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  • 301.
    Krautz, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Damage signals in the insect immune response2014Inngår i: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 5, artikkel-id 342Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Insects and mammals share an ancient innate immune system comprising both humoral and cellular responses. The insect immune system consists of the fat body, which secretes effector molecules into the hemolymph and several classes of hemocytes, which reside in the hemolymph and of protective border epithelia. Key features of wound- and immune responses are shared between insect and mammalian immune systems including the mode of activation by commonly shared microbial (non-self) patterns and the recognition of these patterns by dedicated receptors. It is unclear how metazoan parasites in insects, which lack these shared motifs, are recognized. Research in recent years has demonstrated that during entry into the insect host, many eukaryotic pathogens leave traces that alert potential hosts of the damage they have afflicted. In accordance with terminology used in the mammalian immune systems, these signals have been dubbed danger- or damage-associated signals. Damage signals are necessary byproducts generated during entering hosts either by mechanical or proteolytic damage. Here, we briefly review the current stage of knowledge on how wound closure and wound healing during mechanical damage is regulated and how damage-related signals contribute to these processes. We also discuss how sensors of proteolytic activity induce insect innate immune responses. Strikingly damage-associated signals are also released from cells that have aberrant growth, including tumor cells. These signals may induce apoptosis in the damaged cells, the recruitment of immune cells to the aberrant tissue and even activate humoral responses. Thus, this ensures the removal of aberrant cells and compensatory proliferation to replace lost tissue. Several of these pathways may have been co-opted from wound healing and developmental processes.

  • 302.
    Krautz, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Khalili, Dilan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hauling, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Söll, Iris
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hauptmann, Giselbert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    An innate immune response against dysplasia in a secretory organManuskript (preprint) (Annet vitenskapelig)
  • 303.
    Krautz, Robert
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Khalili, Dilan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Söll, Iris
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hauptmann, Giselbert
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Drosophila larval fat body preparations to reveal regionalized gene expression​Manuskript (preprint) (Annet vitenskapelig)
  • 304. Kreuzer, M.
    et al.
    Auvinen, A.
    Cardis, E.
    Durante, M.
    Harms-Ringdahl, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Jourdain, J. R.
    Madas, B. G.
    Ottolenghi, A.
    Pazzaglia, S.
    Prise, K. M.
    Quintens, R.
    Sabatier, L.
    Bouffler, S.
    Multidisciplinary European Low Dose Initiative (MELODI): strategic research agenda for low dose radiation risk research2018Inngår i: Radiation and Environmental Biophysics, ISSN 0301-634X, E-ISSN 1432-2099, Vol. 57, nr 1, s. 5-15Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    MELODI (Multidisciplinary European Low Dose Initiative) is a European radiation protection research platform with focus on research on health risks after exposure to low-dose ionising radiation. It was founded in 2010 and currently includes 44 members from 18 countries. A major activity of MELODI is the continuous development of a long-term European Strategic Research Agenda (SRA) on low-dose risk for radiation protection. The SRA is intended to identify priorities for national and European radiation protection research programs as a basis for the preparation of competitive calls at the European level. Among those key priorities is the improvement of health risk estimates for exposures close to the dose limits for workers and to reference levels for the population in emergency situations. Another activity of MELODI is to ensure the availability of European key infrastructures for research activities, and the long-term maintenance of competences in radiation research via an integrated European approach for training and education. The MELODI SRA identifies three key research topics in low dose or low dose-rate radiation risk research: (1) dose and dose rate dependence of cancer risk, (2) radiation-induced non-cancer effects and (3) individual radiation sensitivity. The research required to improve the evidence base for each of the three key topics relates to three research lines: (1) research to improve understanding of the mechanisms contributing to radiogenic diseases, (2) epidemiological research to improve health risk evaluation of radiation exposure and (3) research to address the effects and risks associated with internal exposures, differing radiation qualities and inhomogeneous exposures. The full SRA and associated documents can be downloaded from the MELODI website (http://www.melodi-online.eu/sra.html).

  • 305.
    Kubrak, Olga I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kucerova, Lucie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nylin, Sören
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Characterization of Reproductive Dormancy in Male Drosophila melanogaster2016Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 7, artikkel-id 572Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insects are known to respond to seasonal and adverse environmental changes by entering dormancy, also known as diapause. In some insect species, including Drosophila melanogaster, dormancy occurs in the adult organism and postpones reproduction. This adult dormancy has been studied in female flies where it is characterized by arrested development of ovaries, altered nutrient stores, lowered metabolism, increased stress and immune resistance and drastically extended lifespan. Male dormancy, however, has not been investigated in D. melanogaster, and its physiology is poorly known in most insects. Here we show that unmated 3-6 h old male flies placed at low temperature (11 degrees C) and short photoperiod (10 Light:14 Dark) enter a state of dormancy with arrested spermatogenesis and development of testes and male accessory glands. Over 3 weeks of diapause we see a dynamic increase in stored carbohydrates and an initial increase and then a decrease in lipids. We also note an up-regulated expression of genes involved in metabolism, stress responses and innate immunity. Interestingly, we found that male flies that entered reproductive dormancy do not attempt to mate females kept under non-diapause conditions (25 degrees C, 1 2L:1 2D), and conversely non-diapausing males do not mate females in dormancy. In summary, our study shows that male D. melanogaster can enter reproductive dormancy. However, our data suggest that dormant male flies deplete stored nutrients faster than females, studied earlier, and that males take longer to recover reproductive capacity after reintroduction to non-diapause conditions.

  • 306.
    Kubrak, Olga I.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Kucerova, Lucie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    The Sleeping Beauty: How Reproductive Diapause Affects Hormone Signaling, Metabolism, Immune Response and Somatic Maintenance in Drosophila melanogaster2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikkel-id e113051Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Some organisms can adapt to seasonal and other environmental challenges by entering a state of dormancy, diapause. Thus, insects exposed to decreased temperature and short photoperiod enter a state of arrested development, lowered metabolism, and increased stress resistance. Drosophila melanogaster females can enter a shallow reproductive diapause in the adult stage, which drastically reduces organismal senescence, but little is known about the physiology and endocrinology associated with this dormancy, and the genes involved in its regulation. We induced diapause in D. melanogaster and monitored effects over 12 weeks on dynamics of ovary development, carbohydrate and lipid metabolism, as well as expression of genes involved in endocrine signaling, metabolism and innate immunity. During diapause food intake diminishes drastically, but circulating and stored carbohydrates and lipids are elevated. Gene transcripts of glucagonand insulin-like peptides increase, and expression of several target genes of these peptides also change. Four key genes in innate immunity can be induced by infection in diapausing flies, and two of these, drosomycin and cecropin A1, are upregulated by diapause independently of infection. Diapausing flies display very low mortality, extended lifespan and decreased aging of the intestinal epithelium. Many phenotypes induced by diapause are reversed after one week of recovery from diapause conditions. Furthermore, mutant flies lacking specific insulin-like peptides (dilp5 and dilp2-3) display increased diapause incidence. Our study provides a first comprehensive characterization of reproductive diapause in D. melanogaster, and evidence that glucagon- and insulin-like signaling are among the key regulators of the altered physiology during this dormancy.

  • 307.
    Kucerova, Lucie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of South Bohemia, Czech Republic.
    Broz, Vaclav
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Maaroufi, Houda Ouns
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hurychova, Jana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Masaryk University, Czech Republic.
    Strnad, Hynek
    Zurovec, Michal
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The Drosophila Chitinase-Like Protein IDGF3 Is Involved in Protection against Nematodes and in Wound Healing2016Inngår i: Journal of Innate Immunity, ISSN 1662-811X, E-ISSN 1662-8128, Vol. 8, nr 2, s. 199-210Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chitinase-like proteins (CLPs) of the 18 glycosyl hydrolase family retain structural similarity to chitinases but lack enzymatic activity. Although CLPs are upregulated in several human disorders that affect regenerative and inflammatory processes, very little is known about their normal physiological function. We show that an insect CLP (Drosophila imaginal disc growth factor 3, IDGF3) plays an immune-protective role during entomopathogenic nematode (EPN) infections. During these infections, nematodes force their entry into the host via border tissues, thus creating wounds. Whole-genome transcriptional analysis of nematode-infected wildtype and Idgf3 mutant larvae have shown that, in addition to the regulation of genes related to immunity and wound closure, IDGF3 represses Jak/STAT and Wingless signaling. Further experiments have confirmed that IDGF3 has multiple roles in innate immunity. It serves as an essential component required for the formation of hemolymph clots that seal wounds, and Idgf3 mutants display an extended developmental delay during wound healing. Altogether, our findings indicate that vertebrate and invertebrate CLP proteins function in analogous settings and have a broad impact on inflammatory reactions and infections. This opens the way to further genetic analysis of Drosophila IDGF3 and will help to elucidate the exact molecular context of CLP function.

  • 308.
    Kucerova, Lucie
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kubrak, Olga I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Bengtsson, Jonas M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Strnad, Hynek
    Nylin, Sören
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nässel, Dick R.
    Stockholms universitet, Naturvetenskapliga fakulteten, Zoologiska institutionen.
    Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster2016Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, artikkel-id 50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. Results: A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin-IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll-dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. Conclusions: We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan.

  • 309. Kukutla, Phanidhar
    et al.
    Lindberg, Bo G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pei, Dong
    Rayl, Melanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Yu, Wanqin
    Steritz, Matthew
    Faye, Ingrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Xu, Jiannong
    Draft Genome Sequences of Elizabethkingia anophelis Strains R26T and Ag1 from the Midgut of the Malaria Mosquito Anopheles gambiae2013Inngår i: Genome Announcements, ISSN 2169-8287, Vol. 1, nr 6, s. e01030-13-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elizabethkingia anophelis is a species in the family Flavobacteriaceae. It is a dominant resident in the mosquito gut and also a human pathogen. We present the draft genome sequences of two strains of E. anophelis, R26T and Ag1, which were isolated from the midgut of the malaria mosquito Anopheles gambiae.

  • 310. Kukutla, Phanidhar
    et al.
    Lindberg, Bo G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pei, Dong
    Rayl, Melanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Yu, Wanqin
    Steritz, Matthew
    Faye, Ingrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Xu, Jiannong
    Insights from the Genome Annotation of Elizabethkingia anophelis from the Malaria Vector Anopheles gambiae2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 5, s. e97715-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elizabethkingia anophelis is a dominant bacterial species in the gut ecosystem of the malaria vector mosquito Anopheles gambiae. We recently sequenced the genomes of two strains of E. anophelis, R26(T) and Ag1, isolated from different strains of A. gambiae. The two bacterial strains are identical with a few exceptions. Phylogenetically, Elizabethkingia is closer to Chryseobacterium and Riemerella than to Flavobacterium. In line with other Bacteroidetes known to utilize various polymers in their ecological niches, the E. anophelis genome contains numerous TonB dependent transporters with various substrate specificities. In addition, several genes belonging to the polysaccharide utilization system and the glycoside hydrolase family were identified that could potentially be of benefit for the mosquito carbohydrate metabolism. In agreement with previous reports of broad antibiotic resistance in E. anophelis, a large number of genes encoding efflux pumps and blactamases are present in the genome. The component genes of resistance-nodulation-division type efflux pumps were found to be syntenic and conserved in different taxa of Bacteroidetes. The bacterium also displays hemolytic activity and encodes several hemolysins that may participate in the digestion of erythrocytes in the mosquito gut. At the same time, the OxyR regulon and antioxidant genes could provide defense against the oxidative stress that is associated with blood digestion. The genome annotation and comparative genomic analysis revealed functional characteristics associated with the symbiotic relationship with the mosquito host.

  • 311. Kulka, U.
    et al.
    Ainsbury, L.
    Atkinson, M.
    Barnard, S.
    Smith, R.
    Barquinero, J. F.
    Barrios, L.
    Bassinet, C.
    Beinke, C.
    Cucu, A.
    Darroudi, F.
    Fattibene, P.
    Bortolin, E.
    Della Monaca, S.
    Gil, O.
    Gregoire, E.
    Hadjidekova, V.
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hatzi, V.
    Hempel, W.
    Herranz, R.
    Jaworska, A.
    Lindholm, C.
    Lumniczky, K.
    M'kacher, R.
    Moertl, S.
    Montoro, A.
    Moquet, J.
    Moreno, M.
    Noditi, M.
    Ogbazghi, A.
    Oestreicher, U.
    Palitti, F.
    Pantelias, G.
    Popescu, I.
    Prieto, M. J.
    Roch-Lefevre, S.
    Roessler, U.
    Romm, H.
    Rothkamm, K.
    Sabatier, L.
    Sebastia, N.
    Sommer, S.
    Terzoudi, G.
    Testa, A.
    Thierens, H.
    Trompier, F.
    Turai, I.
    Vandevoorde, C.
    Vaz, P.
    Voisin, P.
    Vral, A.
    Ugletveit, F.
    Wieser, A.
    Woda, C.
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Realising the European network of biodosimetry: RENEB-status quo2015Inngår i: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 164, nr 1-2, s. 42-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Creating a sustainable network in biological and retrospective dosimetry that involves a large number of experienced laboratories throughout the European Union (EU) will significantly improve the accident and emergency response capabilities in case of a large-scale radiological emergency. A well-organised cooperative action involving EU laboratories will offer the best chance for fast and trustworthy dose assessments that are urgently needed in an emergency situation. To this end, the EC supports the establishment of a European network in biological dosimetry (RENEB). The RENEB project started in January 2012 involving cooperation of 23 organisations from 16 European countries. The purpose of RENEB is to increase the biodosimetry capacities in case of large-scale radiological emergency scenarios. The progress of the project since its inception is presented, comprising the consolidation process of the network with its operational platform, intercomparison exercises, training activities, proceedings in quality assurance and horizon scanning for new methods and partners. Additionally, the benefit of the network for the radiation research community as a whole is addressed.

  • 312. Kulka, Ulrike
    et al.
    Abend, Michael
    Ainsbury, Elizabeth
    Badie, Christophe
    Francesc Barquinero, Joan
    Barrios, Lleonard
    Beinke, Christina
    Bortolin, Emanuela
    Cucu, Alexandra
    De Amicis, Andrea
    Dominguez, Inmaculada
    Fattibene, Paola
    Frovig, Anne Marie
    Gregoire, Eric
    Guogyte, Kamile
    Hadjidekova, Valeria
    Jaworska, Alicja
    Kriehuber, Ralf
    Lindholm, Carita
    Lloyd, David
    Lumniczky, Katalin
    Lyng, Fiona
    Meschini, Roberta
    Moertl, Simone
    Della Monaca, Sara
    Gil, Octavia Monteiro
    Montoro, Alegria
    Moquet, Jayne
    Moren, Mercedes
    Oestreicher, Ursula
    Palitti, Fabrizio
    Pantelias, Gabriel
    Patrono, Clarice
    Piqueret-Stephan, Laure
    Port, Matthias
    Jesus Prieto, Maria
    Quintens, Roel
    Ricoul, Michelle
    Romm, Horst
    Roy, Laurence
    Safrany, Geza
    Sabatier, Laure
    Sebastia, Natividad
    Sommer, Sylwester
    Terzoudi, Georgia
    Testa, Antonella
    Thierens, Hubert
    Turai, Istvan
    Trompier, Francois
    Valente, Marco
    Vaz, Pedro
    Voisin, Philippe
    Vral, Anne
    Woda, Clemens
    Zafiropoulos, Demetre
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    RENEB - Running the European Network of biological dosimetry and physical retrospective dosimetry2017Inngår i: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 93, nr 1, s. 2-14Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: A European network was initiated in 2012 by 23 partners from 16 European countries with the aim to significantly increase individualized dose reconstruction in case of large-scale radiological emergency scenarios. Results: The network was built on three complementary pillars: (1) an operational basis with seven biological and physical dosimetric assays in ready-to-use mode, (2) a basis for education, training and quality assurance, and (3) a basis for further network development regarding new techniques and members. Techniques for individual dose estimation based on biological samples and/or inert personalized devices as mobile phones or smart phones were optimized to support rapid categorization of many potential victims according to the received dose to the blood or personal devices. Communication and cross-border collaboration were also standardized. To assure long-term sustainability of the network, cooperation with national and international emergency preparedness organizations was initiated and links to radiation protection and research platforms have been developed. A legal framework, based on a Memorandum of Understanding, was established and signed by 27 organizations by the end of 2015. Conclusions: RENEB is a European Network of biological and physical-retrospective dosimetry, with the capacity and capability to perform large-scale rapid individualized dose estimation. Specialized to handle large numbers of samples, RENEB is able to contribute to radiological emergency preparedness and wider large-scale research projects.

  • 313. Kumsiri, Ratchanok
    et al.
    Troye-Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Pattanapanyasat, Kovit
    Krudsood, Srivicha
    Maneerat, Yaowapa
    IgE low affinity receptor (CD23) expression, Plasmodium falciparum specific IgE and tumor necrosis factor-alpha production in Thai uncomplicated and severe falciparum malaria patients2016Inngår i: Acta Tropica, ISSN 0001-706X, E-ISSN 1873-6254, Vol. 154, s. 25-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies have suggested that Plasmodium falciparum (P. falciparum) specific IgE in the form of immune complexes crosslinking the low-affinity receptor (CD23) on monocyte results in tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production. However, the roles of these parameters in severity and immune protection are still unclear. This study aimed to determine the association between CD23 expression on monocytes, plasma soluble CD23 (sCD23), total IgE, malaria-specific IgE and IgG, and TNF-alpha levels in P. falciparum infected patients. We evaluated 64 uncomplicated (UC) and 25 severe patients (S), admitted at the Hospital for Tropical Diseases, Mahidol University, and 34 healthy controls (C) enrolled in 2001. Flow cytometry and enzyme linked immunosorbent assays (ELISA) demonstrated that trends of the CD23 expression, levels of sCD23 and specific IgE were higher in the S group as compared to those in the UC and C groups. Plasma levels of P. falciparum specific IgE in the UC (p = 0.011) and S groups (p = 0.025) were significantly higher than those in C group. In contrast the TNF-alpha levels tended to be higher in the UC than those in the S (p = 0343) and significantly higher than those in C (p = 0.004) groups. The specific IgG levels in UC were significantly higher than those in S and C (p < 0.001) groups. At admission, a strong significant negative correlation was found between specific IgG and sCD23 (r = -0.762, p = 0.028), and TNF-alpha and IgE-IgG complexes (r=-0.715, p = 0.002). Significant positive correlations between levels of specific IgE and TNF-alpha (r=0.575, p = 0.010); and sCD23 (r=0.597, p = 0.000) were also observed. In conclusion, our data suggest that CD23 expression and malaria-specific IgE levels may be involved in the severity of the disease while TNF-alpha and the malaria-specific IgG may correlate with protection against falciparum malaria.

  • 314.
    Kunc, Martin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Masaryk University, Czech Republic.
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hyrsl, Pavel
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvae2017Inngår i: fly, ISSN 1933-6934, Vol. 11, nr 3, s. 208-217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    One of the key factors that determine the interaction between hosts and their parasites is the frequency of their interactions, which depends on the locomotory behavior of both parts. To address host behavior we used natural infections involving insect pathogenic nematodes and Drosophila melanogaster larvae as hosts. Using a modified version of a recently described method (FIMTrack) to assess several parameters in larger sets of animals, we initially detected specific differences in larval food searching when comparing Drosophila strains. These differences were further influenced by the presence of nematodes. Given a choice, Drosophila larvae clearly avoided nematodes irrespective of their genetic background. Our newly developed methods will be useful to test candidate genes and pathways involved in host/pathogen interactions in general and to assess specific parameters of their interaction.

  • 315. Kunc, Martin
    et al.
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hyrsl, Pavel
    Theopold, Ulrich
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvaeManuskript (preprint) (Annet vitenskapelig)
  • 316. Kupferschmidt, Natalia
    et al.
    Csikasz, Robert I.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ballell, Lluis
    Bengtsson, Tore
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Garcia-Bennett, Alfonso E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Large pore mesoporous silica induced weight loss in obese mice2014Inngår i: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, nr 9, s. 1353-1362Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There is a need for medical treatments to curb the rising rate of obesity. Weight reduction is correlated with a decrease in associated risk factors and cholesterol levels in humans. Amorphous silica particles have been found to exert a hypocholesterolemic effect in humans, making them popular dietary additives. Aim: To investigate the effect of mesoporous silica, which possess sharp pore size distributions, on: weight loss, cholesterol, triglycerides and glucose blood levels in obese mice. Materials & methods: Mesoporous silicas with differing pore size were mixed in the high-fat diet of obese mice. Results: Animals receiving large pore mesoporous silica with a high-fat diet show a significant reduction in body weight and fat composition, with no observable negative effects. Conclusion: Pore size is an important parameter for reduction of body weight and body fat composition by mesoporous silica, demonstrating promising signs for the treatment of obesity.

  • 317. Kurioka, Ayako
    et al.
    Cosgrove, Cormac
    Simoni, Yannick
    van Wilgenburg, Bonnie
    Geremia, Alessandra
    Björkander, Sophia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Thurnheer, Christine
    Günthard, Huldrych F.
    Khanna, Nina
    Walker, Lucy Jane
    Arancibia-Cárcamo, Carolina V.
    Newell, Evan W.
    Willberg, Christian B.
    Klenerman, Paul
    CD161 Defines a Functionally Distinct Subset of Pro-Inflammatory Natural Killer Cells2018Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, artikkel-id 486Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.

  • 318. Kurioka, Ayako
    et al.
    Jahun, Aminu S.
    Hannaway, Rachel F.
    Walker, Lucy J.
    Fergusson, Joannah R.
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Corbett, Alexandra J.
    Ussher, James E.
    Willberg, Christian B.
    Klenerman, Paul
    Shared and Distinct Phenotypes and Functions of Human CD161++ V alpha 7.2+T Cell Subsets2017Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, artikkel-id 1031Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human mucosal-associated invariant T (MAIT) cells are an important T cell subset that are enriched in tissues and possess potent effector functions. Typically such cells are marked by their expression of V alpha 7.2-J alpha 33/J alpha 20/J alpha 12 T cell receptors, and functionally they are major histocompatibility complex class I-related protein 1 (MR1)-restricted, responding to bacterially derived riboflavin synthesis intermediates. MAIT cells are contained within the CD161++ V alpha 7.2+ T cell population, the majority of which express the CD8 receptor (CD8+), while a smaller fraction expresses neither CD8 or CD4 coreceptor (double negative; DN) and a further minority are CD4+. Whether these cells have distinct homing patterns, phenotype and functions have not been examined in detail. We used a combination of phenotypic staining and functional assays to address the similarities and differences between these CD161++ V alpha 7.2+ T cell subsets. We find that most features are shared between CD8+ and DN CD161++ V alpha 7.2+ T cells, with a small but detectable role evident for CD8 binding in tuning functional responsiveness. By contrast, the CD4+ CD161++ V alpha 7.2+ T cell population, although showing MR1-dependent responsiveness to bacterial stimuli, display reduced T helper 1 effector functions, including cytolytic machinery, while retaining the capacity to secrete interleukin-4 (IL-4) and IL-13. This was consistent with underlying changes in transcription factor (TF) expression. Although we found that only a proportion of CD4+ CD161++ V alpha 7.2+ T cells stained for the MR1-tetramer, explaining some of the heterogeneity of CD4+ CD161++ V alpha 7.2+ T cells, these differences in TF expression were shared with CD4+ CD161++ MR1-tetramer+ cells. These data reveal the functional diversity of human CD161++ V alpha 7.2+ T cells and indicate potentially distinct roles for the different subsets in vivo.

  • 319.
    Kutsenko, Alexey
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Svensson, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Nystedt, Björn
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab). Uppsala University, Sweden.
    Lundeberg, Joakim
    Björk, Petra
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sonnhammer, Erik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Giacomello, Stefania
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Visa, Neus
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wieslander, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The Chironomus tentans genome sequence and the organization of the Balbiani ring genes2014Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 15, s. 819-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The polytene nuclei of the dipteran Chironomus tentans (Ch. tentans) with their Balbiani ring (BR) genes constitute an exceptional model system for studies of the expression of endogenous eukaryotic genes. Here, we report the first draft genome of Ch. tentans and characterize its gene expression machineries and genomic architecture of the BR genes. Results: The genome of Ch. tentans is approximately 200 Mb in size, and has a low GC content (31%) and a low repeat fraction (15%) compared to other Dipteran species. Phylogenetic inference revealed that Ch. tentans is a sister clade to mosquitoes, with a split 150-250 million years ago. To characterize the Ch. tentans gene expression machineries, we identified potential orthologus sequences to more than 600 Drosophila melanogaster (D. melanogaster) proteins involved in the expression of protein-coding genes. We report novel data on the organization of the BR gene loci, including a novel putative BR gene, and we present a model for the organization of chromatin bundles in the BR2 puff based on genic and intergenic in situ hybridizations. Conclusions: We show that the molecular machineries operating in gene expression are largely conserved between Ch. tentans and D. melanogaster, and we provide enhanced insight into the organization and expression of the BR genes. Our data strengthen the generality of the BR genes as a unique model system and provide essential background for in-depth studies of the biogenesis of messenger ribonucleoprotein complexes.

  • 320.
    Lackmann, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    High-throughput RNA structure probing reveals critical folding events during early 60S ribosome assembly in yeastManuskript (preprint) (Annet vitenskapelig)
  • 321.
    Lackmann, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mrd1 is involved in restructuring the U3 snoRNP and central regions in the 90S pre-ribosomeManuskript (preprint) (Annet vitenskapelig)
  • 322.
    Lackmann, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nucleolar Ribosome Assembly2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Ribosomes are macromolecular machines that are responsible for production of every protein in a living cell. Yet we do not know the details about how these machines are formed. The ribosome consists of four RNA strands and roughly 80 proteins that associate with each other in the nucleolus and form pre-ribosomal complexes. Eukaryotes, in contrast to prokaryotes, need more than 200 non-ribosomal factors to assemble ribosomes. These associate with pre-ribosomal complexes at different stages as they travel from the nucleolus to the cytoplasm and are required for pre-rRNA processing. We do however lack knowledge about the molecular function of most of these factors and what enables pre-rRNA processing. Especially, information is missing about how non-ribosomal factors influence folding of the pre-rRNA and to what extent the pre-ribosomal complexes are restructured during their maturation. 

    This thesis aims to obtain a better understanding of the earliest events of ribosome assembly, namely those that take place in the nucleolus. This has been achieved by studying the essential protein Mrd1 by mutational analysis in the yeast Saccharomyces cerevisiae as well as by obtaining structural information of nucleolar pre-ribosomal complexes. Mrd1 has a modular structure consisting of multiple RNA binding domains (RBDs) that we find is conserved throughout eukarya. We show that an evolutionary conserved linker region of Mrd1 is crucial for function of the protein and likely forms an essential module together with adjacent RBDs. By obtaining structural information of pre-ribosomal complexes at different stages, we elucidate what structuring events occur in the nucleolus.  We uncover a direct role of Mrd1 in structuring the pre-rRNA in early pre-ribosomal complexes, which provides an explanation for why pre-rRNA cannot be processed in Mrd1 mutants.

  • 323.
    Lackmann, Fredrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Belikov, Sergey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Burlacu, Elena
    Granneman, Sander
    Wieslander, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Maturation of the 90S pre-ribosome requires Mrd1 dependent U3 snoRNA and 35S pre-rRNA structural rearrangements2018Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr 7, s. 3692-3706Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In eukaryotes, ribosome biogenesis requires folding and assembly of the precursor rRNA (pre-rRNA) with a large number of proteins and snoRNPs into huge RNA-protein complexes. In spite of intense genetic, biochemical and high-resolution cryo-EM studies in Saccharomyces cerevisiae, information about the structure of the 35S pre-rRNA is limited. To overcome this, we performed high-throughput SHAPE chemical probing on the 35S pre-rRNA within 90S pre-ribosomes. We focused our analyses on external (5' ETS) and internal (ITS1) transcribed spacers as well as the 18S rRNA region. We show that in the 35S pre-rRNA, the central pseudoknot is not formed and the central core of the 18S rRNA is in an open configuration but becomes more constrained in 20S pre-rRNA. The essential ribosome biogenesis protein Mrd1 influences the structure of the 18S rRNA region locally and is involved in organizing the central pseudoknot and surrounding structures. We demonstrate that U3 snoRNA dynamically interacts with the 35S pre-rRNA and that Mrd1 is required for disrupting U3 snoRNA base pairing interactions in the 5' ETS. We propose that the dynamic U3 snoRNA interactions and Mrd1 are essential for establishing the structure of the central core of 18S rRNA that is required for processing and 40S subunit function.

  • 324.
    Lackmann, Fredrik
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Belikov, Sergey
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wieslander, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Linker 2 of the eukaryotic pre-ribosomal processing factor Mrd1p is an essential interdomain functionally coupled to upstream RNA Binding Domain 2 (RBD2)2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 4, artikkel-id e0175506Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ribosome synthesis is an essential process in all cells. In Sacharomyces cerevisiae, the precursor rRNA, 35S pre-rRNA, is folded and assembled into a 90S pre-ribosomal complex. The 40S ribosomal subunit is processed from the pre-ribosomal complex. This requires concerted action of small nucleolar RNAs, such as U3 snoRNA, and a large number of transacting factors. Mrd1p, one of the essential small ribosomal subunit synthesis factors is required for cleavage of the 35S pre-rRNA to generate 18S rRNA of the small ribosomal subunit. Mrd1p is evolutionary conserved in all eukaryotes and in yeast it contains five RNA Binding Domains (RBDs) separated by linker regions. One of these linkers, Linker 2 between RBD2 and RBD3, is conserved in length, predicted to be structured and contains conserved clusters of amino acid residues. In this report, we have analysed Linker 2 mutations and demonstrate that it is essential for Mrd1p function during pre-ribosomal processing. Extensive changes of amino acid residues as well as specific changes of conserved clusters of amino acid residues were found to be incompatible with synthesis of pre-40S ribosomes and cell growth. In addition, gross changes in primary sequence of Linker 2 resulted in Mrd1p instability, leading to degradation of the N-terminal part of the protein. Our data indicates that Linker 2 is functionally coupled to RBD2 and argues for that these domains constitute a functional module in Mrd1p. We conclude that Linker 2 has an essential role for Mrd1p beyond just providing a defined length between RBD2 and RBD3.

  • 325.
    Lasaviciute, Gintare
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Björkander, Sophia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Carvalho-Queiroz, Claudia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hed Myrberg, Ida
    Nussbaum, Bianca
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nilsson, Caroline
    Bemark, Mats
    Nilsson, Anna
    Sverremark-Ekström, Eva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Saghafian-Hedengren, Shanie
    Epstein-Barr Virus, but Not Cytomegalovirus, Latency Accelerates the Decay of Childhood Measles and Rubella Vaccine Responses-A 10-Year Follow-up of a Swedish Birth Cohort2017Inngår i: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 8, artikkel-id 1865Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are ubiquitous and persistent herpesviruses commonly acquired during childhood. Both viruses have a significant impact on the immune system, especially through mediating the establishment of cellular immunity, which keeps these viruses under control for life. Far less is known about how these viruses influence B-cell responses. Objectives: To evaluate the impact of latent EBV and CMV infection on rubella- and measles-specific antibody responses as well as on the B-cell compartment in a prospective birth cohort followed during the first 10 years of life. Methods: IgG titers against rubella and measles vaccines were measured in plasma obtained from the same donors at 2, 5, and 10 years of age. Peripheral B-cell subsets were evaluated ex vivo at 2 and 5 years of age. Factors related to optimal B-cell responses including IL-21 and CXCL13 levels in plasma were measured at all-time points. Results: EBV carriage in the absence of CMV associated with an accelerated decline of rubella and measles-specific IgG levels (p = 0.003 and p = 0.019, respectively, linear mixed model analysis), while CMV carriage in the absence of EBV associated with delayed IgG decay over time for rubella (p = 0.034). At 5 years of age, EBV but not CMV latency associated with a lower percentage of plasmablasts, but higher IL-21 levels in the circulation. Conclusion: Our findings suggest that EBV carriage in the absence of CMV influences the B-cell compartment and the dynamics of antibody responses over time during steady state in the otherwise healthy host.

  • 326. Lateef, Dalya M.
    et al.
    Abreu-Vieira, Gustavo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Xiao, Cuiying
    Reitman, Marc L.
    Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-32014Inngår i: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 306, nr 6, s. E681-E687Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and beta 3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.

  • 327.
    Latvala, Siiri
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Vare, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Karlsson, Hanna
    Elihn, Karine
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    In vitro genotoxicity assessment of airborne nickel nanoparticles using air-liquid interface exposure2016Manuskript (preprint) (Annet vitenskapelig)
  • 328.
    Latvala, Siiri
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Vare, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Karlsson, Hanna L.
    Elihn, Karine
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    In vitro genotoxicity of airborne Ni-NP in air-liquid interface2017Inngår i: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 37, nr 12, s. 1420-1427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies using advanced toxicological methods enabling in vitro conditions that are more realistic are currently needed for understanding the risks of pulmonary exposure to airborne nanoparticles. Owing to the carcinogenicity of certain nickel compounds, the increased production of nickel nanoparticles (Ni-NPs) raises occupational safety concerns. The aim of this study was to investigate the genotoxicity of airborne Ni-NPs using a recently developed air-liquid interface exposure system. The wild-type Chinese hamster lung fibroblast cell line (V79) was used and cytotoxicity, DNA damage and mutagenicity were studied by testing colony forming efficiency, alkaline DNA unwinding and HPRT mutation assays, respectively. Additionally, co-exposure to a PARP-1 inhibitor was performed to test possible involvement of base excision repair (BER) in repair of Ni-induced DNA damage. The results showed that cell viability was reduced significantly (to 45% and 46%) after 48hours Ni-NP exposure at concentrations of 0.15 and 0.32g cm(-2). DNA damage was significantly increased after Ni-NP exposure in the presence of the BER inhibitor indicating that Ni-NP-induced DNA damages are subsequently repaired by BER. Furthermore, there was no increased HPRT mutation frequency following Ni-NP exposure. In conclusion, this study shows that Ni-NP treatment of lung fibroblasts in an air-liquid interface system that mimics real-life exposure, results in increased DNA strand breaks and reduced cellular viability. These DNA lesions were repaired with BER in an error-free manner without resulting in mutations. This study also underlines the importance of appropriate quantification of the actual exposure concentrations during air-liquid interface exposure studies. The aim of this study was to investigate the genotoxicity of airborne Ni nanoparticles using a recently developed air-liquid interface exposure system that mimics real-life exposure. Cytotoxicity, DNA damage and mutagenicity were in the V79 cell line. Ni nanoparticle exposure of the cells in the air-liquid interface resulted in increased DNA strand breaks and reduced cellular viability at concentrations of 0.15 and 0.32 g cm (-2). These DNA lesions were repaired with BER in an error-free manner without resulting in mutations

  • 329. Lebaron, Simon
    et al.
    Segerstolpe, Åsa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    French, Sarah L.
    Dudnakova, Tatiana
    Alves, Flavia de Lima
    Granneman, Sander
    Rappsilber, Juri
    Beyer, Ann L.
    Wieslander, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tollervey, David
    Rrp5 Binding at Multiple Sites Coordinates Pre-rRNA Processing and Assembly2013Inngår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 52, nr 5, s. 707-719Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vivo UV crosslinking identified numerous preribosomal RNA (pre-rRNA) binding sites for the large, highly conserved ribosome synthesis factor Rrp5. Intramolecular complementation has shown that the C-terminal domain (CTD) of Rrp5 is required for pre-rRNA cleavage at sites A0-A2 on the pathway of 18S rRNA synthesis, whereas the N-terminal domain (NTD) is required for A3 cleavage on the pathway of 5.8S/25S rRNA synthesis. The CTD was crosslinked to sequences flanking A2 and to the snoRNAs U3, U14, snR30, and snR10, which are required for cleavage at A0-A2. The NTD was crosslinked to sequences flanking A3 and to the RNA component of ribonuclease MRP, which cleaves site A3. Rrp5 could also be directly crosslinked to several large structural proteins and nucleoside triphosphatases. A key role in coordinating preribosomal assembly and processing was confirmed by chromatin spreads. Following depletion of Rrp5, cotranscriptional cleavage was lost and preribosome compaction greatly reduced.

  • 330. Leepiyasakulchai, Chaniya
    et al.
    Taher, Chato
    Chuquimia, Olga D.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Mazurek, Jolanta
    Söderberg-Naucler, Cecilia
    Fernandez, Carmen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sköld, Markus
    Infection Rate and Tissue Localization of Murine IL-12p40-Producing Monocyte-Derived CD103(+) Lung Dendritic Cells during Pulmonary Tuberculosis2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 7, s. e69287-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-hematopoietic cells, including lung epithelial cells, influence host immune responses. By co-culturing primary alveolar epithelial cells and monocytes from naive donor mice, we show that alveolar epithelial cells support monocyte survival and differentiation in vitro, suggesting a role for non-hematopoietic cells in monocyte differentiation during the steady state in vivo. CD103(+) dendritic cells (alpha E-DC) are present at mucosal surfaces. Using a murine primary monocyte adoptive transfer model, we demonstrate that alpha E-DC in the lungs and pulmonary lymph nodes are monocyte-derived during pulmonary tuberculosis. The tissue localization may influence the functional potential of alpha E-DC that accumulate in Mycobacterium tuberculosis-infected lungs. Here, we confirm the localization of alpha E-DC in uninfected mice beneath the bronchial epithelial cell layer and near the vascular wall, and show that alpha E-DC have a similar distribution in the lungs during pulmonary tuberculosis and are detected in the bronchoalveolar lavage fluid from infected mice. Lung DC can be targeted by M. tuberculosis in vivo and play a role in bacterial dissemination to the draining lymph node. In contrast to other DC subsets, only a fraction of lung alpha E-DC are infected with the bacterium. We also show that virulent M. tuberculosis does not significantly alter cell surface expression levels of MHC class II on infected cells in vivo and that alpha E-DC contain the highest frequency of IL-12p40(+) cells among the myeloid cell subsets in infected lungs. Our results support a model in which inflammatory monocytes are recruited into the M. tuberculosis-infected lung tissue and, depending on which non-hematopoietic cells they interact with, differentiate along different paths to give rise to multiple monocyte-derived cells, including DC with a distinctive alpha E-DC phenotype.

  • 331. Leibiger, Christine
    et al.
    Deisel, Jana
    Aufschnaiter, Andreas
    Ambros, Stefanie
    Tereshchenko, Maria
    Verheijen, Bert M.
    Büttner, Sabrina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Graz, Austria.
    Braun, Ralf J.
    TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity2018Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, nr 9, s. 1593-1607Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    TDP-43 is a nuclear RNA-binding protein whose cytoplasmic accumulation is the pathological hallmark of amyotrophic lateral sclerosis (ALS). For a better understanding of this devastating disorder at the molecular level, it is important to identify cellular pathways involved in the clearance of detrimental TDP-43. Using a yeast model system, we systematically analyzed to which extent TDP-43-triggered cytotoxicity is modulated by conserved lysosomal clearance pathways. We observed that the lysosomal fusion machinery and the endolysosomal pathway, which are crucial for proper lysosomal function, were pivotal for survival of cells exposed to TDP-43. Interestingly, TDP-43 itself interfered with these critical TDP-43 clearance pathways. In contrast, autophagy played a complex role in this process. It contributed to the degradation of TDP-43 in the absence of endolysosomal pathway activity, but its induction also enhanced cell death. Thus, TDP-43 interfered with lysosomal function and its own degradation via lysosomal pathways, and triggered lethal autophagy. We propose that these effects critically contribute to cellular dysfunction in TDP-43 proteinopathies.

  • 332. Li, Dianxiang
    et al.
    Luan, Yuanyuan
    Wang, Lei
    Qi, Mei
    Wang, Jinxing
    Xu, Jidong
    Arefin, Badrul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Li, Meixia
    Expression of the Shrimp wap gene in Drosophila elicits defense responses and protease inhibitory activity2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 8779Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The wap gene encodes a single whey acidic protein (WAP) domain-containing peptide from Chinese white shrimp (Fenneropenaeus chinensis), which shows broad-spectrum antimicrobial activities and proteinase inhibitory activities in vitro. To explore the medical applications of the WAP peptide, a wap gene transgenic Drosophila melanogaster was constructed. In wap-expressing flies, high expression levels of wap gene (> 100 times) were achieved, in contrast to those of control flies, by qRT-PCR analysis. The wap gene expression was associated with increased resistance to microbial infection and decreased bacterial numbers in the flies. In addition, the WAP protein extract from wap-expressing flies, compared with control protein extract from control flies, showed improved antimicrobial activities against broad Gram-positive and Gram-negative bacteria, including the clinical drug resistant bacterium of methicillin-resistant S. aureus (MRSA), improved protease inhibitor activities against crude proteinases and commercial proteinases, including elastase, subtilis proteinase A, and proteinase K in vitro, and improved growth rate and microbial resistance, as well as wound-healing in loach and mouse models. These results suggest that wap-expressing flies could be used as a food additive in aquaculture to prevent infections and a potential antibacterial for fighting drug-resistant bacteria.

  • 333. Li, Xianghua
    et al.
    Overton, Ian M.
    Baines, Richard A.
    Keegan, Liam P.
    O'Connell, Mary A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. University of Edinburgh.
    The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster2014Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 42, nr 2, s. 1139-1151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RNA editing by deamination of specific adenosine bases to inosines during pre-mRNA processing generates edited isoforms of proteins. Recoding RNA editing is more widespread in Drosophila than in vertebrates. Editing levels rise strongly at metamorphosis, and Adar(5G1) null mutant flies lack editing events in hundreds of CNS transcripts; mutant flies have reduced viability, severely defective locomotion and age-dependent neurodegeneration. On the other hand, overexpressing an adult dADAR isoform with high enzymatic activity ubiquitously during larval and pupal stages is lethal. Advantage was taken of this to screen for genetic modifiers; Adar overexpression lethality is rescued by reduced dosage of the Rdl (Resistant to dieldrin), gene encoding a subunit of inhibitory GABA receptors. Reduced dosage of the Gad1 gene encoding the GABA synthetase also rescues Adar overexpression lethality. Drosophila Adar(5G1) mutant phenotypes are ameliorated by feeding GABA modulators. We demonstrate that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar(5G1) null mutant or targeted Adar knockdown motor neurons exhibit increased excitability. GABA inhibitory signalling is impaired in human epileptic and autistic conditions, and vertebrate ADARs may have a relevant evolutionarily conserved control over neuronal excitability.

  • 334.
    Lindberg, Bo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Insights from the genome annotation of Elizabethkingia anophelis from the malaria vector Anopheles gambiaeManuskript (preprint) (Annet vitenskapelig)
  • 335.
    Lindberg, Bo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Medium from γ-irradiated Escherichia coli Bacteria Stimulates a Unique Immune Response in Drosophila CellsManuskript (preprint) (Annet vitenskapelig)
  • 336.
    Lindberg, Bo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Novel Modes of Immune Activation in Anopheles gambiae and Drosophila melanogaster2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Malaria is a disease of poverty and continues to plague a great part of the world’s population. An increased understanding of the interactions between the vector mosquito, the malaria parasite, and also the mosquito gut microbiota are pivotal for the development of novel measures against the disease. The first aim of this thesis was to gain a deeper knowledge of the microbial compounds that elicit immune responses in the main malaria vector Anopheles gambiae and also using the model organism Drosophila melanogaster. The second aim was to analyse the genome characteristics in silico of a bacterial symbiont from the mosquito midgut. In Paper I, we investigated the immunogenic effects of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate in Anopheles. This compound is the primary activator of human Vγ9Vδ2 T cells and is only produced by organisms that use the non-mevalonate pathway for isoprenoid synthesis, such as Plasmodium and most eubacteria but not animals. We show that the parasite releases compounds of this nature and that provision of HMBPP in the bloodmeal induces an immune response in the mosquito. In Paper II, we investigated whether bacteria inactivated by gamma-irradiation could still stimulate potent immune responses in Drosophila cells. We show that E. coli retains the capacity to synthesize and release peptidoglycan de novo for several days after the irradiation event. When cells were stimulated with supernatants from irradiated bacteria, however, a unique response was observed. In Paper III, we presented the draft genome sequence of Elizabethkingia anophelis, a predominant gut symbiont of An. gambiae recently described in our lab and subsequently found in another laboratory strain of the mosquito. The genome data were then annotated in Paper IV to gain insights into the symbiotic characteristics of the bacterium, as well as the genetic background for its strong antibiotic resistance. In conclusion, this thesis work has shed light on novel modes for stimulating immune responses in insects and also led to the characterization of a predominant bacteria in the mosquito gut that may be used in future malaria intervention strategies. 

  • 337.
    Lindberg, Bo G.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Merritt, Eleanor A.
    Rayl, Melanie
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Liu, Chenxiao
    Parmryd, Ingela
    Olofsson, Berit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Faye, Ingrid
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Immunogenic and Antioxidant Effects of a Pathogen-Associated Prenyl Pyrophosphate in Anopheles gambiae2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 8, s. e73868-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite efficient vector transmission, Plasmodium parasites suffer great bottlenecks during their developmental stages within Anopheles mosquitoes. The outcome depends on a complex three-way interaction between host, parasite and gut bacteria. Although considerable progress has been made recently in deciphering Anopheles effector responses, little is currently known regarding the underlying microbial immune elicitors. An interesting candidate in this sense is the pathogen-derived prenyl pyrophosphate and designated phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), found in Plasmodium and most eubacteria but not in higher eukaryotes. HMBPP is the most potent stimulant known of human V gamma 9V delta 2 T cells, a unique lymphocyte subset that expands during several infections including malaria. In this study, we show that V(Y)9V delta 2 T cells proliferate when stimulated with supernatants from intraerythrocytic stages of Plasmodium falciparum cultures, suggesting that biologically relevant doses of phosphoantigens are excreted by the parasite. Next, we used Anopheles gambiae to investigate the immune-and redox-stimulating effects of HMBPP. We demonstrate a potent activation in vitro of all but one of the signaling pathways earlier implicated in the human V(Y)9V delta 2 T cell response, as p38, JNK and PI3K/Akt but not ERK were activated in the A. gambiae 4a3B cell line. Additionally, both HMBPP and the downstream endogenous metabolite isopentenyl pyrophosphate displayed antioxidant effects by promoting cellular tolerance to hydrogen peroxide challenge. When provided in the mosquito blood meal, HMBPP induced temporal changes in the expression of several immune genes. In contrast to meso-diaminopimelic acid containing peptidoglycan, HMBPP induced expression of dual oxidase and nitric oxide synthase, two key determinants of Plasmodium infection. Furthermore, temporal fluctuations in midgut bacterial numbers were observed. The multifaceted effects observed in this study indicates that HMBPP is an important elicitor in common for both Plasmodium and gut bacteria in the mosquito.

  • 338.
    Lindberg, Bo G.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Oldenvi, Sandra
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Steiner, Håkan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Medium from gamma-irradiated Escherichia coli bacteria stimulates a unique immune response in Drosophila cells2014Inngår i: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 46, nr 2, s. 392-400Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It is well known that gamma-irradiated, non-dividing bacteria can elicit potent immune responses in mammals. Compared to traditional heat or chemical inactivation of microbes, gamma -irradiation likely preserves metabolic activity and antigenic features to a larger extent. We have previously shown that antimicrobial peptides are induced in Drosophila by peptidoglycan fragments secreted into the medium of exponentially growing bacterial cultures. In this study, we gamma-irradiated Escherichia coil cells at a dose that halted cell division. The temporal synthesis and release of peptidoglycan fragments were followed as well as the potential of bacterial supernatants to induce immune responses in Drosophila S2 cells. We demonstrate that peptidoglycan synthesis continues for several days post irradiation and that monomeric peptidoglycan is shed into the medium. Whole transcriptome analysis revealed a strong immune response against the bacterial medium. The response to medium taken directly post irradiation shows a large overlap to that of peptidoglycan. Medium from prolonged bacterial incubation does, however, stimulate a selective set of immune genes. A shift towards a stress response was instead observed with a striking induction of several heat shock proteins. Our findings suggest that gamma-irradiated bacteria release elicitors that stimulate a novel response in Drosophila.

  • 339.
    Lindberg, Bo G.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Tang, Xiongzhuo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Dantoft, Widad
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Gohel, Priya
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Seyedoleslami Esfahani, Shiva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lindvall, Jessica M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Engström, Ylva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Nubbin isoform antagonism governs Drosophila intestinal immune homeostasis2018Inngår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 14, nr 3, artikkel-id e1006936Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gut immunity is regulated by intricate and dynamic mechanisms to ensure homeostasis despite a constantly changing microbial environment. Several regulatory factors have been described to participate in feedback responses to prevent aberrant immune activity. Little is, however, known about how transcriptional programs are directly tuned to efficiently adapt host gut tissues to the current microbiome. Here we show that the POU/Oct gene nubbin (nub) encodes two transcription factor isoforms, Nub-PB and Nub-PD, which antagonistically regulate immune gene expression in Drosophila. Global transcriptional profiling of adult flies overexpressing Nub-PB in immunocompetent tissues revealed that this form is a strong transcriptional activator of a large set of immune genes. Further genetic analyses showed that Nub-PB is sufficient to drive expression both independently and in conjunction with nuclear factor kappa B (NF-κB), JNK and JAK/STAT pathways. Similar overexpression of Nub-PD did, conversely, repress expression of the same targets. Strikingly, isoform co-overexpression normalized immune gene transcription, suggesting antagonistic activities. RNAi-mediated knockdown of individual nub transcripts in enterocytes confirmed antagonistic regulation by the two isoforms and that both are necessary for normal immune gene transcription in the midgut. Furthermore, enterocyte-specific Nub-PB expression levels had a strong impact on gut bacterial load as well as host lifespan. Overexpression of Nub-PB enhanced bacterial clearance of ingested Erwinia carotovora carotovora 15. Nevertheless, flies quickly succumbed to the infection, suggesting a deleterious immune response. In line with this, prolonged overexpression promoted a proinflammatory signature in the gut with induction of JNK and JAK/STAT pathways, increased apoptosis and stem cell proliferation. These findings highlight a novel regulatory mechanism of host-microbe interactions mediated by antagonistic transcription factor isoforms.

  • 340.
    Lindås, Ann-Christin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bernander, Rolf
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The cell cycle of archaea2013Inngår i: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 11, nr 9, s. 627-638Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Growth and proliferation of all cell types require intricate regulation and coordination of chromosome replication, genome segregation, cell division and the systems that determine cell shape. Recent findings have provided insight into the cell cycle of archaea, including the multiple-origin mode of DNA replication, the initial characterization of a genome segregation machinery and the discovery of a novel cell division system. The first archaeal cytoskeletal protein, crenactin, was also recently described and shown to function in cell shape determination. Here, we outline the current understanding of the archaeal cell cycle and cytoskeleton, with an emphasis on species in the genus Sulfolobus, and consider the major outstanding questions in the field.

  • 341.
    Lindås, Ann-Christin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Chruszcz, Maksymilian
    Bernander, Rolf
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Valegård, Karin
    Structure of crenactin, an archaeal actin homologue active at 90 degrees C2014Inngår i: Acta Crystallographica Section D: Biological Crystallography, ISSN 0907-4449, E-ISSN 1399-0047, Vol. 70, s. 492-500Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The crystal structure of the archaeal actin, crenactin, from the rod-shaped hyperthermophilic (optimal growth at 90 degrees C) crenarchaeon Pyrobaculum calidifontis is reported at 3.35 angstrom resolution. Despite low amino-acid sequence identity, the three-dimensional structure of the protein monomer is highly similar to those of eukaryotic actin and the bacterial MreB protein. Crenactin-specific features are also evident, as well as elements that are shared between crenactin and eukaryotic actin but are not found in MreB. In the crystal, crenactin monomers form right-handed helices, demonstrating that the protein is capable of forming filament-like structures. Monomer interactions in the helix, as well as interactions between crenactin and ADP in the nucleotide-binding pocket, are resolved at the atomic level and compared with those of actin and MreB. The results provide insights into the structural and functional properties of a heat-stable archaeal actin and contribute to the understanding of the evolution of actin-family proteins in the three domains of life.

  • 342. Lisowska, Halina
    et al.
    Brehwens, Karl
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Zoelzer, Friedo
    Wegierek-Ciuk, Aneta
    Czub, Joanna
    Lankoff, Anna
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Jan Kochanowski University, Poland.
    Effect of hypothermia on radiation-induced micronuclei and delay of cell cycle progression in TK6 cells2014Inngår i: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 90, nr 4, s. 318-324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Low temperature (hypothermia) during irradiation leads to a reduced frequency of micronuclei in TK6 cells and it has been suggested that perturbation of cell cycle progression is responsible for this effect. The aim of the study was to test this hypothesis. Materials and methods: Human lymphoblastoid TK6 cells were treated by a combination of hypothermia (0.8 degrees C) and ionizing radiation in varying order (hypothermia before, during or after irradiation) and micronuclei were scored. Growth assay and two-dimensional flow cytometry was used to analyze cell cycle kinetics following irradiated of cells at 0.8 degrees C or 37.0 degrees C. Results: The temperature effect was observed at the level of micronuclei regardless of whether cells were cooled during or immediately before or after the radiation exposure. No indication of cell cycle perturbation by combined exposure to hypothermia and radiation could be detected. Conclusions: The protective effect of hypothermia observed at the level of cytogenetic damage was not due to a modulation of cell cycle progression. A possible alternative mechanism and experiments to test it are discussed.

  • 343. Lisowska, Halina
    et al.
    Cheng, Lei
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sollazzo, Alice
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lundholm, Lovisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wegierek-Ciuk, Aneta
    Sommer, Sylwester
    Lankoff, Anna
    Wojcik, Andrzej
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Jan Kochanowski University, Poland.
    Hypothermia modulates the DNA damage response to ionizing radiation in human peripheral blood lymphocytes2018Inngår i: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 94, nr 6, s. 551-557Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Low temperature at exposure has been shown to act in a radioprotective manner at the level of cytogenetic damage. It was suggested to be due to an effective transformation of DNA damage to chromosomal damage at low temperature. The purpose of the study was to analyze the kinetics of aberration formation during the first hours after exposing human peripheral blood lymphocytes to ionizing radiation at 0.8 degrees C and 37 degrees C.Materials and methods: To this end, we applied the technique of premature chromosome condensation. In addition, DNA damage response was analyzed by measuring the levels of phosphorylated DNA damage responsive proteins ATM, DNA-PK and p53 and mRNA levels of the radiation-responsive genes BBC3, FDXR, GADD45A, XPC, MDM2 and CDKN1A.Results: A consistently lower frequency of chromosomal breaks was observed in cells exposed at 0.8 degrees C as compared to 37 degrees C already after 30minutes postexposure. This effect was accompanied by elevated levels of phosphorylated ATM and DNA-PK proteins and a reduced immediate level of phosphorylated p53 and of the responsive genes.Conclusions: Low temperature at exposure appears to promote DNA repair leading to reduced transformation of DNA damage to chromosomal aberrations.

  • 344. Liu, Han
    et al.
    Orell, Alvaro
    Maes, Dominique
    van Wolferen, Marleen
    Lindås, Ann-Christin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Bernander, Rolf
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Albers, Sonja-Verena
    Charlier, Daniel
    Peeters, Eveline
    BarR, an Lrp-type transcription factor in Sulfolobus acidocaldarius, regulates an aminotransferase gene in a beta- alanine responsive manner2014Inngår i: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 92, nr 3, s. 625-639Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In archaea, nothing is known about the -alanine degradation pathway or its regulation. In this work, we identify and characterize BarR, a novel Lrp-like transcription factor and the first one that has a non-proteinogenic amino acid ligand. BarR is conserved in Sulfolobus acidocaldarius and Sulfolobus tokodaii and is located in a divergent operon with a gene predicted to encode -alanine aminotransferase. Deletion of barR resulted in a reduced exponential growth rate in the presence of -alanine. Furthermore, qRT-PCR and promoter activity assays demonstrated that BarR activates the expression of the adjacent aminotransferase gene, but only upon -alanine supplementation. In contrast, auto-activation proved to be -alanine independent. Heterologously produced BarR is an octamer in solution and forms a single complex by interacting with multiple sites in the 170bp long intergenic region separating the divergently transcribed genes. In vitro, DNA binding is specifically responsive to -alanine and site-mutant analyses indicated that -alanine directly interacts with the ligand-binding pocket. Altogether, this work contributes to the growing body of evidence that in archaea, Lrp-like transcription factors have physiological roles that go beyond the regulation of -amino acid metabolism.

  • 345. Liu, Han
    et al.
    Wang, Kun
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Lindås, Ann-Christin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Peeters, Eveline
    The genome-scale DNA-binding profile of BarR, a beta-alanine responsive transcription factor in the archaeon Sulfolobus acidocaldarius2016Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, artikkel-id 569Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The Leucine-responsive Regulatory Protein (Lrp) family is a widespread family of regulatory transcription factors in prokaryotes. BarR is an Lrp-like transcription factor in the model archaeon Sulfolobus acidocaldarius that activates the expression of a beta-alanine aminotransferase gene, which is involved in beta-alanine degradation. In contrast to classical Lrp-like transcription factors, BarR is not responsive to any of the alpha-amino acids but interacts specifically with beta-alanine. Besides the juxtaposed beta-alanine aminotransferase gene, other regulatory targets of BarR have not yet been identified although beta-alanine is the precursor of coenzyme A and thus an important central metabolite. The aim of this study is to extend the knowledge of the DNA-binding characteristics of BarR and of its corresponding regulon from a local to a genome-wide perspective. Results: We characterized the genome-wide binding profile of BarR using chromatin immunoprecipation combined with high-throughput sequencing (ChIP-seq). This revealed 21 genomic binding loci. High-enrichment binding regions were validated to interact with purified BarR protein in vitro using electrophoretic mobility shift assays and almost all targets were also shown to harbour a conserved semi-palindromic binding motif. Only a small subset of enriched genomic sites are located in intergenic regions at a relative short distance to a promoter, and qRT-PCR analysis demonstrated that only one additional operon is under activation of BarR, namely the glutamine synthase operon. The latter is also a target of other Lrp-like transcription factors. Detailed inspection of the BarR ChIP-seq profile at the beta-alanine aminotransferase promoter region in combination with binding motif predictions indicate that the operator structure is more complicated than previously anticipated, consisting of multiple (major and auxiliary) operators. Conclusions: BarR has a limited regulon, and includes also glutamine synthase genes besides the previously characterized beta-alanine aminotransferase. Regulation of glutamine synthase is suggestive of a link between beta-alanine and alpha-amino acid metabolism in S. acidocaldarius. Furthermore, this work reveals that the BarR regulon overlaps with that of other Lrp-like regulators.

  • 346. Liu, Yan
    et al.
    Zhang, Ding
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Engström, Åke
    Merényi, Gábor
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hagner, Matthias
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Yang, Hairu
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Kuwae, Asaomi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Wan, Yi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sjölinder, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Sjölinder, Hong
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Dynamic niche-specific adaptations in Neisseria meningitidis during infection2016Inngår i: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 18, nr 2, s. 109-117Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neisseria meningitidis is an opportunistic human pathogen that usually colonizes the nasopharyngeal mucosa asymptomatically. Upon invasion into the blood and central nervous system, this bacterium triggers a fulminant inflammatory reaction with the manifestations of septicemia and meningitis, causing high morbidity and mortality. To reveal the bacterial adaptations to specific and dynamic host environments, we performed a comprehensive proteomic survey of N. meningitidis isolated from the nasal mucosa, CSF and blood of a mouse disease model. We could identify 51 proteins whose expression pattern has been changed during infection, many of which have not yet been characterized. The abundance of proteins was markedly lower in the bacteria isolated from the nasal mucosa compared to the bacteria from the blood and CSF, indicating that initiating adhesion is the harshest challenge for meningococci. The high abundance of the glutamate dehydrogenase (GdhA) and Opa1800 proteins in all bacterial isolates suggests their essential role in bacterial survival in vivo. To evaluate the biological relevance of our proteomic findings, four candidate proteins from representative functional groups, such as the bacterial chaperone GroEL, IMP dehydrogenase GuaB, and membrane proteins PilQ and NMC0101, were selected and their impact on bacterial fitness was investigated by mutagenesis assays. This study provides an integrated picture of bacterial niche-specific adaptations during consecutive infection processes.

  • 347. Logan, Angela
    et al.
    Shabalina, Irina G.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Prime, Tracy A.
    Rogatti, Sebastian
    Kalinovich, Anastasia V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Hartley, Richard C.
    Budd, Ralph C.
    Cannon, Barbara
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Murphy, Michael P.
    In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice2014Inngår i: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 13, nr 4, s. 765-768Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In mtDNA mutator mice, mtDNA mutations accumulate leading to a rapidly aging phenotype. However, there is little evidence of oxidative damage to tissues, and when analyzed ex vivo, no change in production of the reactive oxygen species (ROS) superoxide and hydrogen peroxide by mitochondria has been reported, undermining the mitochondrial oxidative damage theory of aging. Paradoxically, interventions that decrease mitochondrial ROS levels in vivo delay onset of aging. To reconcile these findings, we used the mitochondria-targeted mass spectrometry probe MitoB to measure hydrogen peroxide within mitochondria of living mice. Mitochondrial hydrogen peroxide was the same in young mutator and control mice, but as the mutator mice aged, hydrogen peroxide increased. This suggests that the prolonged presence of mtDNA mutations in vivo increases hydrogen peroxide that contributes to an accelerated aging phenotype, perhaps through the activation of pro-apoptotic and pro-inflammatory redox signaling pathways.

  • 348.
    Luijten, Ineke
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    The effects of glucocorticoids on brown fat: physiological and molecular studies.2016Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Brown adipose tissue (BAT) is the main site for non-shivering thermogenesis in most mammals. The BAT-specific uncoupling protein-1 (UCP1) uncouples substrate oxidation from ATP production and hereby decreases metabolic efficiency. Currently, the search is on for factors that decrease BAT activity and hereby contribute to the development of obesity and obesity-related diseases. Antagonizing these could thus provide therapeutic benefits.

    Glucocorticoids are a class of steroid hormones that signal through the nuclear glucocorticoid receptor (GR) and play a role in glucose homeostasis, lipid metabolism and the immune response. Various studies in lean rodents have reported that exogenously administrated glucocorticoids increase BAT weight, fat content and lipid droplet size, and reduce GDP-binding to BAT, NE turnover in BAT and total BAT UCP1 mRNA and protein. In genetically obese ob/ob mice and fa/fa rats that exhibit hypercortisolism, adrenalectomy improves BAT morphology and increases BAT activity. Human studies on the effects of glucocorticoids on BAT are scarce, but indicate a decrease in BAT activity after prolonged hypercortisolism.

    The mechanisms behind the suppressive effects of glucocorticoids on BAT remain unclear. Research in rodents has shown that glucocorticoids may decrease sympathetic output from the central nervous system to BAT in situations of eucortisolism, hereby reducing its thermogenic activity. On the other hand, in vitro experiments show cell autonomous effects of glucocorticoids on the β-adrenergic signalling pathway and a dose-dependent suppression of UCP1 transcription mediated by the GR.

    It remains to be determined in which physiological situations either of these two pathways mediate the suppressive effects of glucocorticoids on BAT. Moreover, more research is needed into the intracellular signalling of glucocorticoids in brown adipocytes.

  • 349.
    Maiga, Bakary
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Human candidate polymorphisms and malaria susceptibility in sympatric ethnic groups, The Fulani and The Dogon of Mali2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In malaria endemic regions, resistance to malaria constitutes a critical selective pressureon genetic polymorphisms that regulate immune defense and inflammatory pathways.Differences in malaria susceptibility between sympatric ethnic groups have been described inMali. The Fulani are less susceptible to malaria compared to the neighboring group the Dogon,in spite of similar socio-economic and environmental conditions.

    Paper I is focused on IL-4-590 T/C polymorphism and correlation with levels of malariaspecific IgG, IgG (1-4) subclasses as well as malaria specific and total IgE level in the two ethnicgroups. Our data show that the Fulani individual carrying the IL-4-590 T allele found to havehigher parasite carriage rate and had higher levels of malaria-specific IgG4 and IgE compared tothe individual carrying the C allele. No such differences were seen within the Dogon.Paper II investigated 166 SNPs in the human host in individuals belonging to the Fulani and theDogon ethnic groups. These SNPs were correlated with total IgG against AMA-1, MSP-1, MSP-2 and CSP antigens as well as total IgE level. All antibody levels were higher in the Fulanicompared to the Dogon and strengthens previous finding that antibodies might play a role in theprotection seen in the Fulani. We identified higher frequencies of the protective blood group O.Several allelic differences between the two ethnic groups were found in CD36, IL-4, RTN3 andADCY9. Moreover several polymorphisms in SLC22A4, IRF1, IL5, LTA and TNF have beenfound to be correlated with anti-MSP antibody level; TLR6, IL3, TNF, and IL22 found to becorrelated with anti-MSP-2 antibody level in the Fulani. Such association was not seen in theDogon.

    In Paper III, the same individuals, as in paper II, were investigated with a focus on the FcγRIIapolymorphism and correlation with levels of anti-AMA-1, MSP-1, MSP-2, CSP specificantibodies as well as total IgE level. The genotype distribution and allele frequency weresignificantly different between the Fulani and the Dogon with the Fulani being HH, H allele- andthe Dogon RR, R allele carriers. A correlation between the HH genotype and the H allele andprotection against mild malaria was seen in the Fulani but not in the DogonTaken together our study has found significant genetic differences between the Fulani and theDogon Ethnic groups, which suggest that ethnicity should be taken into account in monitoring ofimmunological studies and vaccines trials in malaria endemic areas.

  • 350.
    Maiga, Bakary
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut. Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases/Faculty of Medicine, Pharmacy and Odonto, Stomatology, Bamako, Mali.
    Dolo, A
    Touré, O
    Dara, V
    Tapily, A
    Campino, S
    Sepulveda, N
    Corran, P
    Rockett, K
    Clark, T G
    Troye Blomberg, Marita
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Doumbo, O K
    Fc gamma Receptor IIa-H131R Polymorphism and Malaria Susceptibility in Sympatric Ethnic Groups, Fulani and Dogon of Mali2014Inngår i: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, nr 1, s. 43-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It has been previously shown that there are some interethnic differences in susceptibility to malaria between two sympatric ethnic groups of Mali, the Fulani and the Dogon. The lower susceptibility to Plasmodium falciparum malaria seen in the Fulani has not been fully explained by genetic polymorphisms previously known to be associated with malaria resistance, including haemoglobin S (HbS), haemoglobin C (HbC), alpha-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Given the observed differences in the distribution of FcγRIIa allotypes among different ethnic groups and with malaria susceptibility that have been reported, we analysed the rs1801274-R131H polymorphism in the FcγRIIa gene in a study of Dogon and Fulani in Mali (n = 939). We confirm that the Fulani have less parasite densities, less parasite prevalence, more spleen enlargement and higher levels of total IgG antibodies (anti-CSP, anti-AMA1, anti-MSP1 and anti-MSP2) and more total IgE (P < 0.05) compared with the Dogon ethnic group. Furthermore, the Fulani exhibit higher frequencies of the blood group O (56.5%) compared with the Dogon (43.5%) (P < 0.001). With regard to the FcγRIIa polymorphism and allele frequency, the Fulani group have a higher frequency of the H allele (Fulani 0.474, Dogon 0.341, P < 0.0001), which was associated with greater total IgE production (P = 0.004). Our findings show that the FcγRIIa polymorphism might have an implication in the relative protection seen in the Fulani tribe, with confirmatory studies required in other malaria endemic settings.

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