight or obese daughter in comparison to mothers of normal BMI (p < 0.0001). In contrast, the odds ratio of obese mothers having obese daughters was 3.94 (p < 0.0001). This study showed a strong association between maternal obesity and the risk of obesity among their first-born daughters. In addition, we observed a considerable increase in obesity rates across generations in mother-daughter pairs of Swedish women entering pregnancy. Thus, it is important to have preventative strategies in place to halt the worsening intergenerational cycle of obesity.

  • 91.
    Diamanti, Klev
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kumar, Chanchal
    AstraZeneca, R&D BioPharmaceut, Translat Sci & Expt Med, Early Cardiovasc Renal & Metab, Gothenburg, Sweden;Karolinska Inst, AstraZeneca Integrated CardioMetab Ctr KI AZ ICMC, Dept Med, Huddinge, Sweden.
    Skrtic, Stanko
    AstraZeneca AB, Pharmaceut Technol & Dev, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Med, Gothenburg, Sweden.
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Intra- and inter-individual metabolic profiling highlights carnitine and lysophosphatidylcholine pathways as key molecular defects in type 2 diabetes2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 9653Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes (T2D) mellitus is a complex metabolic disease commonly caused by insulin resistance in several tissues. We performed a matched two-dimensional metabolic screening in tissue samples from 43 multi-organ donors. The intra-individual analysis was assessed across five key metabolic tissues (serum, visceral adipose tissue, liver, pancreatic islets and skeletal muscle), and the inter-individual across three different groups reflecting T2D progression. We identified 92 metabolites differing significantly between non-diabetes and T2D subjects. In diabetes cases, carnitines were significantly higher in liver, while lysophosphatidylcholines were significantly lower in muscle and serum. We tracked the primary tissue of origin for multiple metabolites whose alterations were reflected in serum. An investigation of three major stages spanning from controls, to pre-diabetes and to overt T2D indicated that a subset of lysophosphatidylcholines was significantly lower in the muscle of pre-diabetes subjects. Moreover, glycodeoxycholic acid was significantly higher in liver of pre-diabetes subjects while additional increase in T2D was insignificant. We confirmed many previously reported findings and substantially expanded on them with altered markers for early and overt T2D. Overall, the analysis of this unique dataset can increase the understanding of the metabolic interplay between organs in the development of T2D.

  • 92.
    Dias, Mariana Castro
    et al.
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Coisne, Caroline
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Lazarevic, Ivana
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Baden, Pascale
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Hata, Masaki
    Hyogo Coll Med, Lab Tumor Immunol & Cell Therapy, Nishinomiya, Hyogo, Japan.
    Iwamoto, Noriko
    Kobe Univ, Div Cell Biol, Grad Sch Med, Kobe, Hyogo, Japan.
    Francisco, David Miguel Ferreira
    Univ Bern, Interfac Bioinformat Unit, Bern, Switzerland;Univ Bern, Swiss Inst Bioinformat, Bern, Switzerland.
    Vanlandewijck, Michael
    AstraZeneca, Karolinska Inst, Cardio Metab Ctr, KI,AZ ICMC, Huddinge, Sweden.
    He, Liqun
    AstraZeneca, Karolinska Inst, Cardio Metab Ctr, KI,AZ ICMC, Huddinge, Sweden.
    Baier, Felix A.
    Univ Bern, Dept Biomed Res, Visceral Surg Res Lab, Bern, Switzerland.
    Stroka, Deborah
    Univ Bern, Dept Biomed Res, Visceral Surg Res Lab, Bern, Switzerland.
    Bruggmann, Remy
    Kobe Univ, Div Cell Biol, Grad Sch Med, Kobe, Hyogo, Japan;Univ Bern, Interfac Bioinformat Unit, Bern, Switzerland;Univ Bern, Swiss Inst Bioinformat, Bern, Switzerland.
    Lyck, Ruth
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Enzmann, Gaby
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Deutsch, Urban
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. AstraZeneca, Karolinska Inst, Cardio Metab Ctr, KI,AZ ICMC, Huddinge, Sweden.
    Furuse, Mikio
    Natl Inst Physiol Sci, Div Cell Struct, Okazaki, Aichi, Japan;Sch Life Sci, Dept Physiol Sci, Okazaki, Aichi, Japan.
    Tsukita, Shoichiro
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Engelhardt, Britta
    Univ Bern, Theodor Kocher Inst, Bern, Switzerland.
    Claudin-3-deficient C57BL/6J mice display intact brain barriers2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 203Article in journal (Refereed)
    Abstract [en]

    The tight junction protein claudin-3 has been identified as a transcriptional target of the Wnt/beta-catenin signaling pathway regulating blood-brain barrier (BBB) maturation. In neurological disorders loss of claudin-3 immunostaining is observed at the compromised BBB and blood-cerebrospinal fluid barrier (BCSFB). Although these observations support a central role of claudin-3 in regulating brain barriers' tight junction integrity, expression of claudin-3 at the brain barriers has remained a matter of debate. This prompted us to establish claudin-3-/-C57BL/6J mice to study the role of claudin-3 in brain barrier integrity in health and neuroinflammation. Bulk and single cell RNA sequencing and direct comparative qRT-PCR analysis of brain microvascular samples from WT and claudin-3-/- mice show beyond doubt that brain endothelial cells do not express claudin-3 mRNA. Detection of claudin-3 protein at the BBB in vivo and in vitro is rather due to junctional reactivity of anti-claudin-3 antibodies to an unknown antigen still detected in claudin-3-/- brain endothelium. We confirm expression and junctional localization of claudin-3 at the BCSFB of the choroid plexus. Our study clarifies that claudin-3 is not expressed at the BBB and shows that absence of claudin-3 does not impair brain barrier function during health and neuroinflammation in C57BL/6J mice.

  • 93.
    Dierker, Tabea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shao, Chun
    Boston Univ, Dept Biochem, Ctr Biomed Mass Spectrometry, Med Campus, Boston, MA 02215 USA..
    Haitina, Tatjana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zaia, Joseph
    Boston Univ, Dept Biochem, Ctr Biomed Mass Spectrometry, Med Campus, Boston, MA 02215 USA..
    Hinas, Andrea
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Kjellén, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nematodes join the family of chondroitin sulfate-synthesizing organisms: Identification of an active chondroitin sulfotransferase in Caenorhabditis elegans2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 34662Article in journal (Refereed)
    Abstract [en]

    Proteoglycans are proteins that carry sulfated glycosaminoglycans (GAGs). They help form and maintain morphogen gradients, guiding cell migration and differentiation during animal development. While no sulfated GAGs have been found in marine sponges, chondroitin sulfate (CS) and heparan sulfate (HS) have been identified in Cnidarians, Lophotrocozoans and Ecdysozoans. The general view that nematodes such as Caenorhabditis elegans, which belong to Ecdysozoa, produce HS but only chondroitin without sulfation has therefore been puzzling. We have analyzed GAGs in C. elegans using reversed-phase ion-pairing HPLC, mass spectrometry and immunohistochemistry. Our analyses included wild type C. elegans but also a mutant lacking two HS sulfotransferases (hst-6 hst-2), as we suspected that the altered HS structure could boost CS sulfation. We could indeed detect sulfated CS in both wild type and mutant nematodes. While 4-O-sulfation of galactosamine dominated, we also detected 6-O-sulfated galactosamine residues. Finally, we identified the product of the gene C41C4.1 as a C. elegans CS-sulfotransferase and renamed it chst-1 (CarboHydrate SulfoTransferase) based on loss of CS-4-O-sulfation in a C41C4.1 mutant and in vitro sulfotransferase activity of recombinant C41C4.1 protein. We conclude that C. elegans indeed manufactures CS, making this widely used nematode an interesting model for developmental studies involving CS.

  • 94.
    Digre, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Singh, Kailash
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Åbrink, Magnus
    Swedish Univ Agr Sci, Immunol Sect, Dept Biomed Sci & Vet Publ Hlth, VHC, Box 7028, Uppsala, Sweden.
    Reijmers, Rogier M.
    Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vlodavsky, Israel
    Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Overexpression of heparanase enhances T lymphocyte activities and intensifies the inflammatory response in a model of murine rheumatoid arthritis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46229Article in journal (Refereed)
    Abstract [en]

    Heparanase is an endo-glucuronidase that degrades heparan sulfate chains. The enzyme is expressed at a low level in normal organs; however, elevated expression of heparanase has been detected in several inflammatory conditions, e.g. in the synovial joints of rheumatoid arthritis (RA) patients. Herein, we have applied the model of collagen-induced arthritis (CIA) to transgenic mice overexpressing human heparanase (Hpa-tg) along with wildtype (WT) mice. About 50 % of the induced animals developed clinical symptoms, i.e. swelling of joints, and there were no differences between the Hpa-tg and WT mice in the incidence of disease. However, Hpa-tg mice displayed an earlier response and developed more severe symptoms. Examination of cells from thymus, spleen and lymph nodes revealed increased innate and adaptive immune responses of the Hpa-tg mice, reflected by increased proportions of macrophages, antigen presenting cells and plasmacytoid dendritic cells as well as Helios-positive CD4+ and CD8+ T cells. Furthermore, splenic lymphocytes from Hpa-tg mice showed higher proliferation activity. Our results suggest that elevated expression of heparanase augmented both the innate and adaptive immune system and propagated inflammatory reactions in the murine RA model.

  • 95.
    Ding, Zhoujie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dahlin, Joakim S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xu, Hui
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heyman, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    IgE-mediated enhancement of CD4(+) T cell responses requires antigen presentation by CD8 alpha(-) conventional dendritic cells2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 28290Article in journal (Refereed)
    Abstract [en]

    IgE, forming an immune complex with small proteins, can enhance the specific antibody and CD4(+) T cell responses in vivo. The effects require the presence of CD23 (Fc epsilon-receptor II)(+) B cells, which capture IgE-complexed antigens (Ag) in the circulation and transport them to splenic B cell follicles. In addition, also CD11c(+) cells, which do not express CD23, are required for IgE-mediated enhancement of T cell responses. This suggests that some type of dendritic cell obtains IgE-Ag complexes from B cells and presents antigenic peptides to T cells. To elucidate the nature of this dendritic cell, mice were immunized with ovalbumin (OVA)-specific IgE and OVA, and different populations of CD11c(+) cells, obtained from the spleens four hours after immunization, were tested for their ability to present OVA. CD8 alpha(-) conventional dendritic cells (cDCs) were much more efficient in inducing specific CD4(+) T cell proliferation ex vivo than were CD8 alpha(+) cDCs or plasmacytoid dendritic cells. Thus, IgE-Ag complexes administered intravenously are rapidly transported to the spleen by recirculating B cells where they are delivered to CD8 alpha(-) cDCs which induce proliferation of CD4(+) T cells.

  • 96.
    Dinic, Jelena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Riehl, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Adler, Jeremy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Parmryd, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The T cell receptor resides in ordered plasma membrane nanodomains that aggregate upon patching of the receptor2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10082Article in journal (Refereed)
    Abstract [en]

    Two related models for T cell signalling initiation suggest either that T cell receptor (TCR) engagement leads to its recruitment to ordered membrane domains, often referred to as lipid rafts, where signalling molecules are enriched or that ordered TCR-containing membrane nanodomains coalesce upon TCR engagement. That ordered domains form upon TCR engagement, as they do upon lipid raft marker patching, has not been considered. The target of this study was to differentiate between those three options. Plasma membrane order was followed in live T cells at 37 °C using laurdan to report on lipid packing. Patching of the TCR that elicits a signalling response resulted in aggregation, not formation, of ordered plasma membrane domains in both Jurkat and primary T cells. The TCR colocalised with actin filaments at the plasma membrane in unstimulated Jurkat T cells, consistent with it being localised to ordered membrane domains. The colocalisation was most prominent in cells in G1 phase when the cells are ready to commit to proliferation. At other cell cycle phases the TCR was mainly found at perinuclear membranes. Our study suggests that the TCR resides in ordered plasma membrane domains that are linked to actin filaments and aggregate upon TCR engagement.

  • 97.
    Dogan, Jakob
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mu, Xin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jemth, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    The transition state structure for coupled binding and folding of disordered protein domains2013In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3, p. 2076-Article in journal (Refereed)
    Abstract [en]

    Intrinsically disordered proteins are abundant in the eukaryotic proteome, and they are implicated in a range of different diseases. However, there is a paucity of experimental data on molecular details of the coupled binding and folding of such proteins. Two interacting and relatively well studied disordered protein domains are the activation domain from the p160 transcriptional co-activator ACTR and the nuclear co-activator binding domain (NCBD) of CREB binding protein. We have analyzed the transition state for their coupled binding and folding by protein engineering and kinetic experiments (Phi-value analysis) and found that it involves weak native interactions between the N-terminal helices of ACTR and NCBD, but is otherwise "disordered-like". Most native hydrophobic interactions in the interface between the two domains form later, after the rate-limiting barrier for association. Linear free energy relationships suggest a cooperative formation of native interactions, reminiscent of the nucleation-condensation mechanism in protein folding.

  • 98.
    Domsgen, Erna
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden..
    Lind, Katharina
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden..
    Kong, Lingjia
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    Huhn, Michael H.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.;Astra Zeneca AB R&D, Pepparedsleden 1, S-43150 Molndal, Sweden..
    Rasool, Omid
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    van Kuppeveld, Frank
    Univ Utrecht, Div Virol, Dept Infect Dis & Immunol, Fac Vet Med, NL-3584 Utrecht, Netherlands..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lahesmaa, Riitta
    Univ Turku, Turku Ctr Biotechnol, FIN-20520 Turku, Finland.;Abo Akad Univ, FIN-20520 Turku, Finland..
    Flodstrom-Tullberg, Malin
    Karolinska Univ Hosp, Karolinska Inst, Dept Med HS, Ctr Infect Med, S-14186 Stockholm, Sweden.;Univ Tampere, Inst Biosci & Med Technol, Tampere 33520, Finland..
    An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 39378Article in journal (Refereed)
    Abstract [en]

    The IFIH1 gene encodes the pattern recognition receptor MDA5. A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro. Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection. A strong IFN signature was associated with high expression of IFN lambda 1 and IFN lambda 2, linking rs1990760 to the expression of type III IFNs. In the highresponding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positivefeedback on type III IFN transcription. In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D. It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs.

  • 99.
    Dong, Zhihua
    et al.
    KTH Royal Inst Technol, Dept Mat Sci & Engn, Appl Mat Phys, SE-10044 Stockholm, Sweden.
    Schonecker, Stephan
    KTH Royal Inst Technol, Dept Mat Sci & Engn, Appl Mat Phys, SE-10044 Stockholm, Sweden.
    Li, Wei
    KTH Royal Inst Technol, Dept Mat Sci & Engn, Appl Mat Phys, SE-10044 Stockholm, Sweden.
    Chen, Dengfu
    Chongqing Univ, Coll Mat Sci & Engn, Chongqing 400030, Peoples R China.
    Vitos, Levente
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory. KTH Royal Inst Technol, Dept Mat Sci & Engn, Appl Mat Phys, SE-10044 Stockholm, Sweden; Wigner Res Ctr Phys, Res Inst Solid State Phys & Opt, POB 49, H-1525 Budapest, Hungary.
    Thermal spin fluctuations in CoCrFeMnNi high entropy alloy2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12211Article in journal (Refereed)
    Abstract [en]

    High entropy alloys based on 3d transition metals display rich and promising magnetic characteristics for various high-technology applications. Understanding their behavior at finite temperature is, however, limited by the incomplete experimental data for single-phase alloys. Here we use first-principles alloy theory to investigate the magnetic structure of polymorphic CoCrFeMnNi in the paramagnetic state by accounting for the longitudinal spin fluctuations (LSFs) as a function of temperature. In both face-centered cubic (fcc) and hexagonal close-packed (hcp) structures, the LSFs induce sizable magnetic moments for Co, Cr and Ni. The impact of LSFs is demonstrated on the phase stability, stacking fault energy and the fcc-hcp interfacial energy. The hcp phase is energetically preferable to the fcc one at cryogenic temperatures, which results in negative stacking fault energy at these conditions. With increasing temperature, the stacking fault energy increases, suppressing the formation of stacking faults and nano-twins. Our predictions are consistent with recent experimental findings.

  • 100.
    Dorner, Thomas E.
    et al.
    Med Univ Vienna, Ctr Publ Hlth, Dept Social & Prevent Med, Kinderspitalgasse 15-1, A-1090 Vienna, Austria.
    Helgesson, Magnus
    Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Berzeliusv 3, S-17177 Stockholm, Sweden.
    Nilsson, Kerstin
    Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Berzeliusv 3, S-17177 Stockholm, Sweden.
    Pazarlis, Konstantinos A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ropponen, Annina
    Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Berzeliusv 3, S-17177 Stockholm, Sweden;Finnish Inst Occupat Hlth, POB 18, Helsinki 00390, Finland.
    Svedberg, Pia
    Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Berzeliusv 3, S-17177 Stockholm, Sweden.
    Mittendorfer-Rutz, Ellenor
    Karolinska Inst, Div Insurance Med, Dept Clin Neurosci, Berzeliusv 3, S-17177 Stockholm, Sweden.
    Course and characteristics of work disability 3 years before and after lumbar spine decompression surgery: a national population-based study2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 11811Article in journal (Refereed)
    Abstract [en]

    Despite decompression surgery being a widespread intervention for patients with dorsopathies (i.e. back pain) affecting the lumbar spine, the scientific knowledge on patterns and characteristics of work disability before and after the surgery is limited. Sickness absence (SA) and disability pension (DP) were examined three years before and after surgery in 8558 patients aged 25-60 years who underwent lumbar spine decompression surgery in Sweden. They were compared to individuals with diagnosed dorsopathies but no surgery and individuals from the general population as matched comparison groups. According to Group Based Trajectory models, in patients with decompression surgery, 39% had low levels of SA/DP during the entire study period and 15% started with low levels of SA/DP, which increased in the year before, and declined to almost zero in the second year after surgery. Three trajectory groups (12%, 17%, and 18%) started at different levels of SA/DP, which increased in the years before, and declined in the third year after surgery. The trajectory groups in the comparison groups showed lower levels of work disability. Sex, education, and the use of antidepressants and analgesics the year before surgery played an important role to explain the variance of trajectory groups in patients with surgery.

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