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  • 1.
    Adam, Iris
    et al.
    Department of Biology, University of Southern Denmark, Odense, Denmark.
    Riebel, Katharina
    Institute of Biology, Animal Sciences & Health, Leiden University, Leiden, Netherlands.
    Stål, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Wood, Neil
    Department of Molecular Physiology and Biophysics, Larner College of Medicine, University of Vermont, NJ, Burlington, United States.
    Previs, Michael J.
    Department of Molecular Physiology and Biophysics, Larner College of Medicine, University of Vermont, NJ, Burlington, United States.
    Elemans, Coen P. H.
    Department of Biology, University of Southern Denmark, Odense, Denmark.
    Daily vocal exercise is necessary for peak performance singing in a songbird2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 7787Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vocal signals, including human speech and birdsong, are produced by complicated, precisely coordinated body movements, whose execution is fitness-determining in resource competition and mate choice. While the acquisition and maintenance of motor skills generally requires practice to develop and maintain both motor circuitry and muscle performance, it is unknown whether vocal muscles, like limb muscles, exhibit exercise-induced plasticity. Here, we show that juvenile and adult zebra finches (Taeniopygia castanotis) require daily vocal exercise to first gain and subsequently maintain peak vocal muscle performance. Experimentally preventing male birds from singing alters both vocal muscle physiology and vocal performance within days. Furthermore, we find females prefer song of vocally exercised males in choice experiments. Vocal output thus contains information on recent exercise status, and acts as an honest indicator of past exercise investment in songbirds, and possibly in all vocalising vertebrates.

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  • 2. Adderley, Jack D.
    et al.
    von Freyend, Simona John
    Jackson, Sarah A.
    Bird, Megan J.
    Burns, Amy L.
    Anar, Burcu
    Metcalf, Tom
    Semblat, Jean-Philippe
    Billker, Oliver
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
    Wilson, Danny W.
    Doerig, Christian
    Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention2020Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 11, nr 1, artikel-id 4015Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.

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  • 3. Arbeitman, Claudia R.
    et al.
    Rojas, Pablo
    Ojeda-May, Pedro
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Högpresterande beräkningscentrum norr (HPC2N). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Garcia, Martin E.
    The SARS-CoV-2 spike protein is vulnerable to moderate electric fields2021Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikel-id 5407Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most of the ongoing projects aimed at the development of specific therapies and vaccines against COVID-19 use the SARS-CoV-2 spike (S) protein as the main target. The binding of the spike protein with the ACE2 receptor (ACE2) of the host cell constitutes the first and key step for virus entry. During this process, the receptor binding domain (RBD) of the S protein plays an essential role, since it contains the receptor binding motif (RBM), responsible for the docking to the receptor. So far, mostly biochemical methods are being tested in order to prevent binding of the virus to ACE2. Here we show, with the help of atomistic simulations, that external electric fields of easily achievable and moderate strengths can dramatically destabilise the S protein, inducing long-lasting structural damage. One striking field-induced conformational change occurs at the level of the recognition loop L3 of the RBD where two parallel beta sheets, believed to be responsible for a high affinity to ACE2, undergo a change into an unstructured coil, which exhibits almost no binding possibilities to the ACE2 receptor. We also show that these severe structural changes upon electric-field application also occur in the mutant RBDs corresponding to the variants of concern (VOC) B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil). Remarkably, while the structural flexibility of S allows the virus to improve its probability of entering the cell, it is also the origin of the surprising vulnerability of S upon application of electric fields of strengths at least two orders of magnitude smaller than those required for damaging most proteins. Our findings suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus without further biochemical processing. Moreover, the effect could be used for infection prevention purposes and also to develop technologies for in-vitro structural manipulation of S. Since the method is largely unspecific, it can be suitable for application to other mutations in S, to other proteins of SARS-CoV-2 and in general to membrane proteins of other virus types.

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  • 4.
    Avican, Kemal
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Aldahdooh, Jehad
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Togninalli, Matteo
    Department for Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland; Swiss Institute for Bioinformatics, Lausanne, Switzerland.
    Mahmud, A. K. M. Firoj
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Tang, Jing
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Borgwardt, Karsten M.
    Department for Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland; Swiss Institute for Bioinformatics, Lausanne, Switzerland.
    Rhen, Mikael
    Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden.
    Fällman, Maria
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    RNA atlas of human bacterial pathogens uncovers stress dynamics linked to infection2021Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikel-id 3282Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bacterial processes necessary for adaption to stressful host environments are potential targets for new antimicrobials. Here, we report large-scale transcriptomic analyses of 32 human bacterial pathogens grown under 11 stress conditions mimicking human host environments. The potential relevance of the in vitro stress conditions and responses is supported by comparisons with available in vivo transcriptomes of clinically important pathogens. Calculation of a probability score enables comparative cross-microbial analyses of the stress responses, revealing common and unique regulatory responses to different stresses, as well as overlapping processes participating in different stress responses. We identify conserved and species-specific ‘universal stress responders’, that is, genes showing altered expression in multiple stress conditions. Non-coding RNAs are involved in a substantial proportion of the responses. The data are collected in a freely available, interactive online resource (PATHOgenex).

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  • 5.
    Bag, Pushan
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Chukhutsina, Volha
    Zhang, Zishan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Present address: State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, Shandong, China.
    Paul, Suman
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Present address: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Ivanov, Alexander G.
    Shutova, Tatiana
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Croce, Roberta
    Holzwarth, Alfred R.
    Jansson, Stefan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik.
    Direct energy transfer from photosystem II to photosystem I confers winter sustainability in Scots Pine2020Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 11, nr 1, artikel-id 6388Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Evergreen conifers in boreal forests can survive extremely cold (freezing) temperatures during long dark winter and fully recover during summer. A phenomenon called "sustained quenching" putatively provides photoprotection and enables their survival, but its precise molecular and physiological mechanisms are not understood. To unveil them, here we have analyzed seasonal adjustment of the photosynthetic machinery of Scots pine (Pinus sylvestris) trees by monitoring multi-year changes in weather, chlorophyll fluorescence, chloroplast ultrastructure, and changes in pigment-protein composition. Analysis of Photosystem II and Photosystem I performance parameters indicate that highly dynamic structural and functional seasonal rearrangements of the photosynthetic apparatus occur. Although several mechanisms might contribute to 'sustained quenching' of winter/early spring pine needles, time-resolved fluorescence analysis shows that extreme down-regulation of photosystem II activity along with direct energy transfer from photosystem II to photosystem I play a major role. This mechanism is enabled by extensive thylakoid destacking allowing for the mixing of PSII with PSI complexes. These two linked phenomena play crucial roles in winter acclimation and protection. Evergreen conifers rely on 'sustained quenching' to protect their photosynthetic machinery during long, cold winters. Here, Bag et al. show that direct energy transfer (spillover) from photosystem II to photosystem I triggered by loss of grana stacking in chloroplast is the major component of sustained quenching in Scots pine.

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  • 6.
    Bag, Pushan
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Shutova, Tatiana
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Shevela, Dmitriy
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lihavainen, Jenna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Nanda, Sanchali
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Ivanov, Alexander G.
    Department of Biology, University of Western Ontario, ON, London, Canada; Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria.
    Messinger, Johannes
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Chemistry, Ångström laboratory, Uppsala University, Uppsala, Sweden.
    Jansson, Stefan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Flavodiiron-mediated O2 photoreduction at photosystem I acceptor-side provides photoprotection to conifer thylakoids in early spring2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 3210Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Green organisms evolve oxygen (O2) via photosynthesis and consume it by respiration. Generally, net O2 consumption only becomes dominant when photosynthesis is suppressed at night. Here, we show that green thylakoid membranes of Scots pine (Pinus sylvestris L) and Norway spruce (Picea abies) needles display strong O2 consumption even in the presence of light when extremely low temperatures coincide with high solar irradiation during early spring (ES). By employing different electron transport chain inhibitors, we show that this unusual light-induced O2 consumption occurs around photosystem (PS) I and correlates with higher abundance of flavodiiron (Flv) A protein in ES thylakoids. With P700 absorption changes, we demonstrate that electron scavenging from the acceptor-side of PSI via O2 photoreduction is a major alternative pathway in ES. This photoprotection mechanism in vascular plants indicates that conifers have developed an adaptative evolution trajectory for growing in harsh environments.

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  • 7. Baptista, Marisa A. P.
    et al.
    Keszei, Marton
    Oliveira, Mariana
    Sunahara, Karen K. S.
    Andersson, John
    Dahlberg, Carin I. M.
    Worth, Austen J.
    Lieden, Agne
    Kuo, I-Chun
    Wallin, Robert P. A.
    Snapper, Scott B.
    Eidsmo, Liv
    Scheynius, Annika
    Karlsson, Mikael C. I.
    Bouma, Gerben
    Burns, Siobhan O.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Thrasher, Adrian J.
    Nylén, Susanne
    Westerberg, Lisa S.
    Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells2016Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 7, artikel-id 12175Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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  • 8. Bartelt, Alexander
    et al.
    John, Clara
    Schaltenberg, Nicola
    Berbee, Jimmy F. P.
    Worthmann, Anna
    Cherradi, M. Lisa
    Schlein, Christian
    Piepenburg, Julia
    Boon, Mariette R.
    Rinninger, Franz
    Heine, Markus
    Toedter, Klaus
    Niemeier, Andreas
    Nilsson, Stefan K.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Fysiologisk kemi. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
    Fischer, Markus
    Wijers, Sander L.
    Lichtenbelt, Wouter van Marken
    Scheja, Ludger
    Rensen, Patrick C. N.
    Heeren, Joerg
    Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport2017Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 8, artikel-id 15010Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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  • 9.
    Blume-Werry, Gesche
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Experimental Plant Ecology, Institute of Botany and Landscape Ecology, University of Greifswald, Soldmannstraße, Greifswald, Germany.
    Krab, Eveline J
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Swedish University of Agricultural Sciences, Department of Soil and Environment, Uppsala, Sweden.
    Olofsson, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Sundqvist, Maja K.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap. Department of Earth Sciences, University of Gothenburg, Gothenburg, Sweden.
    Väisänen, Maria
    Klaminder, Jonatan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Invasive earthworms unlock arctic plant nitrogen limitation2020Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 11, nr 1Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Arctic plant growth is predominantly nitrogen (N) limited. This limitation is generally attributed to slow soil microbial processes due to low temperatures. Here, we show that arctic plant-soil N cycling is also substantially constrained by the lack of larger detritivores (earthworms) able to mineralize and physically translocate litter and soil organic matter. These new functions provided by earthworms increased shrub and grass N concentration in our common garden experiment. Earthworm activity also increased either the height or number of floral shoots, while enhancing fine root production and vegetation greenness in heath and meadow communities to a level that exceeded the inherent differences between these two common arctic plant communities. Moreover, these worming effects on plant N and greening exceeded reported effects of warming, herbivory and nutrient addition, suggesting that human spreading of earthworms may lead to substantial changes in the structure and function of arctic ecosystems. Arctic plant growth is predominantly nitrogen limited, where the slow nitrogen turnover in the soil is commonly attributed to the cold arctic climate. Here the authors show that the arctic plant-soil nitrogen cycling is also constrained by the lack of larger detritivores like earthworms.

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  • 10.
    Boström, Adrian Desai E.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Women's and Children's Health/Neuropediatrics, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm, Sweden; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Karolinska University Hospital, SE-171 76, Stockholm, Sweden. adrian.desai.bostrom@ki.se.
    Andersson, Peter
    Division of Psychology, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Centre for Clinical Research, Uppsala University, Dalarna, Falun, Sweden.
    Rask-Andersen, Mathias
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Jarbin, Håkan
    Department of Clinical Sciences Lund, Section of Child and Adolescent Psychiatry, Lund University, Lund, Sweden; Child and Adolescent Psychiatry, Region Halland, Halland, Sweden.
    Lundberg, Johan
    Stockholm Health Care Services, Stockholm, Sweden; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Region Stockholm, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Regional clozapine, ECT and lithium usage inversely associated with excess suicide rates in male adolescents2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 1281Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Advanced psychiatric treatments remain uncertain in preventing suicide among adolescents. Across the 21 Swedish regions, using nationwide registers between 2016-2020, we found negative correlation between adolescent excess suicide mortality (AESM) and regional frequencies of clozapine, ECT, and lithium (CEL) usage among adolescents (β = -0.613, p = 0.0003, 95% CI: -0.338, -0.889) and males (β = -0.404, p = 0.009, 95% CI: -0.130, -0.678). No correlation was found among females (p = 0.197). Highest CEL usage among male adolescents was seen in regions with lowest quartile (Q1) AESM (W = 74, p = 0.012). Regional CEL treatment frequency in 15-19-year-olds was related to lower AESM in males, reflecting potential treatment efficacy, treatment compliance or better-quality mental health care. Suicide prevention may benefit from early recognition and CEL treatment for severe mental illness in male adolescents. The results indicate association but further research, using independent samples and both prospective and observational methodologies, is needed to confirm causality.

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  • 11.
    Bozdag, G. Ozan
    et al.
    School of Biological Sciences, Georgia Institute of Technology, GA, Atlanta, United States.
    Libby, Eric
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Santa Fe Institute, NM, Santa Fe, United States.
    Pineau, Rozenn
    School of Biological Sciences, Georgia Institute of Technology, GA, Atlanta, United States; Interdisciplinary Graduate Program in Quantitative Biosciences, Georgia Institute of Technology, GA, United States.
    Reinhard, Christopher T.
    School of Earth and Atmospheric Sciences, Georgia Institute of Technology, GA, Atlanta, United States; NASA Astrobiology Institute, Alternative Earths Team, CA, Riverside, United States.
    Ratcliff, William C.
    School of Biological Sciences, Georgia Institute of Technology, GA, Atlanta, United States; NASA Astrobiology Institute, Reliving the Past Team, GA, Atlanta, United States.
    Oxygen suppression of macroscopic multicellularity2021Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikel-id 2838Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Atmospheric oxygen is thought to have played a vital role in the evolution of large, complex multicellular organisms. Challenging the prevailing theory, we show that the transition from an anaerobic to an aerobic world can strongly suppress the evolution of macroscopic multicellularity. Here we select for increased size in multicellular ‘snowflake’ yeast across a range of metabolically-available O2 levels. While yeast under anaerobic and high-O2 conditions evolved to be considerably larger, intermediate O2 constrained the evolution of large size. Through sequencing and synthetic strain construction, we confirm that this is due to O2-mediated divergent selection acting on organism size. We show via mathematical modeling that our results stem from nearly universal evolutionary and biophysical trade-offs, and thus should apply broadly. These results highlight the fact that oxygen is a double-edged sword: while it provides significant metabolic advantages, selection for efficient use of this resource may paradoxically suppress the evolution of macroscopic multicellular organisms.

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  • 12. Bravo, Andrea G.
    et al.
    Bouchet, Sylvain
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tolu, Julie
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Björn, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mateos-Rivera, Alejandro
    Bertilsson, Stefan
    Molecular composition of organic matter controls methylmercury formation in boreal lakes2017Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 8, artikel-id 14255Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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  • 13. Broglia, Laura
    et al.
    Lécrivain, Anne-Laure
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Renault, Thibaud T.
    Hahnke, Karin
    Ahmed-Begrich, Rina
    Le Rhun, Anais
    Charpentier, Emmanuelle
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    An RNA-seq based comparative approach reveals the transcriptome-wide interplay between 3 '-to-5 ' exoRNases and RNase Y2020Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 11, nr 1, artikel-id 1587Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RNA degradation is an essential process that allows bacteria to control gene expression and adapt to various environmental conditions. It is usually initiated by endoribonucleases (endoRNases), which produce intermediate fragments that are subsequently degraded by exoribonucleases (exoRNases). However, global studies of the coordinated action of these enzymes are lacking. Here, we compare the targetome of endoRNase Y with the targetomes of 3-to-5 ' exoRNases from Streptococcus pyogenes, namely, PNPase, YhaM, and RNase R. We observe that RNase Y preferentially cleaves after guanosine, generating substrate RNAs for the 3 '-to-5 ' exoRNases. We demonstrate that RNase Y processing is followed by trimming of the newly generated 3 ' ends by PNPase and YhaM. Conversely, the RNA 5 ' ends produced by RNase Y are rarely further trimmed. Our strategy enables the identification of processing events that are otherwise undetectable. Importantly, this approach allows investigation of the intricate interplay between endo- and exoRNases on a genome-wide scale.

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  • 14.
    Campeau, A.
    et al.
    Department of Forest Ecology and Management, Swedish University of Agricultural Sciences, Umeå, Sweden; Department of Air, Water and Landscape, Uppsala University, Uppsala, Sweden.
    Vachon, Dominic
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Bishop, K.
    Department of Aquatic Sciences and Assessment, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Nilsson, M.B.
    Department of Forest Ecology and Management, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Wallin, M.B.
    Department of Air, Water and Landscape, Uppsala University, Uppsala, Sweden; Department of Aquatic Sciences and Assessment, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Autumn destabilization of deep porewater CO2 store in a northern peatland driven by turbulent diffusion2021Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikel-id 6857Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The deep porewater of northern peatlands stores large amounts of carbon dioxide (CO2). This store is viewed as a stable feature in the peatland CO2 cycle. Here, we report large and rapid fluctuations in deep porewater CO2 concentration recurring every autumn over four consecutive years in a boreal peatland. Estimates of the vertical diffusion of heat indicate that CO2 diffusion occurs at the turbulent rather than molecular rate. The weakening of porewater thermal stratification in autumn likely increases turbulent diffusion, thus fostering a rapid diffusion of deeper porewater CO2 towards the surface where net losses occur. This phenomenon periodically decreases the peat porewater CO2 store by between 29 and 90 g C m−2 throughout autumn, which is comparable to the peatland’s annual C-sink. Our results establish the need to consider the role of turbulent diffusion in regularly destabilizing the CO2 store in peat porewater.

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  • 15.
    Casas-Ruiz, Joan P.
    et al.
    Research Group on Ecology of Inland Waters (GRECO), Institute of Aquatic Ecology, University of Girona, Girona, Spain.
    Bodmer, Pascal
    Groupe de Recherche Interuniversitaire en Limnologie (GRIL), Département des sciences biologiques, Université du Québec à Montréal, QC, Montréal, Canada.
    Bona, Kelly Ann
    Environment and Climate Change Canada, QC, Gatineau, Canada.
    Butman, David
    Department of Civil and Environmental Engineering, University of Washington, WA, Seattle, United States.
    Couturier, Mathilde
    Groupe de Recherche Interuniversitaire en Limnologie (GRIL), Département des sciences biologiques, Université du Québec à Montréal, QC, Montréal, Canada.
    Emilson, Erik J. S.
    Natural Resources Canada, Sault Ste. Marie, Ontario, Canada.
    Finlay, Kerri
    University of Regina, SK, Regina, Canada.
    Genet, Hélène
    University of Alaska Fairbanks, AK, Fairbanks, United States.
    Hayes, Daniel
    University of Maine, ME, Orono, United States.
    Karlsson, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Paré, David
    Natural Resources Canada, QC, Québec, Canada.
    Peng, Changhui
    Groupe de Recherche Interuniversitaire en Limnologie (GRIL), Département des sciences biologiques, Université du Québec à Montréal, QC, Montréal, Canada.
    Striegl, Rob
    United States Geological Survey, CO, Boulder, United States.
    Webb, Jackie
    Centre for Regional and Rural Futures (CeRRF), Faculty of Science, Engineering and Built Environment, Deakin University, NSW, Griffith, Australia.
    Wei, Xinyuan
    University of Maine, ME, Orono, United States.
    Ziegler, Susan E.
    Memorial University of Newfoundland, NL, St. John’s, Canada.
    del Giorgio, Paul A.
    Groupe de Recherche Interuniversitaire en Limnologie (GRIL), Département des sciences biologiques, Université du Québec à Montréal, QC, Montréal, Canada.
    Integrating terrestrial and aquatic ecosystems to constrain estimates of land-atmosphere carbon exchange2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 1571Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this Perspective, we put forward an integrative framework to improve estimates of land-atmosphere carbon exchange based on the accumulation of carbon in the landscape as constrained by its lateral export through rivers. The framework uses the watershed as the fundamental spatial unit and integrates all terrestrial and aquatic ecosystems as well as their hydrologic carbon exchanges. Application of the framework should help bridge the existing gap between land and atmosphere-based approaches and offers a platform to increase communication and synergy among the terrestrial, aquatic, and atmospheric research communities that is paramount to advance landscape carbon budget assessments.

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  • 16.
    Chakraborty, Chaitali
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Nissen, Itzel
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Vincent, Craig A.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Hägglund, Anna-Carin
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Hörnblad, Andreas
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Remeseiro, Silvia
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 6446Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer. Here, we map the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks in glioblastoma. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodelling. SMAD3 and PITX1 emerge as major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote proliferation of glioblastoma cells in co-culture with glutamatergic neurons, and in mice bearing patient-derived xenografts. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.

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  • 17.
    Chavhan, Yashraj
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Dey, Sutirth
    Indian Institute of Science Education and Research (IISER) Pune, Pune, India.
    Lind, Peter A
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Bacteria evolve macroscopic multicellularity by the genetic assimilation of phenotypically plastic cell clustering2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 3555Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The evolutionary transition from unicellularity to multicellularity was a key innovation in the history of life. Experimental evolution is an important tool to study the formation of undifferentiated cellular clusters, the likely first step of this transition. Although multicellularity first evolved in bacteria, previous experimental evolution research has primarily used eukaryotes. Moreover, it focuses on mutationally driven (and not environmentally induced) phenotypes. Here we show that both Gram-negative and Gram-positive bacteria exhibit phenotypically plastic (i.e., environmentally induced) cell clustering. Under high salinity, they form elongated clusters of ~ 2 cm. However, under habitual salinity, the clusters disintegrate and grow planktonically. We used experimental evolution with Escherichia coli to show that such clustering can be assimilated genetically: the evolved bacteria inherently grow as macroscopic multicellular clusters, even without environmental induction. Highly parallel mutations in genes linked to cell wall assembly formed the genomic basis of assimilated multicellularity. While the wildtype also showed cell shape plasticity across high versus low salinity, it was either assimilated or reversed after evolution. Interestingly, a single mutation could genetically assimilate multicellularity by modulating plasticity at multiple levels of organization. Taken together, we show that phenotypic plasticity can prime bacteria for evolving undifferentiated macroscopic multicellularity.

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  • 18. Chen, Yuqing
    et al.
    He, Qiu
    Zhao, Yun
    Zhou, Wang
    Xiao, Peitao
    Gao, Peng
    Tavajohi Hassan Kiadeh, Naser
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tu, Jian
    Li, Baohua
    He, Xiangming
    Xing, Lidan
    Fan, Xiulin
    Liu, Jilei
    Breaking solvation dominance of ethylene carbonate via molecular charge engineering enables lower temperature battery2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, artikel-id 8326Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Low temperatures severely impair the performance of lithium-ion batteries, which demand powerful electrolytes with wide liquidity ranges, facilitated ion diffusion, and lower desolvation energy. The keys lie in establishing mild interactions between Li+ and solvent molecules internally, which are hard to achieve in commercial ethylene-carbonate based electrolytes. Herein, we tailor the solvation structure with low-ε solvent-dominated coordination, and unlock ethylene-carbonate via electronegativity regulation of carbonyl oxygen. The modified electrolyte exhibits high ion conductivity (1.46 mS·cm−1) at −90 °C, and remains liquid at −110 °C. Consequently, 4.5 V graphite-based pouch cells achieve ~98% capacity over 200 cycles at −10 °C without lithium dendrite. These cells also retain ~60% of their room-temperature discharge capacity at −70 °C, and miraculously retain discharge functionality even at ~−100 °C after being fully charged at 25 °C. This strategy of disrupting solvation dominance of ethylene-carbonate through molecular charge engineering, opens new avenues for advanced electrolyte design.

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  • 19.
    Chernyshev, Mark
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Sakharkar, Mrunal
    NH, United States.
    Connor, Ruth I.
    Department of Pediatrics, Dartmouth-Hitchcock Medical Center, NH, United States.
    Dugan, Haley L.
    NH, United States.
    Sheward, Daniel J.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Rappazzo, C.G.
    NH, United States.
    Stålmarck, Aron
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Wright, Peter F.
    Department of Pediatrics, Dartmouth-Hitchcock Medical Center, NH, United States.
    Corcoran, Martin
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Murrell, Ben
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Walker, Laura M.
    NH, United States, MA, Waltham, United States.
    Karlsson Hedestam, Gunilla B.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Vaccination of SARS-CoV-2-infected individuals expands a broad range of clonally diverse affinity-matured B cell lineages2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 2249Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vaccination of SARS-CoV-2 convalescent individuals generates broad and potent antibody responses. Here, we isolate 459 spike-specific monoclonal antibodies (mAbs) from two individuals who were infected with the index variant of SARS-CoV-2 and later boosted with mRNA-1273. We characterize mAb genetic features by sequence assignments to the donors' personal immunoglobulin genotypes and assess antibody neutralizing activities against index SARS-CoV-2, Beta, Delta, and Omicron variants. The mAbs used a broad range of immunoglobulin heavy chain (IGH) V genes in the response to all sub-determinants of the spike examined, with similar characteristics observed in both donors. IGH repertoire sequencing and B cell lineage tracing at longitudinal time points reveals extensive evolution of SARS-CoV-2 spike-binding antibodies from acute infection until vaccination five months later. These results demonstrate that highly polyclonal repertoires of affinity-matured memory B cells are efficiently recalled by vaccination, providing a basis for the potent antibody responses observed in convalescent persons following vaccination.

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  • 20.
    Chotiwan, Nunya
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand.
    Rosendal, Ebba
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Willekens, Stefanie M. A.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Schexnaydre, Erin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Lindquist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Hahn, Max
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Mihai, Ionut Sebastian
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Morini, Federico
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Zhang, Jianguo
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Ebel, Gregory D.
    Department of Microbiology, Immunology and Pathology, Colorado State University, CO, Fort Collins, United States.
    Carlson, Lars-Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ahlgren, Ulf
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Överby, Anna K.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Type I interferon shapes brain distribution and tropism of tick-borne flavivirus2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 2007Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.

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  • 21. Corbin, Laura J.
    et al.
    Tan, Vanessa Y.
    Hughes, David A.
    Wade, Kaitlin H.
    Paul, Dirk S.
    Tansey, Katherine E.
    Butcher, Frances
    Dudbridge, Frank
    Howson, Joanna M.
    Jallow, Momodou W.
    John, Catherine
    Kingston, Nathalie
    Lindgren, Cecilia M.
    O'Donavan, Michael
    O'Rahilly, Stephen
    Owen, Michael J.
    Palmer, Colin N. A.
    Pearson, Ewan R.
    Scott, Robert A.
    van Heel, David A.
    Whittaker, John
    Frayling, Tim
    Tobin, Martin D.
    Wain, Louise V.
    Smith, George Davey
    Evans, David M.
    Karpe, Fredrik
    McCarthy, Mark I.
    Danesh, John
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, SE-205 02, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
    Timpson, Nicholas J.
    Formalising recall by genotype as an efficient approach to detailed phenotyping and causal inference2018Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 9, artikel-id 711Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

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  • 22.
    Crowe-McAuliffe, Caillan
    et al.
    Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, Hamburg, Germany.
    Murina, Victoriia
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Turnbull, Kathryn Jane
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark.
    Huch, Susanne
    SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet, Solna, Sweden.
    Kasari, Marje
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). University of Tartu, Institute of Technology, Tartu, Estonia.
    Takada, Hiraku
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo, Motoyama, Kita-ku, Kyoto, Japan.
    Nersisyan, Lilit
    SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet, Solna, Sweden.
    Sundsfjord, Arnfinn
    Department of Microbiology and Infection Control, Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, University Hospital of North Norway, Tromsø, Norway; Research Group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
    Hegstad, Kristin
    Department of Microbiology and Infection Control, Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, University Hospital of North Norway, Tromsø, Norway; Research Group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
    Atkinson, Gemma C.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Pelechano, Vicent
    SciLifeLab, Department of Microbiology, Tumor and Cell Biology. Karolinska Institutet, Solna, Sweden.
    Wilson, Daniel N.
    Institute for Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, Hamburg, Germany.
    Hauryliuk, Vasili
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). University of Tartu, Institute of Technology, Tartu, Estonia; Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics2022Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 13, nr 1, artikel-id 1860Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Å out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.

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  • 23.
    Crowe-McAuliffe, Caillan
    et al.
    Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
    Murina, Victoriia
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Turnbull, Kathryn Jane
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Kasari, Marje
    University of Tartu, Institute of Technology, Tartu, Estonia.
    Mohamad, Merianne
    Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
    Polte, Christine
    Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
    Takada, Hiraku
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Vaitkevicius, Karolis
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Johansson, Jörgen
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ignatova, Zoya
    Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
    Atkinson, Gemma C.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    O’Neill, Alex J.
    Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
    Hauryliuk, Vasili
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). University of Tartu, Institute of Technology, Tartu, Estonia; Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Wilson, Daniel N.
    Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany.
    Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens2021Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikel-id 3577Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Target protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.

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  • 24.
    Dahmane, Selma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Kerviel, Adeline
    Laboratory of Host-Pathogen Dynamics, National Heart Lung and Blood Institute, National Institutes of Health, MD, Bethesda, United States.
    Morado, Dustin R.
    Department of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Stockholm, Sweden.
    Shankar, Kasturika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Ahlman, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Lazarou, Michael
    Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Australia.
    Altan-Bonnet, Nihal
    Laboratory of Host-Pathogen Dynamics, National Heart Lung and Blood Institute, National Institutes of Health, MD, Bethesda, United States.
    Carlson, Lars-Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Membrane-assisted assembly and selective secretory autophagy of enteroviruses2022Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 13, nr 1, artikel-id 5986Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Enteroviruses are non-enveloped positive-sense RNA viruses that cause diverse diseases in humans. Their rapid multiplication depends on remodeling of cytoplasmic membranes for viral genome replication. It is unknown how virions assemble around these newly synthesized genomes and how they are then loaded into autophagic membranes for release through secretory autophagy. Here, we use cryo-electron tomography of infected cells to show that poliovirus assembles directly on replication membranes. Pharmacological untethering of capsids from membranes abrogates RNA encapsidation. Our data directly visualize a membrane-bound half-capsid as a prominent virion assembly intermediate. Assembly progression past this intermediate depends on the class III phosphatidylinositol 3-kinase VPS34, a key host-cell autophagy factor. On the other hand, the canonical autophagy initiator ULK1 is shown to restrict virion production since its inhibition leads to increased accumulation of virions in vast intracellular arrays, followed by an increased vesicular release at later time points. Finally, we identify multiple layers of selectivity in virus-induced autophagy, with a strong selection for RNA-loaded virions over empty capsids and the segregation of virions from other types of autophagosome contents. These findings provide an integrated structural framework for multiple stages of the poliovirus life cycle.

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  • 25. Davies, Gail
    et al.
    Lam, Max
    Harris, Sarah E.
    Trampush, Joey W.
    Luciano, Michelle
    Hill, W. David
    Hagenaars, Saskia P.
    Ritchie, Stuart J.
    Marioni, Riccardo E.
    Fawns-Ritchie, Chloe
    Liewald, David C. M.
    Okely, Judith A.
    Ahola-Olli, Ari V.
    Barnes, Catriona L. K.
    Bertram, Lars
    Bis, Joshua C.
    Burdick, Katherine E.
    Christoforou, Andrea
    DeRosse, Pamela
    Djurovic, Srdjan
    Espeseth, Thomas
    Giakoumaki, Stella
    Giddaluru, Sudheer
    Gustavson, Daniel E.
    Hayward, Caroline
    Hofer, Edith
    Ikram, M. Arfan
    Karlsson, Robert
    Knowles, Emma
    Lahti, Jari
    Leber, Markus
    Li, Shuo
    Mather, Karen A.
    Melle, Ingrid
    Morris, Derek
    Oldmeadow, Christopher
    Palviainen, Teemu
    Payton, Antony
    Pazoki, Raha
    Petrovic, Katja
    Reynolds, Chandra A.
    Sargurupremraj, Muralidharan
    Scholz, Markus
    Smith, Jennifer A.
    Smith, Albert V.
    Terzikhan, Natalie
    Thalamuthu, Anbupalam
    Trompet, Stella
    van der Lee, Sven J.
    Ware, Erin B.
    Windham, B. Gwen
    Wright, Margaret J.
    Yang, Jingyun
    Yu, Jin
    Ames, David
    Amin, Najaf
    Amouyel, Philippe
    Andreassen, Ole A.
    Armstrong, Nicola J.
    Assareh, Amelia A.
    Attia, John R.
    Attix, Deborah
    Avramopoulos, Dimitrios
    Bennett, David A.
    Boehmer, Anne C.
    Boyle, Patricia A.
    Brodaty, Henry
    Campbell, Harry
    Cannon, Tyrone D.
    Cirulli, Elizabeth T.
    Congdon, Eliza
    Conley, Emily Drabant
    Corley, Janie
    Cox, Simon R.
    Dale, Anders M.
    Dehghan, Abbas
    Dick, Danielle
    Dickinson, Dwight
    Eriksson, Johan G.
    Evangelou, Evangelos
    Faul, Jessica D.
    Ford, Ian
    Freimer, Nelson A.
    Gao, He
    Giegling, Ina
    Gillespie, Nathan A.
    Gordon, Scott D.
    Gottesman, Rebecca F.
    Griswold, Michael E.
    Gudnason, Vilmundur
    Harris, Tamara B.
    Hartmann, Annette M.
    Hatzimanolis, Alex
    Heiss, Gerardo
    Holliday, Elizabeth G.
    Joshi, Peter K.
    Kahonen, Mika
    Kardia, Sharon L. R.
    Karlsson, Ida
    Kleineidam, Luca
    Knopman, David S.
    Kochan, Nicole A.
    Konte, Bettina
    Kwok, John B.
    Le Hellard, Stephanie
    Lee, Teresa
    Lehtimaki, Terho
    Li, Shu-Chen
    Liu, Tian
    Koini, Marisa
    London, Edythe
    Longstreth, Will T., Jr.
    Lopez, Oscar L.
    Loukola, Anu
    Luck, Tobias
    Lundervold, Astri J.
    Lundquist, Anders
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Lyytikainen, Leo-Pekka
    Martin, Nicholas G.
    Montgomery, Grant W.
    Murray, Alison D.
    Need, Anna C.
    Noordam, Raymond
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Ollier, William
    Papenberg, Goran
    Pattie, Alison
    Polasek, Ozren
    Poldrack, Russell A.
    Psaty, Bruce M.
    Reppermund, Simone
    Riedel-Heller, Steffi G.
    Rose, Richard J.
    Rotter, Jerome I.
    Roussos, Panos
    Rovio, Suvi P.
    Saba, Yasaman
    Sabb, Fred W.
    Sachdev, Perminder S.
    Satizabal, Claudia L.
    Schmid, Matthias
    Scott, Rodney J.
    Scult, Matthew A.
    Simino, Jeannette
    Slagboom, P. Eline
    Smyrnis, Nikolaos
    Soumare, Aicha
    Stefanis, Nikos C.
    Stott, David J.
    Straub, Richard E.
    Sundet, Kjetil
    Taylor, Adele M.
    Taylor, Kent D.
    Tzoulaki, Ioanna
    Tzourio, Christophe
    Uitterlinden, Andre
    Vitart, Veronique
    Voineskos, Aristotle N.
    Kaprio, Jaakko
    Wagner, Michael
    Wagner, Holger
    Weinhold, Leonie
    Wen, K. Hoyan
    Widen, Elisabeth
    Yang, Qiong
    Zhao, Wei
    Adams, Hieab H. H.
    Arking, Dan E.
    Bilder, Robert M.
    Bitsios, Panos
    Boerwinkle, Eric
    Chiba-Falek, Ornit
    Corvin, Aiden
    De Jager, Philip L.
    Debette, Stephanie
    Donohoe, Gary
    Elliott, Paul
    Fitzpatrick, Annette L.
    Gill, Michael
    Glahn, David C.
    Hagg, Sara
    Hansell, Narelle K.
    Hariri, Ahmad R.
    Ikram, M. Kamran
    Jukema, J. Wouter
    Vuoksimaa, Eero
    Keller, Matthew C.
    Kremen, William S.
    Launer, Lenore
    Lindenberger, Ulman
    Palotie, Aarno
    Pedersen, Nancy L.
    Pendleton, Neil
    Porteous, David J.
    Raikkonen, Katri
    Raitakari, Olli T.
    Ramirez, Alfredo
    Reinvang, Ivar
    Rudan, Igor
    Rujescu, Dan
    Schmidt, Reinhold
    Schmidt, Helena
    Schofield, Peter W.
    Schofield, Peter R.
    Starr, John M.
    Steen, Vidar M.
    Trollor, Julian N.
    Turner, Steven T.
    Van Duijn, Cornelia M.
    Villringer, Arno
    Weinberger, Daniel R.
    Weir, David R.
    Wilson, James F.
    Malhotra, Anil
    McIntosh, Andrew M.
    Gale, Catharine R.
    Seshadri, Sudha
    Mosley, Thomas H., Jr.
    Bressler, Jan
    Lencz, Todd
    Deary, Ian J.
    Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function2018Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 9, artikel-id 2098Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 x 10-8) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.

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  • 26. Dejonghe, Wim
    et al.
    Kuenen, Sabine
    Mylle, Evelien
    Vasileva, Mina
    Keech, Olivier
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Viotti, Corrado
    Swerts, Jef
    Fendrych, Matyas
    Ortiz-Morea, Fausto Andres
    Mishev, Kiril
    Delang, Simon
    Scholl, Stefan
    Zarza, Xavier
    Heilmann, Mareike
    Kourelis, Jiorgos
    Kasprowicz, Jaroslaw
    Nguyen, Le Son Long
    Drozdzecki, Andrzej
    Van Houtte, Isabelle
    Szatmari, Anna-Maria
    Majda, Mateusz
    Baisa, Gary
    Bednarek, Sebastian York
    Robert, Stephanie
    Audenaert, Dominique
    Testerink, Christa
    Munnik, Teun
    Van Damme, Daniel
    Heilmann, Ingo
    Schumacher, Karin
    Winne, Johan
    Friml, Jiri
    Verstreken, Patrik
    Russinova, Eugenia
    Mitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification2016Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 7, artikel-id 11710Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ATP production requires the establishment of an electrochemical proton gradient across the inner mitochondrial membrane. Mitochondrial uncouplers dissipate this proton gradient and disrupt numerous cellular processes, including vesicular trafficking, mainly through energy depletion. Here we show that Endosidin9 (ES9), a novel mitochondrial uncoupler, is a potent inhibitor of clathrin-mediated endocytosis (CME) in different systems and that ES9 induces inhibition of CME not because of its effect on cellular ATP, but rather due to its protonophore activity that leads to cytoplasm acidification. We show that the known tyrosine kinase inhibitor tyrphostinA23, which is routinely used to block CME, displays similar properties, thus questioning its use as a specific inhibitor of cargo recognition by the AP-2 adaptor complex via tyrosine motif-based endocytosis signals. Furthermore, we show that cytoplasm acidification dramatically affects the dynamics and recruitment of clathrin and associated adaptors, and leads to reduction of phosphatidylinositol 4,5-biphosphate from the plasma membrane.

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  • 27.
    Dennhag, Nils
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Kahsay, Abraha
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Nissen, Itzel
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Nord, Hanna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Chermenina, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Liu, Jiao
    Div. Thoracic Surgery, Dept. Clinical Sciences, Lund University, Lund, Sweden; College of Life Sciences, South-Central University for Nationalities, Wuhan, China.
    Arner, Anders
    Div. Thoracic Surgery, Dept. Clinical Sciences, Lund University, Lund, Sweden.
    Liu, Jing-Xia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Remeseiro, Silvia
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    von Hofsten, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    Domellöf, Fatima Pedrosa
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk och translationell biologi.
    fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles2024Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 15, nr 1, artikel-id 1950Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In muscular dystrophies, muscle fibers loose integrity and die, causing significant suffering and premature death. Strikingly, the extraocular muscles (EOMs) are spared, functioning well despite the disease progression. Although EOMs have been shown to differ from body musculature, the mechanisms underlying this inherent resistance to muscle dystrophies remain unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscles in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is increased in response to the knockout of desmin, plectin and obscurin, cytoskeletal proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival. Therefore, Fhl2 is a protective agent and a candidate target gene for therapy of muscular dystrophies.

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  • 28.
    Diessl, Jutta
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Berndtsson, Jens
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Broeskamp, Filomena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Habernig, Lukas
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Kohler, Verena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Vazquez-Calvo, Carmela
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Nandy, Arpita
    Institute of Biochemistry and Molecular Biology, ZBMZ, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany.
    Peselj, Carlotta
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Drobysheva, Sofia
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Pelosi, Ludovic
    Univ. Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble, France.
    Vögtle, F.-Nora
    Institute of Biochemistry and Molecular Biology, ZBMZ, University of Freiburg, Freiburg, Germany;CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany; Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany; Network Aging Research, Heidelberg University, Heidelberg, Germany.
    Pierrel, Fabien
    Univ. Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, Grenoble, France.
    Ott, Martin
    Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Manganese-driven CoQ deficiency2022Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 13, nr 1, artikel-id 6061Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Overexposure to manganese disrupts cellular energy metabolism across species, but the molecular mechanism underlying manganese toxicity remains enigmatic. Here, we report that excess cellular manganese selectively disrupts coenzyme Q (CoQ) biosynthesis, resulting in failure of mitochondrial bioenergetics. While respiratory chain complexes remain intact, the lack of CoQ as lipophilic electron carrier precludes oxidative phosphorylation and leads to premature cell and organismal death. At a molecular level, manganese overload causes mismetallation and proteolytic degradation of Coq7, a diiron hydroxylase that catalyzes the penultimate step in CoQ biosynthesis. Coq7 overexpression or supplementation with a CoQ headgroup analog that bypasses Coq7 function fully corrects electron transport, thus restoring respiration and viability. We uncover a unique sensitivity of a diiron enzyme to mismetallation and define the molecular mechanism for manganese-induced bioenergetic failure that is conserved across species.

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  • 29.
    Du, Jiqing
    et al.
    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technical University of Munich, Garching, Germany; Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany.
    Wrisberg, Marie-Kristin von
    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technical University of Munich, Institute for Advanced Study, Garching, Germany.
    Gulen, Burak
    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technical University of Munich, Garching, Germany; Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany.
    Stahl, Matthias
    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technical University of Munich, Garching, Germany; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Box 1031, 171 21 Solna, Stockholm, Sweden.
    Pett, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hedberg, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lang, Kathrin
    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technical University of Munich, Institute for Advanced Study, Garching, Germany.
    Schneider, Sabine
    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Ludwig-Maximilians-University Munich, München, Germany.
    Itzen, Aymelt
    Center for Integrated Protein Science Munich (CIPSM), Department of Chemistry, Technical University of Munich, Garching, Germany; Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany; Center for Structural Systems Biology (CSSB), University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany.
    Rab1-AMPylation by Legionella DrrA is allosterically activated by Rab12021Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikel-id 460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Legionella pneumophila infects eukaryotic cells by forming a replicative organelle – the Legionella containing vacuole. During this process, the bacterial protein DrrA/SidM is secreted and manipulates the activity and post-translational modification (PTM) states of the vesicular trafficking regulator Rab1. As a result, Rab1 is modified with an adenosine monophosphate (AMP), and this process is referred to as AMPylation. Here, we use a chemical approach to stabilise low-affinity Rab:DrrA complexes in a site-specific manner to gain insight into the molecular basis of the interaction between the Rab protein and the AMPylation domain of DrrA. The crystal structure of the Rab:DrrA complex reveals a previously unknown non-conventional Rab-binding site (NC-RBS). Biochemical characterisation demonstrates allosteric stimulation of the AMPylation activity of DrrA via Rab binding to the NC-RBS. We speculate that allosteric control of DrrA could in principle prevent random and potentially cytotoxic AMPylation in the host, thereby perhaps ensuring efficient infection by Legionella.

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  • 30. Dudding, Tom
    et al.
    Haworth, Simon
    Lind, Penelope A.
    Sathirapongsasuti, J. Fah
    Tung, Joyce Y.
    Mitchell, Ruth
    Colodro-Conde, Lucia
    Medland, Sarah E.
    Gordon, Scott
    Elsworth, Benjamin
    Paternoster, Lavinia
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Sweden ; Department of Nutrition, Harvard. Chan School of Public Health, Harvard University, Boston USA.
    Thomas, Steven J.
    Martin, Nicholas G.
    Timpson, Nicholas J.
    Agee, Michelle
    Alipanahi, Babak
    Auton, Adam
    Bell, Robert K.
    Bryc, Katarzyna
    Elson, Sarah L.
    Fontanillas, Pierre
    Furlotte, Nicholas A.
    Hicks, Barry
    Hinds, David A.
    Huber, Karen E.
    Jewett, Ethan M.
    Jiang, Yunxuan
    Kleinman, Aaron
    Lin, Keng-Han
    Litterman, Nadia K.
    McCeight, Jennifer C.
    McIntyre, Matthew H.
    McManus, Kimberly F.
    Mountain, Joanna L.
    Noblin, Elizabeth S.
    Northover, Carrie A. M.
    Pitts, Steven J.
    Poznik, David
    Shelton, Janie F.
    Shringarpure, Suyash
    Tian, Chao
    Vacic, Vladimir
    Wang, Xin
    Wilson, Catherine H.
    Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci2019Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 10, s. 1-12, artikel-id 1052Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.

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  • 31. Elvsåshagen, Torbjørn
    et al.
    Bahrami, Shahram
    van der Meer, Dennis
    Agartz, Ingrid
    Alnæs, Dag
    Barch, Deanna M.
    Baur-Streubel, Ramona
    Bertolino, Alessandro
    Beyer, Mona K.
    Blasi, Giuseppe
    Borgwardt, Stefan
    Boye, Birgitte
    Buitelaar, Jan
    Bøen, Erlend
    Celius, Elisabeth Gulowsen
    Cervenka, Simon
    Conzelmann, Annette
    Coynel, David
    Di Carlo, Pasquale
    Djurovic, Srdjan
    Eisenacher, Sarah
    Espeseth, Thomas
    Fatouros-Bergman, Helena
    Flyckt, Lena
    Franke, Barbara
    Frei, Oleksandr
    Gelao, Barbara
    Harbo, Hanne Flinstad
    Hartman, Catharina A.
    Håberg, Asta
    Heslenfeld, Dirk
    Hoekstra, Pieter J.
    Høgestøl, Einar A.
    Jonassen, Rune
    Jönsson, Erik G.
    Kirsch, Peter
    Kłoszewska, Iwona
    Lagerberg, Trine Vik
    Landrø, Nils Inge
    Le Hellard, Stephanie
    Lesch, Klaus-Peter
    Maglanoc, Luigi A.
    Malt, Ulrik F.
    Mecocci, Patrizia
    Melle, Ingrid
    Meyer-Lindenberg, Andreas
    Moberget, Torgeir
    Nordvik, Jan Egil
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    O'Connell, Kevin S.
    Oosterlaan, Jaap
    Papalino, Marco
    Papassotiropoulos, Andreas
    Pauli, Paul
    Pergola, Giulio
    Persson, Karin
    de Quervain, Dominique
    Reif, Andreas
    Rokicki, Jaroslav
    van Rooij, Daan
    Shadrin, Alexey A.
    Schmidt, André
    Schwarz, Emanuel
    Selbæk, Geir
    Soininen, Hilkka
    Sowa, Piotr
    Steen, Vidar M.
    Tsolaki, Magda
    Vellas, Bruno
    Wang, Lei
    Westman, Eric
    Ziegler, Georg C.
    Zink, Mathias
    Andreassen, Ole A.
    Westlye, Lars T.
    Kaufmann, Tobias
    Farde, L.
    Flyckt, L.
    Engberg, G.
    Erhardt, S. S.
    Fatouros-Bergman, H.
    Cervenka, S.
    Schwieler, L.
    Piehl, F.
    Agartz, I
    Collste, K.
    Victorsson, P.
    Malmqvist, A.
    Hedberg, M.
    Orhan, F.
    Sellgren, C. M.
    The genetic architecture of human brainstem structures and their involvement in common brain disorders2020Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 11, nr 1, artikel-id 4016Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders. The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.

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  • 32.
    Erdem, Cemal
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Department of Chemical and Biomolecular Engineering, Clemson University, Clemson, SC, USA.
    Gross, Sean M.
    Heiser, Laura M.
    Birtwistle, Marc R.
    MOBILE pipeline enables identification of context-specific networks and regulatory mechanisms2023Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 14, nr 1, artikel-id 3991Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Robust identification of context-specific network features that control cellular phenotypes remains a challenge. We here introduce MOBILE (Multi-Omics Binary Integration via Lasso Ensembles) to nominate molecular features associated with cellular phenotypes and pathways. First, we use MOBILE to nominate mechanisms of interferon-γ (IFNγ) regulated PD-L1 expression. Our analyses suggest that IFNγ-controlled PD-L1 expression involves BST2 , CLIC2 , FAM83D , ACSL5 , and HIST2H2AA3 genes, which were supported by prior literature. We also compare networks activated by related family members transforming growth factor-beta 1 (TGFβ1) and bone morphogenetic protein 2 (BMP2) and find that differences in ligand-induced changes in cell size and clustering properties are related to differences in laminin/collagen pathway activity. Finally, we demonstrate the broad applicability and adaptability of MOBILE by analyzing publicly available molecular datasets to investigate breast cancer subtype specific networks. Given the ever-growing availability of multi-omics datasets, we envision that MOBILE will be broadly useful for identification of context-specific molecular features and pathways.

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  • 33.
    Erdem, Cemal
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Department of Chemical & Biomolecular Engineering, Clemson University, Clemson, SC, USA.
    Mutsuddy, Arnab
    Bensman, Ethan M.
    Dodd, William B.
    Saint-Antoine, Michael M.
    Bouhaddou, Mehdi
    Blake, Robert C.
    Gross, Sean M.
    Heiser, Laura M.
    Feltus, F. Alex
    Birtwistle, Marc R.
    A scalable, open-source implementation of a large-scale mechanistic model for single cell proliferation and death signaling2022Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 13, nr 1, artikel-id 3555Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Abstract Mechanistic models of how single cells respond to different perturbations can help integrate disparate big data sets or predict response to varied drug combinations. However, the construction and simulation of such models have proved challenging. Here, we developed a python-based model creation and simulation pipeline that converts a few structured text files into an SBML standard and is high-performance- and cloud-computing ready. We applied this pipeline to our large-scale, mechanistic pan-cancer signaling model (named SPARCED) and demonstrate it by adding an IFNγ pathway submodel. We then investigated whether a putative crosstalk mechanism could be consistent with experimental observations from the LINCS MCF10A Data Cube that IFNγ acts as an anti-proliferative factor. The analyses suggested this observation can be explained by IFNγ-induced SOCS1 sequestering activated EGF receptors. This work forms a foundational recipe for increased mechanistic model-based data integration on a single-cell level, an important building block for clinically-predictive mechanistic models.

  • 34. Eriksson, Daniel
    et al.
    Røyrvik, Ellen Christine
    Aranda-Guillén, Maribel
    Holte Berger, Amund
    Landegren, Nils
    Artaza, Haydee
    Hallgren, Åsa
    Aardal Grytaas, Marianne
    Ström, Sara
    Bratland, Eirik
    Botusan, Ileana Ruxandra
    Eikeland Oftedal, Bergithe
    Breivik, Lars
    Vaudel, Marc
    Helgeland, Øyvind
    Falorni, Alberto
    Palmstrøm Jørgensen, Anders
    Hulting, Anna-Lena
    Svartberg, Johan
    Ekwall, Olov
    Fougner, Kristian Johan
    Wahlberg, Jeanette
    Nedrebø, Bjørn Gunnar
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Knappskog, Per Morten
    Wolff, Anette Susanne Bøe
    Bensing, Sophie
    Johansson, Stefan
    Kämpe, Olle
    Husebye, Eystein Sverre
    GWAS for autoimmune Addison's disease identifies multiple risk loci and highlights AIRE in disease susceptibility2021Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikel-id 959Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autoimmune Addison's disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10-8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7-4.3), P = 9.0 × 10-25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35-41% of heritability (h2).

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  • 35.
    Erttmann, Saskia F.
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Gekara, Nelson O.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Hydrogen peroxide release by bacteria suppresses inflammasome-dependent innate immunity2019Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 10, artikel-id 3493Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hydrogen peroxide (H2O2) has a major function in host-microbial interactions. Although most studies have focused on the endogenous H2O2 produced by immune cells to kill microbes, bacteria can also produce H2O2. How microbial H2O2 influences the dynamics of host-microbial interactions is unclear. Here we show that H2O2 released by Streptococcus pneumoniae inhibits inflammasomes, key components of the innate immune system, contributing to the pathogen colonization of the host. We also show that the oral commensal H2O2-producing bacteria Streptococcus oralis can block inflammasome activation. This study uncovers an unexpected role of H2O2 in immune suppression and demonstrates how, through this mechanism, bacteria might restrain the immune system to co-exist with the host.

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  • 36.
    Espaillat, Akbar
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Chr. Hansen A/S, Microbial Physiology, R & amp;D, Hoersholm, Denmark.
    Alvarez, Laura
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Torrens, Gabriel
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    ter Beek, Josy
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Miguel-Ruano, Vega
    Department of Crystallography and Structural Biology, Institute of Physical Chemistry “Blas Cabrera”, CSIC, Madrid, Spain.
    Irazoki, Oihane
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Gago, Federico
    Department of Biomedical Sciences & amp; IQM-CSIC Associate Unit, School of Medicine and Health Sciences, University of Alcalá, Alcalá de Henares, Madrid, Spain.
    Hermoso, Juan A.
    Department of Crystallography and Structural Biology, Institute of Physical Chemistry “Blas Cabrera”, CSIC, Madrid, Spain.
    Berntsson, Ronnie P-A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    A distinctive family of L,D-transpeptidases catalyzing L-Ala-mDAP crosslinks in Alpha- and Betaproteobacteria2024Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 15, nr 1, artikel-id 1343Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The bacterial cell-wall peptidoglycan is made of glycan strands crosslinked by short peptide stems. Crosslinks are catalyzed by DD-transpeptidases (4,3-crosslinks) and LD-transpeptidases (3,3-crosslinks). However, recent research on non-model species has revealed novel crosslink types, suggesting the existence of uncharacterized enzymes. Here, we identify an LD-transpeptidase, LDTGo, that generates 1,3-crosslinks in the acetic-acid bacterium Gluconobacter oxydans. LDTGo-like proteins are found in Alpha- and Betaproteobacteria lacking LD3,3-transpeptidases. In contrast with the strict specificity of typical LD- and DD-transpeptidases, LDTGo can use non-terminal amino acid moieties for crosslinking. A high-resolution crystal structure of LDTGo reveals unique features when compared to LD3,3-transpeptidases, including a proline-rich region that appears to limit substrate access, and a cavity accommodating both glycan chain and peptide stem from donor muropeptides. Finally, we show that DD-crosslink turnover is involved in supplying the necessary substrate for LD1,3-transpeptidation. This phenomenon underscores the interplay between distinct crosslinking mechanisms in maintaining cell wall integrity in G. oxydans.

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  • 37. Fang, Hanwei
    et al.
    Gomes, Ana Rita
    Klages, Natacha
    Pino, Paco
    Maco, Bohumil
    Walker, Eloise M.
    Zenonos, Zenon A.
    Angrisano, Fiona
    Baum, Jake
    Doerig, Christian
    Baker, David A.
    Billker, Oliver
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Brochet, Mathieu
    Epistasis studies reveal redundancy among calcium-dependent protein kinases in motility and invasion of malaria parasites2018Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 9, artikel-id 4248Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In malaria parasites, evolution of parasitism has been linked to functional optimisation. Despite this optimisation, most members of a calcium-dependent protein kinase (CDPK) family show genetic redundancy during erythrocytic proliferation. To identify relationships between phospho-signalling pathways, we here screen 294 genetic interactions among protein kinases in Plasmodium berghei. This reveals a synthetic negative interaction between a hypomorphic allele of the protein kinase G (PKG) and CDPK4 to control erythrocyte invasion which is conserved in P. falciparum. CDPK4 becomes critical when PKG-dependent calcium signals are attenuated to phosphorylate proteins important for the stability of the inner membrane complex, which serves as an anchor for the acto-myosin motor required for motility and invasion. Finally, we show that multiple kinases functionally complement CDPK4 during erythrocytic proliferation and transmission to the mosquito. This study reveals how CDPKs are wired within a stage-transcending signalling network to control motility and host cell invasion in malaria parasites.

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  • 38. Fang, Jun
    et al.
    Jia, Jinping
    Makowski, Matthew
    Xu, Mai
    Wang, Zhaoming
    Zhang, Tongwu
    Hoskins, Jason W.
    Choi, Jiyeon
    Han, Younghun
    Zhang, Mingfeng
    Thomas, Janelle
    Kovacs, Michael
    Collins, Irene
    Dzyadyk, Marta
    Thompson, Abbey
    O'Neill, Maura
    Das, Sudipto
    Lan, Qi
    Koster, Roelof
    Stolzenberg-Solomon, Rachael S.
    Kraft, Peter
    Wolpin, Brian M.
    Jansen, Pascal W. T. C.
    Olson, Sara
    McGlynn, Katherine A.
    Kanetsky, Peter A.
    Chatterjee, Nilanjan
    Barrett, Jennifer H.
    Dunning, Alison M.
    Taylor, John C.
    Newton-Bishop, Julia A.
    Bishop, D. Timothy
    Andresson, Thorkell
    Petersen, Gloria M.
    Amos, Christopher I.
    Iles, Mark M.
    Nathanson, Katherine L.
    Landi, Maria Teresa
    Vermeulen, Michiel
    Brown, Kevin M.
    Amundadottir, Laufey T.
    Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF1482017Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 8, artikel-id 15034Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome wide association studies (GWAS) have mapped multiple independent cancer susceptibility loci to chr5p15.33. Here, we show that fine-mapping of pancreatic and testicular cancer GWAS within one of these loci (Region 2 in CLPTM1L) focuses the signal to nine highly correlated SNPs. Of these, rs36115365-C associated with increased pancreatic and testicular but decreased lung cancer and melanoma risk, and exhibited preferred protein-binding and enhanced regulatory activity. Transcriptional gene silencing of this regulatory element repressed TERT expression in an allele-specific manner. Proteomic analysis identifies allele-preferred binding of Zinc finger protein 148 (ZNF148) to rs36115365-C, further supported by binding of purified recombinant ZNF148. Knockdown of ZNF148 results in reduced TERT expression, telomerase activity and telomere length. Our results indicate that the association with chr5p15.33-Region 2 may be explained by rs36115365, a variant influencing TERT expression via ZNF148 in a manner consistent with elevated TERT in carriers of the C allele.

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  • 39. Fasanelli, Francesca
    et al.
    Baglietto, Laura
    Ponzi, Erica
    Guida, Florence
    Campanella, Gianluca
    Johansson, Mattias
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Genetic Epidemiology Division, International Agency for Research on Cancer, Lyon, France.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Assumma, Manuela Bianca
    Naccarati, Alessio
    Chadeau-Hyam, Marc
    Ala, Ugo
    Faltus, Christian
    Kaaks, Rudolf
    Risch, Angela
    De Stavola, Bianca
    Hodge, Allison
    Giles, Graham G
    Southey, Melissa C
    Relton, Caroline L
    Haycock, Philip C
    Lund, Eiliv
    Polidoro, Silvia
    Sandanger, Torkjel M
    Severi, Gianluca
    Vineis, Paolo
    Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts2015Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 6, artikel-id 10192Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case–control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31–0.54, P-value=3.3 × 10−11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31–0.56, P-value=3.9 × 10−10), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case–control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

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  • 40.
    Fauser, Joel
    et al.
    Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; Center for Integrated Protein Science Munich (CIPSM), Department Chemistry, Technical University of Munich, Garching, Germany.
    Gulen, Burak
    Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; Center for Integrated Protein Science Munich (CIPSM), Department Chemistry, Technical University of Munich, Garching, Germany.
    Pogenberg, Vivian
    Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
    Pett, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pourjafar-Dehkordi, Danial
    Physics Department T38, Technical University of Munich, Garching, Germany.
    Krisp, Christoph
    Institute of Clinical Chemistry and Laboratory Medicine, Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
    Höpfner, Dorothea
    Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; Center for Integrated Protein Science Munich (CIPSM), Department Chemistry, Technical University of Munich, Garching, Germany.
    König, Gesa
    Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
    Schlüter, Hartmut
    Institute of Clinical Chemistry and Laboratory Medicine, Mass Spectrometric Proteomics, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
    Feige, Matthias J.
    Center for Integrated Protein Science Munich (CIPSM), Department Chemistry, Technical University of Munich, Garching, Germany; Institute for Advanced Study, Technical University of Munich, Garching, Germany.
    Zacharias, Martin
    Physics Department T38, Technical University of Munich, Garching, Germany.
    Hedberg, Christian
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Itzen, Aymelt
    Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; Center for Integrated Protein Science Munich (CIPSM), Department Chemistry, Technical University of Munich, Garching, Germany; Center for Structural Systems Biology (CSSB), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
    Specificity of AMPylation of the human chaperone BiP is mediated by TPR motifs of FICD2021Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 12, nr 1, artikel-id 2426Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To adapt to fluctuating protein folding loads in the endoplasmic reticulum (ER), the Hsp70 chaperone BiP is reversibly modified with adenosine monophosphate (AMP) by the ER-resident Fic-enzyme FICD/HYPE. The structural basis for BiP binding and AMPylation by FICD has remained elusive due to the transient nature of the enzyme-substrate-complex. Here, we use thiol-reactive derivatives of the cosubstrate adenosine triphosphate (ATP) to covalently stabilize the transient FICD:BiP complex and determine its crystal structure. The complex reveals that the TPR-motifs of FICD bind specifically to the conserved hydrophobic linker of BiP and thus mediate specificity for the domain-docked conformation of BiP. Furthermore, we show that both AMPylation and deAMPylation of BiP are not directly regulated by the presence of unfolded proteins. Together, combining chemical biology, crystallography and biochemistry, our study provides structural insights into a key regulatory mechanism that safeguards ER homeostasis.

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  • 41. Ferreiro-Iglesias, Aida
    et al.
    Lesseur, Corina
    McKay, James
    Hung, Rayjean J.
    Han, Younghun
    Zong, Xuchen
    Christiani, David
    Johansson, Mattias
    Xiao, Xiangjun
    Li, Yafang
    Qian, David C.
    Ji, Xuemei
    Liu, Geoffrey
    Caporaso, Neil
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Kontic, Milica
    Ognjanovic, Simona
    Lissowska, Jolanta
    Szolkowska, Malgorzata
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Bolca, Ciprian
    Savic, Milan
    Ognjanovic, Miodrag
    Bojesen, Stig Egil
    Wu, Xifeng
    Albanes, Demetrios
    Aldrich, Melinda C.
    Tardon, Adonina
    Fernandez-Somoano, Ana
    Fernandez-Tardon, Guillermo
    Le Marchand, Loic
    Rennert, Gadi
    Chen, Chu
    Doherty, Jennifer
    Goodman, Gary
    Bickeboeller, Heike
    Wichmann, H-Erich
    Risch, Angela
    Rosenberger, Albert
    Shen, Hongbing
    Dai, Juncheng
    Field, John K.
    Davies, Michael
    Woll, Penella
    Teare, M. Dawn
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Yuan, Jian-Min
    Hong, Yun-Chul
    Haugen, Aage
    Zienolddiny, Shanbeh
    Lam, Stephen
    Tsao, Ming-Sound
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Schabath, Matthew B.
    Andrew, Angeline
    Duell, Eric
    Melander, Olle
    Brunnstrom, Hans
    Lazarus, Philip
    Arnold, Susanne
    Slone, Stacey
    Byun, Jinyoung
    Kamal, Ahsan
    Zhu, Dakai
    Landi, Maria Teresa
    Amos, Christopher, I
    Brennan, Paul
    Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity2018Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 9, artikel-id 3927Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

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  • 42. Flynn, Sean M
    et al.
    Chen, Changchun
    Cell Biology Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
    Artan, Murat
    Barratt, Stephen
    Crisp, Alastair
    Nelson, Geoffrey M
    Peak-Chew, Sew-Yeu
    Begum, Farida
    Skehel, Mark
    de Bono, Mario
    MALT-1 mediates IL-17 neural signaling to regulate C. elegans behavior, immunity and longevity2020Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 11, nr 1, artikel-id 2099Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Besides pro-inflammatory roles, the ancient cytokine interleukin-17 (IL-17) modulates neural circuit function. We investigate IL-17 signaling in neurons, and the extent it can alter organismal phenotypes. We combine immunoprecipitation and mass spectrometry to biochemically characterize endogenous signaling complexes that function downstream of IL-17 receptors in C. elegans neurons. We identify the paracaspase MALT-1 as a critical output of the pathway. MALT1 mediates signaling from many immune receptors in mammals, but was not previously implicated in IL-17 signaling or nervous system function. C. elegans MALT-1 forms a complex with homologs of Act1 and IRAK and appears to function both as a scaffold and a protease. MALT-1 is expressed broadly in the C. elegans nervous system, and neuronal IL-17–MALT-1 signaling regulates multiple phenotypes, including escape behavior, associative learning, immunity and longevity. Our data suggest MALT1 has an ancient role modulating neural circuit function downstream of IL-17 to remodel physiology and behavior.

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  • 43.
    Gamfeldt, Lars
    et al.
    SLU; Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, Sweden.
    Snäll, Tord
    SLU.
    Bagchi, Robert
    Department of Biological and Biomedical Sciences, Durham University, Durham UK.
    Jonsson, Micael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Gustafsson, Lena
    SLU.
    Kjellander, Petter
    Grimsö Wildlife Research Station, Department of Ecology, Swedish University of Agricultural Sciences, Riddarhyttan, Sweden.
    Ruiz-Jaen, María C
    Environmental Change Institute, Oxford, UK.
    Fröberg, Mats
    SLU.
    Stendahl, Johan
    SLU.
    Philipson, Christopher D
    Institute of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland.
    Mikusiński, Grzegorz
    Grimsö Wildlife Research Station, Department of Ecology, Swedish University of Agricultural Sciences, Riddarhyttan, Sweden.
    Andersson, Erik
    SLU; Stockholm Resilience Centre, Stockholm University, Stockholm, Sweden.
    Westerlund, Bertil
    SLU.
    Andrén, Henrik
    Grimsö Wildlife Research Station, Department of Ecology, Swedish University of Agricultural Sciences, Riddarhyttan, Sweden.
    Moberg, Fredrik
    Stockholm Resilience Centre, Stockholm University, Stockholm, Sweden.
    Moen, Jon
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Bengtsson, Jan
    SLU.
    Higher levels of multiple ecosystem services are found in forests with more tree species2013Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 4, artikel-id 1340Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Forests are of major importance to human society, contributing several crucial ecosystem services. Biodiversity is suggested to positively influence multiple services but evidence from natural systems at scales relevant to management is scarce. Here, across a scale of 400,000 km(2), we report that tree species richness in production forests shows positive to positively hump-shaped relationships with multiple ecosystem services. These include production of tree biomass, soil carbon storage, berry production and game production potential. For example, biomass production was approximately 50% greater with five than with one tree species. In addition, we show positive relationships between tree species richness and proxies for other biodiversity components. Importantly, no single tree species was able to promote all services, and some services were negatively correlated to each other. Management of production forests will therefore benefit from considering multiple tree species to sustain the full range of benefits that the society obtains from forests.

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  • 44.
    Gilmore, Michael C.
    et al.
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Cava, Felipe
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Peptidoglycan recycling mediated by an ABC transporter in the plant pathogen Agrobacterium tumefaciens2022Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 13, nr 1, artikel-id 7927Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During growth and division, the bacterial cell wall peptidoglycan (PG) is remodelled, resulting in the liberation of PG muropeptides which are typically reinternalized and recycled. Bacteria belonging to the Rhizobiales and Rhodobacterales orders of the Alphaproteobacteria lack the muropeptide transporter AmpG, despite having other key PG recycling enzymes. Here, we show that an alternative transporter, YejBEF-YepA, takes over this role in the Rhizobiales phytopathogen Agrobacterium tumefaciens. Muropeptide import by YejBEF-YepA governs expression of the β-lactamase AmpC in A. tumefaciens, contributing to β-lactam resistance. However, we show that the absence of YejBEF-YepA causes severe cell wall defects that go far beyond lowered AmpC activity. Thus, contrary to previously established Gram-negative models, PG recycling is vital for cell wall integrity in A. tumefaciens. YepA is widespread in the Rhizobiales and Rhodobacterales, suggesting that YejBEF-YepA-mediated PG recycling could represent an important but overlooked aspect of cell wall biology in these bacteria.

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  • 45. Gnanasundram, Sivakumar Vadivel
    et al.
    Pyndiah, Slovenie
    Daskalogianni, Chrysoula
    Armfield, Kate
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wilson, Joanna B.
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Inserm UMRS1162, Equipe Labellisée la Ligue Contre le Cancer, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010, Paris, France; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653, Brno, Czech Republic.
    PI3Kδ delta activates E2F1 synthesis in response to mRNA translation stress2017Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 8, artikel-id 2103Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein–Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kδ inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kδ prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress–response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV-carrying cancers.

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  • 46.
    Grill, Filip
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Guitart-Masip, Marc
    Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Center for Psychiatry Research, Region Stockholm, Stockholm, Sweden; Center for Cognitive and Computational Neuropsychiatry (CCNP), Karolinska Institutet, Stockholm, Sweden; Max Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London, London, United Kingdom.
    Johansson, Jarkko
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Stiernman, Lars
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Axelsson, Jan
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi.
    Rieckmann, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Diagnostisk radiologi. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Institute for Psychology, University of the Bundeswehr Munich, Neubiberg, Germany.
    Dopamine release in human associative striatum during reversal learning2024Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 15, nr 1, artikel-id 59Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The dopaminergic system is firmly implicated in reversal learning but human measurements of dopamine release as a correlate of reversal learning success are lacking. Dopamine release and hemodynamic brain activity in response to unexpected changes in action-outcome probabilities are here explored using simultaneous dynamic [11C]Raclopride PET-fMRI and computational modelling of behavior. When participants encounter reversed reward probabilities during a card guessing game, dopamine release is observed in associative striatum. Individual differences in absolute reward prediction error and sensitivity to errors are associated with peak dopamine receptor occupancy. The fMRI response to perseverance errors at the onset of a reversal spatially overlap with the site of dopamine release. Trial-by-trial fMRI correlates of absolute prediction errors show a response in striatum and association cortices, closely overlapping with the location of dopamine release, and separable from a valence signal in ventral striatum. The results converge to implicate striatal dopamine release in associative striatum as a central component of reversal learning, possibly signifying the need for increased cognitive control when new stimuli-responses should be learned.

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  • 47.
    Grönlund, Andreas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Lötstedt, Per
    Elf, Johan
    Transcription factor binding kinetics constrain noise suppression via negative feedback2013Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 4, s. 1864-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Negative autoregulation, where a transcription factor regulates its own expression by preventing transcription, is commonly used to suppress fluctuations in gene expression. Recent single molecule in vivo imaging has shown that it takes significant time for a transcription factor molecule to bind its chromosomal binding site. Given the slow association kinetics, transcription factor mediated feedback cannot at the same time be fast and strong. Here we show that with a limited association rate follows an optimal transcription factor binding strength where noise is maximally suppressed. At the optimal binding strength the binding site is free a fixed fraction of the time independent of the transcription factor concentration. One consequence is that high-copy number transcription factors should bind weakly to their operators, which is observed for transcription factors in Escherichia coli. The results demonstrate that a binding site's strength may be uncorrelated to its functional importance.

  • 48.
    Guinea Diaz, Manuel
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Hernandez-Verdeja, Tamara
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Kremnev, Dmitry
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Crawford, Tim
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Dubreuil, Carole
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Strand, Åsa
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Redox regulation of PEP activity during seedling establishment in Arabidopsis thaliana2018Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 9, artikel-id 50Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Activation of the plastid-encoded RNA polymerase is tightly controlled and involves a network of phosphorylation and, as yet unidentified, thiol-mediated events. Here, we characterize PLASTID REDOX INSENSITIVE2, a redox-regulated protein required for full PEP-driven transcription. PRIN2 dimers can be reduced into the active monomeric form by thioredoxins through reduction of a disulfide bond. Exposure to light increases the ratio between the monomeric and dimeric forms of PRIN2. Complementation of prin2-2 with different PRIN2 protein variants demonstrates that the monomer is required for light-activated PEP-dependent transcription and that expression of the nuclear-encoded photosynthesis genes is linked to the activity of PEP. Activation of PEP during chloroplast development likely is the source of a retrograde signal that promotes nuclear LHCB expression. Thus, regulation of PRIN2 is the thiol-mediated mechanism required for full PEP activity, with PRIN2 monomerization via reduction by TRXs providing a mechanistic link between photosynthetic electron transport and activation of photosynthetic gene expression.

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  • 49.
    Guo, Zongxin
    et al.
    Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark.
    Orädd, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bågenholm, Viktoria
    Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark.
    Grønberg, Christina
    Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark.
    Ma, Jian Feng
    Institute of Plant Science and Resources, Okayama University, Japan.
    Ott, Peter
    Medical Department of Hepatology and Gastroenterology, Aarhus University Hospital, Skejby, Denmark.
    Wang, Yong
    College of Life Sciences, Zhejiang University, Zhejiang, China.
    Andersson, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Amstrup Pedersen, Per
    Department of Biology, University of Copenhagen, Copenhagen, Denmark.
    Wang, Kaituo
    Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark.
    Gourdon, Pontus
    Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark; Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases2024Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 15, artikel-id 2690Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Copper transporting P-type (P1B-1-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P1B-1-ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P1B-1-ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD−1, serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD−1, MBD−2, likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in positioning sulfur-providing copper-binding amino acids, allowing for copper uptake, binding and release. As such, our findings unify previously conflicting data on the transport and regulation of P1B-1-ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P1B-1-disorders and ongoing clinical trials.

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  • 50. Gusev, Alexander
    et al.
    Shi, Huwenbo
    Kichaev, Gleb
    Pomerantz, Mark
    Li, Fugen
    Long, Henry W
    Ingles, Sue A
    Kittles, Rick A
    Strom, Sara S
    Rybicki, Benjamin A
    Nemesure, Barbara
    Isaacs, William B
    Zheng, Wei
    Pettaway, Curtis A
    Yeboah, Edward D
    Tettey, Yao
    Biritwum, Richard B
    Adjei, Andrew A
    Tay, Evelyn
    Truelove, Ann
    Niwa, Shelley
    Chokkalingam, Anand P
    John, Esther M
    Murphy, Adam B
    Signorello, Lisa B
    Carpten, John
    Leske, M Cristina
    Wu, Suh-Yuh
    Hennis, Anslem J M
    Neslund-Dudas, Christine
    Hsing, Ann W
    Chu, Lisa
    Goodman, Phyllis J
    Klein, Eric A
    Witte, John S
    Casey, Graham
    Kaggwa, Sam
    Cook, Michael B
    Stram, Daniel O
    Blot, William J
    Eeles, Rosalind A
    Easton, Douglas
    Kote-Jarai, ZSofia
    Al Olama, Ali Amin
    Benlloch, Sara
    Muir, Kenneth
    Giles, Graham G
    Southey, Melissa C
    Fitzgerald, Liesel M
    Gronberg, Henrik
    Wiklund, Fredrik
    Aly, Markus
    Henderson, Brian E
    Schleutker, Johanna
    Wahlfors, Tiina
    Tammela, Teuvo L J
    Nordestgaard, Børge G
    Key, Tim J
    Travis, Ruth C
    Neal, David E
    Donovan, Jenny L
    Hamdy, Freddie C
    Pharoah, Paul
    Pashayan, Nora
    Khaw, Kay-Tee
    Stanford, Janet L
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Schaid, Daniel J
    Maier, Christiane
    Vogel, Walther
    Luedeke, Manuel
    Herkommer, Kathleen
    Kibel, Adam S
    Cybulski, Cezary
    Wokolorczyk, Dominika
    Kluzniak, Wojciech
    Cannon-Albright, Lisa
    Teerlink, Craig
    Brenner, Hermann
    Dieffenbach, Aida K
    Arndt, Volker
    Park, Jong Y
    Sellers, Thomas A
    Lin, Hui-Yi
    Slavov, Chavdar
    Kaneva, Radka
    Mitev, Vanio
    Batra, Jyotsna
    Spurdle, Amanda
    Clements, Judith A
    Teixeira, Manuel R
    Pandha, Hardev
    Michael, Agnieszka
    Paulo, Paula
    Maia, Sofia
    Kierzek, Andrzej
    Conti, David V
    Albanes, Demetrius
    Berg, Christine
    Berndt, Sonja I
    Campa, Daniele
    Crawford, E David
    Diver, W Ryan
    Gapstur, Susan M
    Gaziano, J Michael
    Giovannucci, Edward
    Hoover, Robert
    Hunter, David J
    Johansson, Mattias
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Kraft, Peter
    Le Marchand, Loic
    Lindström, Sara
    Navarro, Carmen
    Overvad, Kim
    Riboli, Elio
    Siddiq, Afshan
    Stevens, Victoria L
    Trichopoulos, Dimitrios
    Vineis, Paolo
    Yeager, Meredith
    Trynka, Gosia
    Raychaudhuri, Soumya
    Schumacher, Frederick R
    Price, Alkes L
    Freedman, Matthew L
    Haiman, Christopher A
    Pasaniuc, Bogdan
    Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.2016Ingår i: Nature Communications, E-ISSN 2041-1723, Vol. 7, artikel-id 10979Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

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