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  • 1. Alneberg, Johannes
    et al.
    Bennke, Christin
    Beier, Sara
    Bunse, Carina
    Quince, Christopher
    Ininbergs, Karolina
    Riemann, Lasse
    Ekman, Martin
    Jürgens, Klaus
    Labrenz, Matthias
    Pinhassi, Jarone
    Andersson, Anders F.
    Ecosystem-wide metagenomic binning enables prediction of ecological niches from genomes2020In: Communications Biology, E-ISSN 2399-3642, Vol. 3, no 1, article id 119Article in journal (Refereed)
    Abstract [en]

    The genome encodes the metabolic and functional capabilities of an organism and should be a major determinant of its ecological niche. Yet, it is unknown if the niche can be predicted directly from the genome. Here, we conduct metagenomic binning on 123 water samples spanning major environmental gradients of the Baltic Sea. The resulting 1961 metagenome-assembled genomes represent 352 species-level clusters that correspond to 1/3 of the metagenome sequences of the prokaryotic size-fraction. By using machine-learning, the placement of a genome cluster along various niche gradients (salinity level, depth, size-fraction) could be predicted based solely on its functional genes. The same approach predicted the genomes’ placement in a virtual niche-space that captures the highest variation in distribution patterns. The predictions generally outperformed those inferred from phylogenetic information. Our study demonstrates a strong link between genome and ecological niche and provides a conceptual framework for predictive ecology based on genomic data.

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  • 2.
    Boussardon, Clément
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Bag, Pushan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Juvany, Marta
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Šimura, Jan
    Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Ljung, Karin
    Department of Forest Genetics and Plant Physiology, Umeå Plant Science Centre, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Keech, Olivier
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    The RPN12a proteasome subunit is essential for the multiple hormonal homeostasis controlling the progression of leaf senescence2022In: Communications Biology, E-ISSN 2399-3642, Vol. 5, no 1, article id 1043Article in journal (Refereed)
    Abstract [en]

    The 26S proteasome is a conserved multi-subunit machinery in eukaryotes. It selectively degrades ubiquitinated proteins, which in turn provides an efficient molecular mechanism to regulate numerous cellular functions and developmental processes. Here, we studied a new loss-of-function allele of RPN12a, a plant ortholog of the yeast and human structural component of the 19S proteasome RPN12. Combining a set of biochemical and molecular approaches, we confirmed that a rpn12a knock-out had exacerbated 20S and impaired 26S activities. The altered proteasomal activity led to a pleiotropic phenotype affecting both the vegetative growth and reproductive phase of the plant, including a striking repression of leaf senescence associate cell-death. Further investigation demonstrated that RPN12a is involved in the regulation of several conjugates associated with the auxin, cytokinin, ethylene and jasmonic acid homeostasis. Such enhanced aptitude of plant cells for survival in rpn12a contrasts with reports on animals, where 26S proteasome mutants generally show an accelerated cell death phenotype.

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  • 3.
    Brys, Ivani
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden; Research Group in Neuroscience and Experimental Psychology, Federal University of Vale do São Francisco, Petrolina, Brazil.
    Barrientos, Sebastian A.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Ward, Jon Ezra
    The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Wallander, Jonathan
    The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Petersson, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Halje, Pär
    The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    5-HT2AR and NMDAR psychedelics induce similar hyper-synchronous states in the rat cognitive-limbic cortex-basal ganglia system2023In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 737Article in journal (Refereed)
    Abstract [en]

    The profound changes in perception and cognition induced by psychedelic drugs are thought to act on several levels, including increased glutamatergic activity, altered functional connectivity and an aberrant increase in high-frequency oscillations. To bridge these different levels of observation, we have here performed large-scale multi-structure recordings in freely behaving rats treated with 5-HT2AR psychedelics (LSD, DOI) and NMDAR psychedelics (ketamine, PCP). While interneurons and principal cells showed disparate firing rate modulations for the two classes of psychedelics, the local field potentials revealed a shared pattern of synchronized high-frequency oscillations in the ventral striatum and several cortical areas. Remarkably, the phase differences between structures were close to zero, corresponding to <1 ms delays. Likely, this hypersynchrony has major effects on the integration of information across neuronal systems and we propose that it is a key contributor to changes in perception and cognition during psychedelic drug use. Potentially, similar mechanisms could induce hallucinations and delusions in psychotic disorders and would constitute promising targets for new antipsychotic treatments.

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  • 4. de Jong, Simone
    et al.
    Abdalla Diniz, Mateus Jose
    Saloma, Andiara
    Gadelha, Ary
    Santoro, Marcos L.
    Ota, Vanessa K.
    Noto, Cristiano
    Curtis, Charlesg
    Newhouse, Stephen J.
    Patel, Hamel
    Hall, Lynsey S.
    O'Reilly, Paul F.
    Belangero, Sintia, I
    Bressan, Rodrigo A.
    Breen, Gerome
    Wray, Naomi R.
    Ripke, Stephan
    Mattheisen, Manuel
    Trzaskowski, Maciej
    Byrne, Enda M.
    Abdellaoui, Abdel
    Adams, Mark J.
    Agerbo, Esben
    Air, Tracy M.
    Andlauer, Till F. M.
    Bacanu, Silviu-Alin
    Baekvad-Hansen, Marie
    Beekman, Aartjan T. F.
    Bigdeli, Tim B.
    Binder, Elisabeth B.
    Blackwood, Douglas H. R.
    Bryois, Julien
    Buttenschon, Henriette N.
    Bybjerg-Grauholm, Jonas
    Cai, Na
    Castelao, Enrique
    Christensen, Jane Hvarregaard
    Clarke, Toni-Kim
    Coleman, Jonathan R., I
    Colodro-Conde, Lucia
    Couvy-Duchesne, Baptiste
    Craddock, Nick
    Crawford, Gregory E.
    Davies, Gail
    Deary, Ian J.
    Degenhardt, Franziska
    Derks, Eske M.
    Direk, Nese
    Dolan, Conor, V
    Dunn, Erin C.
    Eley, Thalia C.
    Escott-Price, Valentina
    Kiadeh, Farnush Farhadi Hassan
    Finucane, Hilary K.
    Forstner, Andreas J.
    Frank, Josef
    Gaspar, Helena A.
    Gill, Michael
    Goes, Fernando S.
    Gordon, Scott D.
    Grove, Jakob
    Hansen, Christine Soholm
    Hansen, Thomas F.
    Herms, Stefan
    Hickie, Ian B.
    Hoffmann, Per
    Homuth, Georg
    Horn, Carsten
    Hottenga, Jouke-Jan
    Hougaard, David M.
    Ising, Marcus
    Jansen, Rick
    Jones, Ian
    Jones, Lisa A.
    Jorgenson, Eric
    Knowles, James A.
    Kohane, Isaac S.
    Kraft, Julia
    Kretzschmar, Warren W.
    Krogh, Jesper
    Kutalik, Zoltan
    Li, Yihan
    Lind, Penelope A.
    MacIntyre, Donald J.
    MacKinnon, Dean F.
    Maier, Robert M.
    Maier, Wolfgang
    Marchini, Jonathan
    Mbarek, Hamdi
    Mcgrath, Patrick
    Mcguffin, Peter
    Medland, Sarah E.
    Mehta, Divya
    Middeldorp, Christel M.
    Mihailov, Evelin
    Milaneschi, Yuri
    Milani, Lili
    Mondimore, Francis M.
    Montgomery, Grant W.
    Mostafavi, Sara
    Mullins, Niamh
    Nauck, Matthias
    Ng, Bernard
    Nivard, Michel G.
    Nyholt, Dale R.
    Oskarsson, Hogni
    Owen, Michael J.
    Painter, Jodie N.
    Pedersen, Carsten Bocker
    Pedersen, Marianne Giortz
    Peterson, Roseann E.
    Pettersson, Erik
    Peyrot, Wouter J.
    Pistis, Giorgio
    Posthuma, Danielle
    Quiroz, Jorge A.
    Qvist, Per
    Rice, John P.
    Riley, Brien P.
    Rivera, Margarita
    Mirza, Saira Saeed
    Schoevers, Robert
    Schulte, Eva C.
    Shen, Ling
    Shyn, Stanley, I
    Sigurdsson, Engilbert
    Sinnamon, Grant C. B.
    Smit, Johannes H.
    Smith, Daniel J.
    Stefansson, Hreinn
    Steinberg, Stacy
    Streit, Fabian
    Strohmaier, Jana
    Tansey, Katherine E.
    Teismann, Henning
    Teumer, Alexander
    Thompson, Wesley
    Thomson, Pippa A.
    Thorgeirsson, Thorgeir E.
    Traylor, Matthew
    Treutlein, Jens
    Trubetskoy, Vassily
    Uitterlinden, Andre G.
    Umbricht, Daniel
    Van der Auwera, Sandra
    van Hemert, Albert M.
    Viktorin, Alexander
    Visscher, Peter M.
    Wang, Yunpeng
    Webb, Bradley T.
    Weinsheimer, Shantel Marie
    Wellmann, Juergen
    Willemsen, Gonneke
    Witt, Stephanie H.
    Wu, Yang
    Xi, Hualin S.
    Yang, Jian
    Zhang, Futao
    Arolt, Volker
    Baune, Bernhard T.
    Berger, Klaus
    Boomsma, Dorret, I
    Cichon, Sven
    Dannlowski, Udo
    de Geus, E. J. C.
    DePaulo, J. Raymond
    Domenici, Enrico
    Domschke, Katharina
    Esko, Tonu
    Grabe, Hans J.
    Hamilton, Steven P.
    Hayward, Caroline
    Heath, Andrew C.
    Kendler, Kenneth S.
    Kloiber, Stefan
    Lewis, Glyn
    Li, Qingqin S.
    Lucae, Susanne
    Madden, Pamela A. F.
    Magnusson, Patrik K.
    Martin, Nicholas G.
    McIntosh, Andrew M.
    Metspalu, Andres
    Mors, Ole
    Mortensen, Preben Bo
    Mueller-Myhsok, Bertram
    Nordentoft, Merete
    Noethen, Markus M.
    O'Donovan, Michael C.
    Paciga, Sara A.
    Pedersen, Nancy L.
    Penninx, Brenda W. J. H.
    Perlis, Roy H.
    Porteous, David J.
    Potash, James B.
    Preisig, Martin
    Rietschel, Marcella
    Schaefer, Catherine
    Schulze, Thomas G.
    Smoller, Jordan W.
    Stefansson, Kari
    Tiemeier, Henning
    Uher, Rudolf
    Voelzke, Henry
    Weissman, Myrna M.
    Werge, Thomas
    Lewis, Cathryn M.
    Levinson, Douglas F.
    Borglum, Anders D.
    Sullivan, Patrick F.
    Meier, Sandra
    Strauss, John
    Xu, Wei
    Vincent, John B.
    Matthews, Keith
    Ferreira, Manuel
    O'Dushlaine, Colm
    Purcell, Shaun
    Raychaudhuri, Soumya
    Ruderfer, Douglas M.
    Sklar, Pamela
    Scott, Laura J.
    Flickinger, Matthew
    Burmeister, Margit
    Li, Jun
    Guan, Weihua
    Absher, Devin
    Thompson, Robert C.
    Meng, Fan Guo
    Schatzberg, Alan F.
    Bunney, William E.
    Barchas, Jack D.
    Watson, Stanley J.
    Myers, Richard M.
    Akil, Huda
    Boehnke, Michael
    Chambert, Kimberly
    Moran, Jennifer
    Scolnick, Edward
    Djurovic, Srdjan
    Melle, Ingrid
    Morken, Gunnar
    Corvin, Aiden
    Anjorin, Adebayo
    Kandaswamy, Radhika
    Lawrence, Jacob
    McLean, Alan W.
    Pickard, Benjamin S.
    Bergen, Sarah E.
    Nimgaonkar, Vishwajit
    Landen, Mikael
    Schalling, Martin
    Osby, Urban
    Backlund, Lena
    Frisen, Louise
    Langstrom, Niklas
    Stahl, Eli
    Dobbyn, Amanda
    Jamain, Stephane
    Etain, Bruno
    Bellivier, Frank
    Leber, Markus
    Maaser, Anna
    Fischer, Sascha B.
    Reinbold, Celine S.
    Kittel-Schneider, Sarah
    Fullerton, Janice M.
    Oruc, Lilijana
    Para, Jose G.
    Mayoral, Fermin
    Rivas, Fabio
    Czerski, Piotr M.
    Kammerer-Ciernioch, Jutta
    Vedder, Helmut
    Borrmann-Hassenbach, Margitta
    Pfennig, Andrea
    Brennan, Paul
    McKay, James D.
    Kogevinas, Manolis
    Schwarz, Markus
    Schofield, Peter R.
    Muehleisen, Thomas W.
    Schumacher, Johannes
    Bauer, Michael
    Wright, Adam
    Mitchell, Philip B.
    Hautzinger, Martin
    Kelsoe, John R.
    Greenwood, Tiffany A.
    Nievergelt, Caroline M.
    Shilling, Paul D.
    Smith, Erin N.
    Bloss, Cinnamon S.
    Edenberg, Howard J.
    Koller, Daniel L.
    Gershon, Elliot S.
    Liu, Chunyu
    Badner, Judith A.
    Scheftner, William A.
    Lawson, William B.
    Nwulia, Evaristus A.
    Hipolito, Maria
    Coryell, William
    Rice, John
    Byerley, William
    McMahon, Francis J.
    Lohoff, Falk W.
    Zandi, Peter P.
    Mahon, Pamela B.
    McInnis, Melvin G.
    Zollner, Sebastian
    Zhang, Peng
    Szelinger, Szabolcs
    St Clair, David
    Caesar, Sian
    Gordon-Smith, Katherine
    Fraser, Christine
    Green, Elaine K.
    Grozeva, Detelina
    Hamshere, Marian L.
    Kirov, George
    Nikolov, Ivan
    Collier, David A.
    Elkin, Amanda
    Williamson, Richard
    Young, Allan H.
    Ferrier, I. Nicol
    Milanova, Vihra
    Alda, Martin
    Cervantes, Pablo
    Cruceanu, Cristiana
    Rouleau, Guy A.
    Turecki, Gustavo
    Paciga, Sara
    Winslow, Ashley R.
    Grigoroiu-Serbanescu, Maria
    Ophoff, Roel
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Nordin Adolfsson, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Del-Favero, Jurgen
    Pato, Carlos
    Biernacka, Joanna M.
    Frye, Mark A.
    Morris, Derek
    Schork, Nicholas J.
    Reif, Andreas
    Lissowska, Jolanta
    Hauser, Joanna
    Szeszenia-Dabrowska, Neonila
    McGhee, Kevin
    Quinn, Emma
    Moskvina, Valentina
    Holmans, Peter A.
    Farmer, Anne
    Kennedy, James L.
    Andreassen, Ole A.
    Mattingsdal, Morten
    Bass, Nicholas J.
    Gurling, Hugh
    McQuillin, Andrew
    Breuer, Rene
    Hultman, Christina
    Lichtenstein, Paul
    Huckins, Laura M.
    Leboyer, Marion
    Lathrop, Mark
    Nurnberger, John
    Steffens, Michael
    Foroud, Tatiana M.
    Berrettini, Wade H.
    Craig, David W.
    Shi, Jianxin
    Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder2018In: Communications Biology, E-ISSN 2399-3642, Vol. 1, article id 163Article in journal (Refereed)
    Abstract [en]

    Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.

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  • 5.
    Dongre, Mitesh
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Singh, Bhupender
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Aung, Kyaw Min
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Larsson, Per
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Miftakhova, Regina R.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Persson, Karina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Askarian, Fatemeh
    Johannessen, Mona
    von Hofsten, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Persson, Jenny L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Erhardt, Marc
    Tuck, Simon
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Flagella-mediated secretion of a novel Vibrio cholerae cytotoxin affecting both vertebrate and invertebrate hosts2018In: Communications Biology, E-ISSN 2399-3642, Vol. 1, article id 59Article in journal (Refereed)
    Abstract [en]

    Using Caenorhabditis elegans as an infection host model for Vibrio cholerae predator interactions, we discovered a bacterial cytotoxin, MakA, whose function as a virulence factor relies on secretion via the flagellum channel in a proton motive force-dependent manner. The MakA protein is expressed from the polycistronic makDCBA (motility-associated killing factor) operon. Bacteria expressing makDCBA induced dramatic changes in intestinal morphology leading to a defecation defect, starvation and death in C. elegans. The Mak proteins also promoted V. cholerae colonization of the zebrafish gut causing lethal infection. A structural model of purified MakA at 1.9 Å resolution indicated similarities to members of a superfamily of bacterial toxins with unknown biological roles. Our findings reveal an unrecognized role for V. cholerae flagella in cytotoxin export that may contribute both to environmental spread of the bacteria by promoting survival and proliferation in encounters with predators, and to pathophysiological effects during infections.

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  • 6.
    Ericsson, Madelene
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Steneberg, Pär
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nyrén, Rakel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice2021In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 1306Article in journal (Refereed)
    Abstract [en]

    Age is associated with progressively impaired, metabolic, cardiac and vascular function, as well as reduced work/exercise capacity, mobility, and hence quality of life. Exercise exhibit positive effects on age-related dysfunctions and diseases. However, for a variety of reasons many aged individuals are unable to engage in regular physical activity, making the development of pharmacological treatments that mimics the beneficial effects of exercise highly desirable. Here we show that the pan-AMPK activator O304, which is well tolerated in humans, prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice. These results provide preclinical evidence that O304 mimics the beneficial effects of exercise. Thus, as an exercise mimetic in clinical development, AMPK activator O304 holds great potential to mitigate metabolic dysfunction, and to improve cardiac function and exercise capacity, and hence quality of life in aged individuals.

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  • 7. Gross, Sean M.
    et al.
    Dane, Mark A.
    Smith, Rebecca L.
    Devlin, Kaylyn L.
    McLean, Ian C.
    Derrick, Daniel S.
    Mills, Caitlin E.
    Subramanian, Kartik
    London, Alexandra B.
    Torre, Denis
    Evangelista, John Erol
    Clarke, Daniel J. B.
    Xie, Zhuorui
    Erdem, Cemal
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Chemical and Biomolecular Engineering, Clemson University, Clemson, SC, USA.
    Lyons, Nicholas
    Natoli, Ted
    Pessa, Sarah
    Lu, Xiaodong
    Mullahoo, James
    Li, Jonathan
    Adam, Miriam
    Wassie, Brook
    Liu, Moqing
    Kilburn, David F.
    Liby, Tiera A.
    Bucher, Elmar
    Sanchez-Aguila, Crystal
    Daily, Kenneth
    Omberg, Larsson
    Wang, Yunguan
    Jacobson, Connor
    Yapp, Clarence
    Chung, Mirra
    Vidovic, Dusica
    Lu, Yiling
    Schurer, Stephan
    Lee, Albert
    Pillai, Ajay
    Subramanian, Aravind
    Papanastasiou, Malvina
    Fraenkel, Ernest
    Feiler, Heidi S.
    Mills, Gordon B.
    Jaffe, Jake D.
    Ma’ayan, Avi
    Birtwistle, Marc R.
    Sorger, Peter K.
    Korkola, James E.
    Gray, Joe W.
    Heiser, Laura M.
    A multi-omic analysis of MCF10A cells provides a resource for integrative assessment of ligand-mediated molecular and phenotypic responses2022In: Communications Biology, E-ISSN 2399-3642, Vol. 5, no 1, article id 1066Article in journal (Refereed)
    Abstract [en]

    The phenotype of a cell and its underlying molecular state is strongly influenced by extracellular signals, including growth factors, hormones, and extracellular matrix proteins. While these signals are normally tightly controlled, their dysregulation leads to phenotypic and molecular states associated with diverse diseases. To develop a detailed understanding of the linkage between molecular and phenotypic changes, we generated a comprehensive dataset that catalogs the transcriptional, proteomic, epigenomic and phenotypic responses of MCF10A mammary epithelial cells after exposure to the ligands EGF, HGF, OSM, IFNG, TGFB and BMP2. Systematic assessment of the molecular and cellular phenotypes induced by these ligands comprise the LINCS Microenvironment (ME) perturbation dataset, which has been curated and made publicly available for community-wide analysis and development of novel computational methods ( synapse.org/LINCS_MCF10A ). In illustrative analyses, we demonstrate how this dataset can be used to discover functionally related molecular features linked to specific cellular phenotypes. Beyond these analyses, this dataset will serve as a resource for the broader scientific community to mine for biological insights, to compare signals carried across distinct molecular modalities, and to develop new computational methods for integrative data analysis.

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  • 8.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Korsgren, Olle
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    3D imaging of human organs with micrometer resolution - applied to the endocrine pancreas2021In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 1063Article in journal (Refereed)
    Abstract [en]

    The possibility to quantitatively study specific molecular/cellular features of complete human organs with preserved spatial 3D context would have widespread implications for pre-clinical and clinical medicine. Whereas optical 3D imaging approaches have experienced a formidable revolution, they have remained limited due to current incapacities in obtaining specific labelling within large tissue volumes. We present a simple approach enabling reconstruction of antibody labeled cells within entire human organs with preserved organ context. We demonstrate the utility of the approach by providing volumetric data and 3D distribution of hundreds of thousands of islets of Langerhans within the human pancreas. By assessments of pancreata from non-diabetic and type 2 diabetic individuals, we display previously unrecognized features of the human islet mass distribution and pathology. As such, this method may contribute not only in unraveling new information of the pancreatic anatomy/pathophysiology, but it may be translated to essentially any antibody marker or organ system.

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  • 9.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    van Krieken, Pim P.
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Xiong, Yan
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mayer, Jurgen
    Kostromina, Elena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ruas, Jorge L.
    Sharpe, James
    Pereira, Teresa
    Berggren, Per-Olof
    Ilegems, Erwin
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes2020In: Communications Biology, E-ISSN 2399-3642, Vol. 3, no 1, article id 541Article in journal (Refereed)
    Abstract [en]

    Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems. We applied state of the art optical imaging schemes, spanning from single islet resolution to the whole organ, providing a first longitudinal, 3D-spatial and quantitative account of β-cell mass (BCM) dynamics and islet longevity in STZ-treated mice. We demonstrate that STZ-induced β-cell destruction predominantly affects large islets in the pancreatic core. Further, we show that hyperglycemic STZ-treated mice still harbor a large pool of remaining β-cells but display pancreas-wide downregulation of glucose transporter type 2 (GLUT2). Islet gene expression studies confirmed this downregulation and revealed impaired β-cell maturity. Reversing hyperglycemia by islet transplantation partially restored the expression of markers for islet function, but not BCM. Jointly our results indicate that STZ-induced hyperglycemia results from β-cell dysfunction rather than β-cell ablation and that hyperglycemia in itself sustains a negative feedback loop restraining islet function recovery.

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  • 10.
    Heidler, Thomas V.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ernits, Karin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ziolkowska, Agnieszka
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Persson, Karina
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Porphyromonas gingivalis fimbrial protein Mfa5 contains a von Willebrand factor domain and an intramolecular isopeptide2021In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 106Article in journal (Refereed)
    Abstract [en]

    The Gram-negative bacterium Porphyromonas gingivalis is a secondary colonizer of the oral biofilm and is involved in the onset and progression of periodontitis. Its fimbriae, of type-V, are important for attachment to other microorganisms in the biofilm and for adhesion to host cells. The fimbriae are assembled from five proteins encoded by the mfa1 operon, of which Mfa5 is one of the ancillary tip proteins. Here we report the X-ray structure of the N-terminal half of Mfa5, which reveals a von Willebrand factor domain and two IgG-like domains. One of the IgG-like domains is stabilized by an intramolecular isopeptide bond, which is the first such bond observed in a Gram-negative bacterium. These features make Mfa5 structurally more related to streptococcal adhesins than to the other P. gingivalis Mfa proteins. The structure reported here indicates that horizontal gene transfer has occurred among the bacteria within the oral biofilm.

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  • 11.
    Herdenberg, Carl
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Mutie, Pascal
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Abdullah, Ahmad
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Strawbridge, Rona J.
    Dahlman, Ingrid
    Tuck, Simon
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Arner, Peter
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Franks, Paul W.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes2021In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 90Article in journal (Refereed)
    Abstract [en]

    Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins have been implicated as regulators of growth factor signaling; however, the possible redundancy among mammalian LRIG1, LRIG2, and LRIG3 has hindered detailed elucidation of their physiological functions. Here, we show that Lrig-null mouse embryonic fibroblasts (MEFs) are deficient in adipogenesis and bone morphogenetic protein (BMP) signaling. In contrast, transforming growth factor-beta (TGF-beta) and receptor tyrosine kinase (RTK) signaling appeared unaltered in Lrig-null cells. The BMP signaling defect was rescued by ectopic expression of LRIG1 or LRIG3 but not by expression of LRIG2. Caenorhabditis elegans with mutant LRIG/sma-10 variants also exhibited a lipid storage defect. Human LRIG1 variants were strongly associated with increased body mass index (BMI) yet protected against type 2 diabetes; these effects were likely mediated by altered adipocyte morphology. These results demonstrate that LRIG proteins function as evolutionarily conserved regulators of lipid metabolism and BMP signaling and have implications for human disease. Herdenberg et al. show that adipogenesis and BMP signaling are altered in mouse cells deficient in LRIG (Leucine-rich repeats and immunoglobulin-like domains) proteins. They find that mutant LRIG/sma-10 variant worms exhibit lipid storage defects and that human LRIG1 variants are associated with higher body mass index, yet protect against type 2 diabetes. This study suggests an evolutionarily conserved role of LRIG proteins for lipid metabolism and BMP signaling.

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  • 12. Jonsson, Hans
    et al.
    Hugerth, Luisa W.
    Sundh, John
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Anders F.
    Genome sequence of segmented filamentous bacteria present in the human intestine2020In: Communications Biology, E-ISSN 2399-3642, Vol. 3, no 1, article id 485Article in journal (Refereed)
    Abstract [en]

    Segmented filamentous bacteria (SFB) are unique immune modulatory bacteria colonizing the small intestine of a variety of animals in a host-specific manner. SFB exhibit filamentous growth and attach to the host's intestinal epithelium, offering a physical route of interaction. SFB affect functions of the host immune system, among them IgA production and T-cell maturation. Until now, no human-specific SFB genome has been reported. Here, we report the metagenomic reconstruction of an SFB genome from a human ileostomy sample. Phylogenomic analysis clusters the genome with SFB genomes from mouse, rat and turkey, but the genome is genetically distinct, displaying 65-71% average amino acid identity to the others. By screening human faecal metagenomic datasets, we identified individuals carrying sequences identical to the new SFB genome. We thus conclude that a unique SFB variant exists in humans and foresee a renewed interest in the elucidation of SFB functionality in this environment. Hans Jonsson et al. report the metagenomic reconstruction of the genome of a potentially immune modulatory segmented filamentous bacteria (SFB) from a human ileostomy sample. They demonstrate that the genome clusters closely with SFB genomes from other species. They also detect the unique SFB variant in human faecal metagenomics datasets.

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  • 13.
    Lawir, Divine-Fondzenyuy
    et al.
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Soza-Ried, Cristian
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Iwanami, Norimasa
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Siamishi, Iliana
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Bylund, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    O´Meara, Connor
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Sikora, Katarzyna
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Bioinformatic Unit, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Kanzler, Benoît
    Transgenic Mouse Core Facility, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Schorpp, Michael
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Cauchy, Pierre
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
    Boehm, Thomas
    Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
    Antagonistic interactions safeguard mitotic propagation of genetic and epigenetic information in zebrafish2024In: Communications Biology, E-ISSN 2399-3642, Vol. 7, no 1, article id 31Article in journal (Refereed)
    Abstract [en]

    The stability of cellular phenotypes in developing organisms depends on error-free transmission of epigenetic and genetic information during mitosis. Methylation of cytosine residues in genomic DNA is a key epigenetic mark that modulates gene expression and prevents genome instability. Here, we report on a genetic test of the relationship between DNA replication and methylation in the context of the developing vertebrate organism instead of cell lines. Our analysis is based on the identification of hypomorphic alleles of dnmt1, encoding the DNA maintenance methylase Dnmt1, and pole1, encoding the catalytic subunit of leading-strand DNA polymerase epsilon holoenzyme (Pole). Homozygous dnmt1 mutants exhibit genome-wide DNA hypomethylation, whereas the pole1 mutation is associated with increased DNA methylation levels. In dnmt1/pole1 double-mutant zebrafish larvae, DNA methylation levels are restored to near normal values, associated with partial rescue of mutant-associated transcriptional changes and phenotypes. Hence, a balancing antagonism between DNA replication and maintenance methylation buffers against replicative errors contributing to the robustness of vertebrate development.

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  • 14.
    Marreiros, Inês M.
    et al.
    Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
    Marques, Sofia
    Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
    Parreira, Ana
    Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
    Mastrodomenico, Vincent
    Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, IL, Maywood, United States.
    Mounce, Bryan C.
    Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, IL, Maywood, United States; Infectious Disease and Immunology Research Institute, Stritch School of Medicine, Loyola University Chicago, IL, Maywood, United States.
    Harris, Chantal T.
    Department of Microbiology and Immunology, Weill Cornell Medical College, NY, New York, United States; Immunology & Microbial Pathogenesis Graduate Program, Weill Cornell Medicine, NY, New York, United States.
    Kafsack, Björn F.
    Department of Microbiology and Immunology, Weill Cornell Medical College, NY, New York, United States.
    Billker, Oliver
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Zuzarte-Luís, Vanessa
    Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
    Mota, Maria M.
    Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
    A non-canonical sensing pathway mediates Plasmodium adaptation to amino acid deficiency2023In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 205Article in journal (Refereed)
    Abstract [en]

    Eukaryotes have canonical pathways for responding to amino acid (AA) availability. Under AA-limiting conditions, the TOR complex is repressed, whereas the sensor kinase GCN2 is activated. While these pathways have been highly conserved throughout evolution, malaria parasites are a rare exception. Despite auxotrophic for most AA, Plasmodium does not have either a TOR complex nor the GCN2-downstream transcription factors. While Ile starvation has been shown to trigger eIF2α phosphorylation and a hibernation-like response, the overall mechanisms mediating detection and response to AA fluctuation in the absence of such pathways has remained elusive. Here we show that Plasmodium parasites rely on an efficient sensing pathway to respond to AA fluctuations. A phenotypic screen of kinase knockout mutant parasites identified nek4, eIK1 and eIK2—the last two clustering with the eukaryotic eIF2α kinases—as critical for Plasmodium to sense and respond to distinct AA-limiting conditions. Such AA-sensing pathway is temporally regulated at distinct life cycle stages, allowing parasites to actively fine-tune replication and development in response to AA availability. Collectively, our data disclose a set of heterogeneous responses to AA depletion in malaria parasites, mediated by a complex mechanism that is critical for modulating parasite growth and survival.

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  • 15. Miguel, Sissi
    et al.
    Legrand, Guillaume
    Duriot, Leonor
    Delporte, Marianne
    Menin, Barbara
    Michel, Cindy
    Olry, Alexandre
    Chataigne, Gabrielle
    Salwinski, Aleksander
    Bygdell, Joakim
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vercaigne, Dominique
    Wingsle, Gunnar
    Hilbert, Jean Louis
    Bourgaud, Frederic
    Hehn, Alain
    Gagneul, David
    A GDSL lipase-like from Ipomoea batatas catalyzes efficient production of 3,5-diCQA when expressed in Pichia pastoris2020In: Communications Biology, E-ISSN 2399-3642, Vol. 3, no 1, article id 673Article in journal (Refereed)
    Abstract [en]

    The synthesis of 3,5-dicaffeoylquinic acid (3,5-DiCQA) has attracted the interest of many researchers for more than 30 years. Recently, enzymes belonging to the BAHD acyltransferase family were shown to mediate its synthesis, albeit with notably low efficiency. In this study, a new enzyme belonging to the GDSL lipase-like family was identified and proven to be able to transform chlorogenic acid (5-O-caffeoylquinic acid, 5-CQA, CGA) in 3,5-DiCQA with a conversion rate of more than 60%. The enzyme has been produced in different expression systems but has only been shown to be active when transiently synthesized in Nicotiana benthamiana or stably expressed in Pichia pastoris. The synthesis of the molecule could be performed in vitro but also by a bioconversion approach beginning from pure 5-CQA or from green coffee bean extract, thereby paving the road for producing it on an industrial scale. Miguel et al. identify a new enzyme belonging to the GDSL lipase-like family that is involved in the final stage of transformation of 5-CQA into 3,5-diCQA. This enzyme is able to realize an efficient transformation by over 60%, making the transformation process a valuable technological tool that can be easily transferred on an industrial scale.

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  • 16.
    Norlin, Stefan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function2023In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 877Article in journal (Refereed)
    Abstract [en]

    Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.

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  • 17.
    Rojas, Alexis
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Calatayud, Joaquín
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Kowalewski, Michał
    Florida Museum of Natural History, Division of Invertebrate Paleontology, University of Florida, FL, Gainesville, United States.
    Neuman, Magnus
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Rosvall, Martin
    Umeå University, Faculty of Science and Technology, Department of Physics.
    A multiscale view of the Phanerozoic fossil record reveals the three major biotic transitions2021In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 309Article in journal (Refereed)
    Abstract [en]

    The hypothesis of the Great Evolutionary Faunas is a foundational concept of macroevolutionary research postulating that three global mega-assemblages have dominated Phanerozoic oceans following abrupt biotic transitions. Empirical estimates of this large-scale pattern depend on several methodological decisions and are based on approaches unable to capture multiscale dynamics of the underlying Earth-Life System. Combining a multilayer network representation of fossil data with a multilevel clustering that eliminates the subjectivity inherent to distance-based approaches, we demonstrate that Phanerozoic oceans sequentially harbored four global benthic mega-assemblages. Shifts in dominance patterns among these global marine mega-assemblages were abrupt (end-Cambrian 494 Ma; end-Permian 252 Ma) or protracted (mid-Cretaceous 129 Ma), and represent the three major biotic transitions in Earth's history. Our findings suggest that gradual ecological changes associated with the Mesozoic Marine Revolution triggered a protracted biotic transition comparable in magnitude to the end-Permian transition initiated by the most severe biotic crisis of the past 500 million years. Overall, our study supports the notion that both long-term ecological changes and major geological events have played crucial roles in shaping the mega-assemblages that dominated Phanerozoic oceans.

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  • 18.
    Roy, Shovonlal
    et al.
    Department of Geography and Environmental Science, University of Reading, Reading, Whiteknights, United Kingdom.
    Brännström, Åke
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Advancing Systems Analysis Program, International Institute for Applied Systems Analysis (IIASA), Schlossplatz 1, Laxenburg, Austria; Complexity Science and Evolution Unit, Okinawa Institute of Science and Technology Graduate University (OIST), 1919-1 Tancha, Onna, Kunigami, Okinawa, Japan.
    Dieckmann, Ulf
    Advancing Systems Analysis Program, International Institute for Applied Systems Analysis (IIASA), Schlossplatz 1, Laxenburg, Austria; Complexity Science and Evolution Unit, Okinawa Institute of Science and Technology Graduate University (OIST), 1919-1 Tancha, Onna, Kunigami, Okinawa, Japan; Department of Evolutionary Studies of Biosystems, The Graduate University for Advanced Studies (Sokendai), Kanagawa, Hayama, Japan.
    Ecological determinants of Cope’s rule and its inverse2024In: Communications Biology, E-ISSN 2399-3642, Vol. 7, no 1, article id 38Article in journal (Refereed)
    Abstract [en]

    Cope’s rule posits that evolution gradually increases the body size in lineages. Over the last decades, two schools of thought have fueled a debate on the applicability of Cope’s rule by reporting empirical evidence, respectively, for and against Cope’s rule. The apparent contradictions thus documented highlight the need for a comprehensive process-based synthesis through which both positions of this debate can be understood and reconciled. Here, we use a process-based community-evolution model to investigate the eco-evolutionary emergence of Cope’s rule. We report three characteristic macroevolutionary patterns, of which only two are consistent with Cope’s rule. First, we find that Cope’s rule applies when species interactions solely depend on relative differences in body size and the risk of lineage extinction is low. Second, in environments with higher risk of lineage extinction, the recurrent evolutionary elimination of top predators induces cyclic evolution toward larger body sizes, according to a macroevolutionary pattern we call the recurrent Cope’s rule. Third, when interactions between species are determined not only by their body sizes but also by their ecological niches, the recurrent Cope’s rule may get inverted, leading to cyclic evolution toward smaller body sizes. This recurrent inverse Cope’s rule is characterized by highly dynamic community evolution, involving the diversification of species with large body sizes and the extinction of species with small body sizes. To our knowledge, these results provide the first theoretical foundation for reconciling the contrasting empirical evidence reported on body-size evolution.

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  • 19.
    Tran, Buu Minh
    et al.
    Department of Biochemistry, University of Groningen, Groningen, Netherlands.
    Linnik, Dmitrii Sergeevich
    Department of Biochemistry, University of Groningen, Groningen, Netherlands.
    Punter, Christiaan Michiel
    Department of Biochemistry, University of Groningen, Groningen, Netherlands.
    Śmigiel, Wojciech Mikołaj
    Department of Biochemistry, University of Groningen, Groningen, Netherlands.
    Mantovanelli, Luca
    Department of Biochemistry, University of Groningen, Groningen, Netherlands.
    Iyer, Aditya
    Department of Biochemistry, University of Groningen, Groningen, Netherlands.
    O’Byrne, Conor
    Microbiology, School of Biological & Chemical Sciences, Ryan Institute, University of Galway, Galway, Ireland.
    Abee, Tjakko
    Laboratory of Food Microbiology, Wageningen University & Research, Wageningen, Netherlands.
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Poolman, Bert
    Department of Biochemistry, University of Groningen, Groningen, Netherlands.
    Super-resolving microscopy reveals the localizations and movement dynamics of stressosome proteins in Listeria monocytogenes2023In: Communications Biology, E-ISSN 2399-3642, Vol. 6, no 1, article id 51Article in journal (Refereed)
    Abstract [en]

    The human pathogen Listeria monocytogenes can cope with severe environmental challenges, for which the high molecular weight stressosome complex acts as the sensing hub in a complicated signal transduction pathway. Here, we show the dynamics and functional roles of the stressosome protein RsbR1 and its paralogue, the blue-light receptor RsbL, using photo-activated localization microscopy combined with single-particle tracking and single-molecule displacement mapping and supported by physiological studies. In live cells, RsbR1 is present in multiple states: in protomers with RsbS, large clusters of stressosome complexes, and in connection with the plasma membrane via Prli42. RsbL diffuses freely in the cytoplasm but forms clusters upon exposure to light. The clustering of RsbL is independent of the presence of Prli42. Our work provides a comprehensive view of the spatial organization and intracellular dynamics of the stressosome proteins in L. monocytogenes, which paves the way towards uncovering the stress-sensing mechanism of this signal transduction pathway.

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  • 20.
    Ul Mushtaq, Ameeq
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ådén, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Clifton, Luke A.
    Wacklin-Knecht, Hanna
    Campana, Mario
    Dingeldein, Artur P. G.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Persson, Cecilia
    Sparrman, Tobias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation2021In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 507Article in journal (Refereed)
    Abstract [en]

    B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region.

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  • 21.
    Zhao, Xiaodan
    et al.
    Department of Physics, National University of Singapore, Singapore, Singapore.
    Vogirala, Vinod Kumar
    School of Biological Sciences, Nanyang Technology University, Singapore, Singapore; Electron Bio-Imaging Centre (eBIC), Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom.
    Liu, Meihan
    Mechanobiology Institute, National University of Singapore, Singapore, Singapore.
    Zhou, Yu
    Mechanobiology Institute, National University of Singapore, Singapore, Singapore.
    Rhodes, Daniela
    School of Biological Sciences, Nanyang Technology University, Singapore, Singapore; NTU Institute of Structural Biology, Nanyang Technology University, Singapore, Singapore; Medical Research Council, Laboratory of Molecular Biology, Cambridge, United Kingdom.
    Sandin, Sara
    Umeå University, Faculty of Science and Technology, Department of Chemistry. School of Biological Sciences, Nanyang Technology University, Singapore, Singapore; NTU Institute of Structural Biology, Nanyang Technology University, Singapore, Singapore.
    Yan, Jie
    Department of Physics, National University of Singapore, Singapore, Singapore; Mechanobiology Institute, National University of Singapore, Singapore, Singapore; Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai New City, Fuzhou, China.
    Exploring TRF2-dependent dna distortion through single-DNA manipulation studies2024In: Communications Biology, E-ISSN 2399-3642, Vol. 7, no 1, article id 148Article in journal (Refereed)
    Abstract [en]

    TRF2 is a component of shelterin, a telomere-specific protein complex that protects the ends of mammalian chromosomes from DNA damage signaling and improper repair. TRF2 functions as a homodimer and its interaction with telomeric DNA has been studied, but its full-length DNA-binding properties are unknown. This study examines TRF2’s interaction with single-DNA strands and focuses on the conformation of the TRF2-DNA complex and TRF2’s preference for DNA chirality. The results show that TRF2-DNA can switch between extended and compact conformations, indicating multiple DNA-binding modes, and TRF2’s binding does not have a strong preference for DNA supercoiling chirality when DNA is under low tension. Instead, TRF2 induces DNA bending under tension. Furthermore, both the N-terminal domain of TRF2 and the Myb domain enhance its affinity for the telomere sequence, highlighting the crucial role of multivalent DNA binding in enhancing its affinity and specificity for telomere sequence. These discoveries offer unique insights into TRF2’s interaction with telomeric DNA.

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  • 22.
    Özalay, Özgun
    et al.
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Mediavilla, Tomás
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Giacobbo, Bruno Lima
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Hanzeplein 1, Groningen, Netherlands.
    Pedersen, Robin
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Rieckmann, Anna
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology. Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Institute for Psychology, University of the Bundeswehr Munich, Neubiberg, Germany.
    Sultan, Fahad
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging2024In: Communications Biology, E-ISSN 2399-3642, Vol. 7, no 1, article id 210Article in journal (Refereed)
    Abstract [en]

    The human aging brain is characterized by changes in network efficiency that are currently best captured through longitudinal resting-state functional MRI (rs-fMRI). These studies however are challenging due to the long human lifespan. Here we show that the mouse animal model with a much shorter lifespan allows us to follow the functional network organization over most of the animal’s adult lifetime. We used a longitudinal study of the functional connectivity of different brain regions with rs-fMRI under anesthesia. Our analysis uncovers network modules similar to those reported in younger mice and in humans (i.e., prefrontal/default mode network (DMN), somatomotor and somatosensory networks). Statistical analysis reveals different patterns of network reorganization during aging. Female mice showed a pattern akin to human aging, with de-differentiation of the connectome, mainly due to increases in connectivity of the prefrontal/DMN cortical networks to other modules. Our male cohorts revealed heterogenous aging patterns with only one group confirming the de- differentiation, while the majority showed an increase in connectivity of the somatomotor cortex to the Nucleus accumbens. In summary, in line with human work, our analysis in mice supports the concept of de-differentiation in the aging mammalian brain and reveals additional trajectories in aging mice networks.

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