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  • 1.
    Dou, Dan
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hernández-Neuta, Iván
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wang, Hao
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Östbye, Henrik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Qian, Xiaoyan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Thiele, Swantje
    Resa-Infante, Patricia
    Mounogou Kouassi, Nancy
    Sender, Vicky
    Hentrich, Karina
    Mellroth, Peter
    Henriques-Normark, Birgitta
    Gabriel, Gülsah
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Daniels, Robert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Analysis of IAV Replication and Co-infection Dynamics by a Versatile RNA Viral Genome Labeling Method2017In: Cell Reports, E-ISSN 2211-1247, Vol. 20, no 1, p. 251-263Article in journal (Refereed)
    Abstract [en]

    Genome delivery to the proper cellular compartment for transcription and replication is a primary goal of viruses. However, methods for analyzing viral genome localization and differentiating genomes with high identity are lacking, making it difficult to investigate entry-related processes and co-examine heterogeneous RNA viral populations. Here, we present an RNA labeling approach for single-cell analysis of RNA viral replication and co-infection dynamics in situ, which uses the versatility of padlock probes. We applied this method to identify influenza A virus (IAV) infections in cells and lung tissue with single-nucleotide specificity and to classify entry and replication stages by gene segment localization. Extending the classification strategy to co-infections of IAVs with single-nucleotide variations, we found that the dependence on intracellular trafficking places a time restriction on secondary co-infections necessary for genome reassortment. Altogether, these data demonstrate how RNA viral genome labeling can help dissect entry and co-infections.

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  • 2.
    Duan, Jianli
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Chinese Academy of Sciences, China.
    Zhao, Yunpo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Chinese Academy of Sciences, China; University of British Columbia, Canada.
    Li, Haichao
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Gordon, Michael D.
    Miao, Xuexia
    Engström, Ylva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Bab2 Functions as an Ecdysone-Responsive Transcriptional Repressor during Drosophila Development2020In: Cell Reports, E-ISSN 2211-1247, Vol. 32, no 4, article id 107972Article in journal (Refereed)
    Abstract [en]

    Drosophila development is governed by distinct ecdysone steroid pulses that initiate spatially and temporally defined gene expression programs. The translation of these signals into tissue-specific responses is crucial for metamorphosis, but the mechanisms that confer specificity to systemic ecdysone pulses are far from understood. Here, we identify Bric-a-brac 2 (Bab2) as an ecdysone-responsive transcriptional repressor that controls temporal gene expression during larval to pupal transition. Bab2 is necessary to terminate Salivary gland secretion (Sgs) gene expression, while premature Bab2 expression blocks Sgs genes and causes precocious salivary gland histolysis. The timely expression of bab2 is controlled by the ecdysone-responsive transcription factor Broad, and manipulation of EcR/USP/Broad signaling induces inappropriate Bab2 expression and termination of Sgs gene expression. Bab2 directly binds to Sgs loci in vitro and represses all Sgs genes in vivo. Our work characterizes Bab2 as a temporal regulator of somatic gene expression in response to systemic ecdysone signaling.

  • 3. Fergusson, Joannah R.
    et al.
    Smith, Kira E.
    Fleming, Vicki M.
    Rajoriya, Neil
    Newell, Evan W.
    Simmons, Ruth
    Marchi, Emanuele
    Björkander, Sophia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kang, Yu-Hoi
    Swadling, Leo
    Kurioka, Ayako
    Sahgal, Natasha
    Lockstone, Helen
    Baban, Dilair
    Freeman, Gordon J.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Davis, Mark M.
    Davenport, Miles P.
    Venturi, Vanessa
    Ussher, James E.
    Willberg, Christian B.
    Klenerman, Paul
    CD161 Defines a Transcriptional and Functional Phenotype across Distinct Human T Cell Lineages2014In: Cell Reports, E-ISSN 2211-1247, Vol. 9, no 3, p. 1075-1088Article in journal (Refereed)
    Abstract [en]

    The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCR gamma delta+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.

  • 4.
    Fischer, Alexander W.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg-Eppendorf, Germany.
    Hoefig, Carolin S.
    Abreu-Vieira, Gustavo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    de Jong, Jasper M. A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mittag, Jens
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Leptin Raises Defended Body Temperature without Activating Thermogenesis2016In: Cell Reports, E-ISSN 2211-1247, Vol. 14, no 7, p. 1621-1631Article in journal (Refereed)
    Abstract [en]

    Leptin has been believed to exert its weight-reducing action not only by inducing hypophagia but also by increasing energy expenditure/thermogenesis. Leptin-deficient ob/ob mice have correspondingly been thought to be thermogenically limited and to show hypothermia, mainly due to atrophied brown adipose tissue (BAT). In contrast to these established views, we found that BAT is fully functional and that leptin treatment did not increase thermogenesis in wildtype or in ob/ob mice. Rather, ob/ob mice showed a decreased but defended body temperature (i. e., were anapyrexic, not hypothermic) that was normalized to wild-type levels after leptin treatment. This was not accompanied by increased energy expenditure or BAT recruitment but, instead, was mediated by decreased tail heat loss. The weight-reducing hypophagic effects of leptin are, therefore, not augmented through a thermogenic effect of leptin; leptin is, however, pyrexic, i. e., it alters centrally regulated thresholds of thermoregulatory mechanisms, in parallel to effects of other cytokines.

  • 5. Fourati, Zaineb
    et al.
    Howard, Rebecca J.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Heusser, Stephanie A.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Hu, Haidai
    Ruza, Reinis R.
    Sauguet, Ludovic
    Lindahl, Erik
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). KTH Royal Institute of Technology, Sweden.
    Delarue, Marc
    Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels2018In: Cell Reports, E-ISSN 2211-1247, Vol. 23, no 4, p. 993-1004Article in journal (Refereed)
    Abstract [en]

    Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking[1] . The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore, or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

  • 6. Fukuda, Nanaho
    et al.
    Fukuda, Tomoyuki
    Percipalle, Piergiorgio
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. New York University Abu Dhabi, UAE.
    Oda, Kanako
    Takei, Nobuyuki
    Czaplinski, Kevin
    Touhara, Kazushige
    Yoshihara, Yoshihiro
    Sasaoka, Toshikuni
    Axonal mRNA binding of hnRNP A/B is crucial for axon targeting and maturation of olfactory sensory neurons2023In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 5, article id 112398Article in journal (Refereed)
    Abstract [en]

    Spatiotemporal control of gene expression is important for neural development and function. Here, we show that heterogeneous nuclear ribonucleoprotein (hnRNP) A/B is highly expressed in developing olfactory sensory neurons (OSNs), and its knockout results in reduction in mature OSNs and aberrant targeting of OSN axons to the olfactory bulb. RNA immunoprecipitation analysis reveals that hnRNP A/B binds to a group of mRNAs that are highly related to axon projections and synapse assembly. Approximately 11% of the identified hnRNP A/B targets, including Pcdha and Ncam2, encode cell adhesion molecules. In Hnrnpab knockout mice, PCDHA and NCAM2 levels are significantly reduced at the axon terminals of OSNs. Furthermore, deletion of the hnRNP A/B-recognition motif in the 3′ UTR of Pcdha leads to impaired PCDHA expression at the OSN axon terminals. Therefore, we propose that hnRNP A/B facilitates OSN maturation and axon projection by regulating the local expression of its target genes at axon terminals.

  • 7. Galmozzi, Andrea
    et al.
    Sonne, Si B.
    Altshuler-Keylin, Svetlana
    Hasegawa, Yutaka
    Shinoda, Kosaku
    Luijten, Ineke H. N.
    University of California, USA.
    Won Chang, Jae
    Sharp, Louis Z.
    Cravatt, Benjamin F.
    Saez, Enrique
    Kajimura, Shingo
    ThermoMouse: An In Vivo Model to Identify Modulators of UCP1 Expression in Brown Adipose Tissue2014In: Cell Reports, E-ISSN 2211-1247, Vol. 9, no 5, p. 1584-1593Article in journal (Refereed)
    Abstract [en]

    Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial uncoupling protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as antiobesity medications, we developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis.

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  • 8. Hagberg, Carolina E.
    et al.
    Li, Qian
    Kutschke, Maria
    Bhowmick, Debajit
    Kiss, Endre
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Harms, Matthew J.
    Shilkova, Olga
    Kozina, Viviana
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Boucher, Jeremie
    Thorell, Anders
    Spalding, Kirsty L.
    Flow Cytometry of Mouse and Human Adipocytes for the Analysis of Browning and Cellular Heterogeneity2018In: Cell Reports, E-ISSN 2211-1247, Vol. 24, no 10, p. 2746-2756Article in journal (Refereed)
    Abstract [en]

    Adipocytes, once considered simple lipid-storing cells, are rapidly emerging as complex cells with many biologically diverse functions. A powerful high-throughput method for analyzing single cells is flow cytometry. Several groups have attempted to analyze and sort freshly isolated adipocytes; however, using an adipocyte-specific reporter mouse, we demonstrate that these studies fail to detect the majority of white adipocytes. We define critical settings required for adipocyte flow cytometry and provide a rigid strategy for analyzing and sorting white and brown adipocyte populations. The applicability of our protocol is shown by sorting mouse adipocytes based on size or UCP1 expression and demonstrating that a subset of human adipocytes lacks the beta(2)-adrenergic receptor, particularly in the insulin-resistant state. In conclusion, the present study confers key technological insights for analyzing and sorting mature adipocytes, opening up numerous downstream research applications.

  • 9. Holst, Mikkel Roland
    et al.
    Vidal-Quadras, Maite
    Larsson, Elin
    Song, Jie
    Hubert, Madlen
    Blomberg, Jeanette
    Lundborg, Magnus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Landström, Maréne
    Lundmark, Richard
    Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion2017In: Cell Reports, E-ISSN 2211-1247, Vol. 20, no 8, p. 1893-1905Article in journal (Refereed)
    Abstract [en]

    Cellular blebbing, caused by local alterations in cellsurface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrinindependent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension- mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol- interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

  • 10. Jenull, Sabrina
    et al.
    Mair, Theresia
    Tscherner, Michael
    Penninger, Philipp
    Zwolanek, Florian
    Silao, Fitz-Gerald S.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Martinez de San Vicente, Kontxi
    Riedelberger, Michael
    Bandari, Naga C.
    Shivarathri, Raju
    Petryshyn, Andriy
    Chauhan, Neeraj
    Zacchi, Lucia F.
    Leibundgut Landmann, Salomé
    Ljungdahl, Per O.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kuchler, Karl
    The histone chaperone HIR maintains chromatin states to control nitrogen assimilation and fungal virulence2021In: Cell Reports, E-ISSN 2211-1247, Vol. 36, no 3, article id 109406Article in journal (Refereed)
    Abstract [en]

    Adaptation to changing environments and immune evasion is pivotal for fitness of pathogens. Yet, the underlying mechanisms remain largely unknown. Adaptation is governed by dynamic transcriptional re-programming, which is tightly connected to chromatin architecture. Here, we report a pivotal role for the HIR histone chaperone complex in modulating virulence of the human fungal pathogen Candida albicans. Genetic ablation of HIR function alters chromatin accessibility linked to aberrant transcriptional responses to protein as nitrogen source. This accelerates metabolic adaptation and increases the release of extracellular proteases, which enables scavenging of alternative nitrogen sources. Furthermore, HIR controls fungal virulence, as HIR1 deletion leads to differential recognition by immune cells and hypervirulence in a mouse model of systemic infection. This work provides mechanistic insights into chromatin-coupled regulatory mechanisms that fine-tune pathogen gene expression and virulence. Furthermore, the data point toward the requirement of refined screening approaches to exploit chromatin modifications as antifungal strategies.

  • 11. Johansson, Jarkko
    et al.
    Nordin, Kristin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Pedersen, Robin
    Karalija, Nina
    Papenberg, Göran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Andersson, Micael
    Korkki, Saana M.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Riklund, Katrine
    Guitart-Masip, Marc
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University College London, UK.
    Rieckmann, Anna
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Nyberg, Lars
    Salami, Alireza
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå University, Sweden.
    Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan2023In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 9, article id 113107Article in journal (Refereed)
    Abstract [en]

    Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing preand post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.

  • 12. Johansson, Patrik
    et al.
    Krona, Cecilia
    Kundu, Soumi
    Doroszko, Milena
    Baskaran, Sathishkumar
    Schmidt, Linnéa
    Vinel, Claire
    Almstedt, Elin
    Elgendy, Ramy
    Elfineh, Ludmila
    Gallant, Caroline
    Lundsten, Sara
    Ferrer Gago, Fernando J.
    Hakkarainen, Aleksi
    Sipila, Petra
    Häggblad, Maria
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Martens, Ulf
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Lundgren, Bo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Frigault, Melanie M.
    Lane, David P.
    Swartling, Fredrik J.
    Uhrbom, Lene
    Nestor, Marika
    Marino, Silvia
    Nelander, Sven
    A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma2020In: Cell Reports, E-ISSN 2211-1247, Vol. 32, no 2, article id 107897Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.

  • 13.
    Kang, Wenjing
    et al.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fromm, Bastian
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. UiT - The Arctic University of Norway, Norway.
    Houben, Anna J.
    Høye, Eirik
    Bezdan, Daniela
    Arnan, Carme
    Thrane, Kim
    Asp, Michaela
    Johnson, Rory
    Biryukova, Inna
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Friedländer, Marc R.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    MapToCleave: High-throughput profiling of microRNA biogenesis in living cells2021In: Cell Reports, E-ISSN 2211-1247, Vol. 37, no 7, article id 110015Article in journal (Refereed)
    Abstract [en]

    Previous large-scale studies have uncovered many features that determine the processing of microRNA (miRNA) precursors; however, they have been conducted in vitro. Here, we introduce MapToCleave, a method to simultaneously profile processing of thousands of distinct RNA structures in living cells. We find that miRNA precursors with a stable lower basal stem are more efficiently processed and also have higher expression in vivo in tissues from 20 animal species. We systematically compare the importance of known and novel sequence and structural features and test biogenesis of miRNA precursors from 10 animal and plant species in human cells. Lastly, we provide evidence that the GHG motif better predicts processing when defined as a structure rather than sequence motif, consistent with recent cryogenic electron microscopy (cryo-EM) studies. In summary, we apply a screening assay in living cells to reveal the importance of lower basal stem stability for miRNA processing and in vivo expression.

  • 14.
    Kehrein, Kirsten
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Schilling, Ramon
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Vargas Möller-Hergt, Braulio
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wurm, Christian A.
    Jakobs, Stefan
    Lamkemeyer, Tobias
    Langer, Thomas
    Ott, Martin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Organization of Mitochondrial Gene Expression in Two Distinct Ribosome-Containing Assemblies2015In: Cell Reports, E-ISSN 2211-1247, Vol. 10, no 6, p. 843-853Article in journal (Refereed)
    Abstract [en]

    Mitochondria contain their own genetic system that provides subunits of the complexes driving oxidative phosphorylation. A quarter of the mitochondrial proteome participates in gene expression, but how all these factors are orchestrated and spatially organized is currently unknown. Here, we established a method to purify and analyze native and intact complexes of mitochondrial ribosomes. Quantitative mass spectrometry revealed extensive interactions of ribosomes with factors involved in all the steps of posttranscriptional gene expression. These interactions result in large expressosome-like assemblies that we termed mitochondrial organization of gene expression (MIOREX) complexes. Superresolution microscopy revealed that most MIOREX complexes are evenly distributed throughout the mitochondrial network, whereas a subset is present as nucleoid-MIOREX complexes that unite the whole spectrum of organellar gene expression. Our work therefore provides a conceptual framework for the spatial organization of mitochondrial protein synthesis that likely developed to facilitate gene expression in the organelle.

  • 15. Kim, Tae Kyung
    et al.
    Sul, Jai-Yoon
    Helmfors, Henrik
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kim, Junhyong
    Eberwine, James
    Dendritic Glutamate Receptor mRNAs Show Contingent Local Hotspot-Dependent Translational Dynamics2013In: Cell Reports, E-ISSN 2211-1247, Vol. 5, no 1, p. 114-125Article in journal (Refereed)
    Abstract [en]

    Protein synthesis in neuronal dendrites underlies long-term memory formation in the brain. Local translation of reporter mRNAs has demonstrated translation in dendrites at focal points called translational hotspots. Various reports have shown that hundreds to thousands of mRNAs are localized to dendrites, yet the dynamics of translation of multiple dendritic mRNAs has remained elusive. Here, we show that the protein translational activities of two dendritically localized mRNAs are spatiotemporally complex but constrained by the translational hotspots in which they are colocalized. Cotransfection of glutamate receptor 2 (GluR2) and GluR4 mRNAs (engineered to encode different fluorescent proteins) into rat hippocampal neurons demonstrates a heterogeneous distribution of translational hotspots for the two mRNAs along dendrites. Stimulation with s-3,5-dihydroxy-phenylglycine modifies the translational dynamics of both of these RNAs in a complex saturable manner. These results suggest that the translational hotspot is a primary structural regulator of the simultaneous yet differential translation of multiple mRNAs in the neuronal dendrite.

  • 16. Kinsolving, Julia
    et al.
    Bous, Julien
    Kozielewicz, Pawel
    Košenina, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Shekhani, Rawan
    Gratz, Lukas
    Masuyer, Geoffrey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Wang, Yuankai
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dong, Min
    Schulte, Gunnar
    Structural and functional insight into the interaction of Clostridioides difficile toxin B and FZD72024In: Cell Reports, E-ISSN 2211-1247, Vol. 43, no 2, article id 113727Article in journal (Refereed)
    Abstract [en]

    The G protein -coupled receptors of the Frizzled (FZD) family, in particular FZD1,2,7, are receptors that are exploited by Clostridioides difficile toxin B (TcdB), the major virulence factor responsible for pathogenesis associated with Clostridioides difficile infection. We employ a live -cell assay examining the affinity between full-length FZDs and TcdB. Moreover, we present cryoelectron microscopy structures of TcdB alone and in complex with full-length FZD7, which reveal that large structural rearrangements of the combined repetitive polypeptide domain are required for interaction with FZDs and other TcdB receptors, constituting a first step for receptor recognition. Furthermore, we show that bezlotoxumab, an FDA -approved monoclonal antibody to treat Clostridioides difficile infection, favors the apo-TcdB structure and thus disrupts binding with FZD7. The dynamic transition between the two conformations of TcdB also governs the stability of the pore -forming region. Thus, our work provides structural and functional insight into how conformational dynamics of TcdB determine receptor binding.

  • 17.
    Luijten, Ineke H. N.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Brooks, Katie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Boulet, Nathalie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Shabalina, Irina G.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Jaiprakash, Ankita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carlsson, Bo
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Fischer, Alexander W.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University Medical Center Hamburg Eppendor, Germany.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Glucocorticoid-Induced Obesity Develops Independently of UCP12019In: Cell Reports, E-ISSN 2211-1247, Vol. 27, no 6, p. 1686-1698Article in journal (Refereed)
    Abstract [en]

    An excess of glucocorticoids leads to the development of obesity in both mice and humans, but the mechanism for this is unknown. Here, we determine the extent to which decreased BAT thermogenic capacity (as a result of glucocorticoid treatment) contributes to the development of obesity. Contrary to previous suggestions, we show that only in mice housed at thermoneutrality (30 degrees C) does corticosterone treatment reduce total BAT UCP1 protein. This reduction is reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity develops to the same extent in animals housed at 21 degrees C and 30 degrees C, whereas total BAT UCP1 protein levels differ 100-fold between the two groups. In corticosterone-treated wild-type and UCP1 knockout mice housed at 30 degrees C, obesity also develops to the same extent. Thus, our results demonstrate that the development of glucocorticoid-induced obesity is not caused by a decreased UCP1-dependent thermogenic capacity.

  • 18. Malkani, Sherina
    et al.
    Chin, Christopher R.
    Cekanaviciute, Egle
    Mortreux, Marie
    Okinula, Hazeem
    Tarbier, Marcel
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Schreurs, Ann-Sofie
    Shirazi-Fard, Yasaman
    Tahimic, Candice G. T.
    Rodriguez, Deyra N.
    Sexton, Brittany S.
    Butler, Daniel
    Verma, Akanksha
    Bezdan, Daniela
    Durmaz, Ceyda
    MacKay, Matthew
    Melnick, Ari
    Meydan, Cem
    Li, Sheng
    Garrett-Bakelman, Francine
    Fromm, Bastian
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Afshinnekoo, Ebrahim
    Langhorst, Brad W.
    Dimalanta, Eileen T.
    Cheng-Campbell, Margareth
    Blaber, Elizabeth
    Schisler, Jonathan C.
    Vanderburg, Charles
    Friedländer, Marc R.
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    McDonald, J. Tyson
    Costes, Sylvain
    Rutkove, Seward
    Grabham, Peter
    Mason, Christopher E.
    Beheshti, Afshin
    Circulating miRNA Spaceflight Signature Reveals Targets for Countermeasure Development2020In: Cell Reports, E-ISSN 2211-1247, Vol. 33, no 10, article id 108448Article in journal (Refereed)
    Abstract [en]

    We have identified and validated a spaceflight-associated microRNA (miRNA) signature that is shared by rodents and humans in response to simulated, short-duration and long-duration spaceflight. Previous studies have identified miRNAs that regulate rodent responses to spaceflight in low-Earth orbit, and we have confirmed the expression of these proposed spaceflight-associated miRNAs in rodents reacting to simulated spaceflight conditions. Moreover, astronaut samples from the NASA Twins Study confirmed these expression signatures in miRNA sequencing, single-cell RNA sequencing (scRNA-seq), and single-cell assay for transposase accessible chromatin (scATAC-seq) data. Additionally, a subset of these miRNAs (miR-125, miR-16, and let-7a) was found to regulate vascular damage caused by simulated deep space radiation. To demonstrate the physiological relevance of key spaceflight-associated miRNAs, we utilized antagomirs to inhibit their expression and successfully rescue simulated deep-space-radiation-mediated damage in human 3D vascular constructs.

  • 19. Mannion, Niamh M.
    et al.
    Greenwood, Sam M.
    Young, Robert
    Cox, Sarah
    Brindle, James
    Read, David
    Nellaker, Christoffer
    Vesely, Cornelia
    Ponting, Chris P.
    McLaughlin, Paul J.
    Jantsch, Michael F.
    Dorin, Julia
    Adams, Ian R.
    Scadden, A. D. J.
    Öhman, Marie
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Keegan, Liam P.
    O'Connell, Mary A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Cambridge, England.
    The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA2014In: Cell Reports, E-ISSN 2211-1247, Vol. 9, no 4, p. 1482-1494Article in journal (Refereed)
    Abstract [en]

    The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutieres syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform.

  • 20. Mathew, Nimitha R.
    et al.
    Jayanthan, Jayalal K.
    Smirnov, Ilya
    Robinson, Jonathan L.
    Axelsson, Hannes
    Nakka, Sravya S.
    Emmanouilidi, Aikaterini
    Czarnewski, Paulo
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Yewdell, William T.
    Schön, Karin
    Lebrero-Fernández, Cristina
    Bernasconi, Valentina
    Rodin, William
    Harandi, Ali M.
    Lycke, Nils
    Borcherding, Nicholas
    Yewdell, Jonathan W.
    Greiff, Victor
    Bemark, Mats
    Angeletti, Davide
    Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells2021In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 12, article id 109286Article in journal (Refereed)
    Abstract [en]

    B cell responses are critical for antiviral immunity. However, a comprehensive picture of antigen-specific B cell differentiation, clonal proliferation, and dynamics in different organs after infection is lacking. Here, by combining single-cell RNA and B cell receptor (BCR) sequencing of antigen-specific cells in lymph nodes, spleen, and lungs after influenza infection in mice, we identify several germinal center (GC) B cell subpopulations and organ-specific differences that persist over the course of the response. We discover transcriptional differences between memory cells in lungs and lymphoid organs and organ-restricted clonal expansion. Remarkably, we find significant clonal overlap between GC-derived memory and plasma cells. By combining BCR-mutational analyses with monoclonal antibody (mAb) expression and affinity measurements, we find that memory B cells are highly diverse and can be selected from both low- and high-affinity precursors. By linking antigen recognition with transcriptional programming, clonal proliferation, and differentiation, these finding provide important advances in our understanding of antiviral immunity.

  • 21. Moore, Steven
    et al.
    Evans, Lewis D. B.
    Andersson, Therese
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Portelius, Erik
    Smith, James
    Dias, Tatyana B.
    Saurat, Nathalie
    McGlade, Amelia
    Kirwan, Peter
    Blennow, Kaj
    Hardy, John
    Zetterberg, Henrik
    Livesey, Frederick J.
    APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons2015In: Cell Reports, E-ISSN 2211-1247, Vol. 11, no 5, p. 689-696Article in journal (Refereed)
    Abstract [en]

    Accumulation of A beta peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic A beta peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by beta-secretase and gamma-secretase inhibition, as well as gamma-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular A beta signaling to neurons.

  • 22.
    Nilsson, Ola B.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hedman, Rickard
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Marino, Jacopo
    Wickles, Stephan
    Bischoff, Lukas
    Johansson, Magnus
    Müller-Lucks, Annika
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Trovato, Fabio
    Puglisi, Joseph D.
    O’Brien, Edward P.
    Beckmann, Roland
    von Heijne, Gunnar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Cotranslational Protein Folding inside the Ribosome Exit Tunnel2015In: Cell Reports, E-ISSN 2211-1247, Vol. 12, no 10, p. 1533-1540Article in journal (Refereed)
    Abstract [en]

    At what point during translation do proteins fold? It is well established that proteins can fold cotranslationally outside the ribosome exit tunnel, whereas studies of folding inside the exit tunnel have so far detected only the formation of helical secondary structure and collapsed or partially structured folding intermediates. Here, using a combination of co-translational nascent chain force measurements, inter-subunit fluorescence resonance energy transfer studies on single translating ribosomes, molecular dynamics simulations, and cryoelectron microscopy, we show that a small zinc-finger domain protein can fold deep inside the vestibule of the ribosome exit tunnel. Thus, for small protein domains, the ribosome itself can provide the kind of sheltered folding environment that chaperones provide for larger proteins.

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  • 23.
    Schlegel, Susan
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Genevaux, Pierre
    de Gier, Jan-Willem
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    De-convoluting the Genetic Adaptations of E-coli C41(DE3) in Real Time Reveals How Alleviating Protein Production Stress Improves Yields2015In: Cell Reports, E-ISSN 2211-1247, Vol. 10, no 10, p. 1758-1766Article in journal (Refereed)
    Abstract [en]

    The well-established E. coli protein production strain C41(DE3) was isolated from the T7 RNA polymerase-based BL21(DE3) strain for its ability to produce difficult recombinant proteins, and it acquired multiple mutations during its isolation. Standard allelic replacement and competition experiments were insufficient to de-convolute these mutations. By reconstructing the evolution of C41(DE3) in real time, we identified the time frames when the different mutations occurred, enabling us to link them to particular stress events. Starvation stress imposed by the isolation procedure selected for mutations enhancing nutrient uptake, and protein production stress for mutations weakening the lacUV5 promoter, which governs t7rnap expression. Moreover, recapitulating protein production stress in BL21(DE3) showed that mutations weakening the lacUV5 promoter occur through RecA-dependent recombination with the wild-type lac-promoter and are selected for upon the production of any protein. Thus, the instability of the lacUV5 promoter in BL21(DE3) alleviates protein production stress and can be harnessed to enhance production.

  • 24.
    Shabalina, Irina G.
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Petrovic, Natasa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    de Jong, Jasper M. A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kalinovich, Anastasia
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Cannon, Barbara
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    UCP1 in Brite/Beige Adipose Tissue Mitochondria Is Functionally Thermogenic2013In: Cell Reports, E-ISSN 2211-1247, Vol. 5, no 5, p. 1196-1203Article in journal (Refereed)
    Abstract [en]

    The phenomenon of white fat browning, in which certain white adipose tissue depots significantly increase gene expression for the uncoupling protein UCP1 and thus supposedly acquire thermogenic, fat-burning properties, has attracted considerable attention. Because the mRNA increases are from very low initial levels, the metabolic relevance of the change is unclear: is the UCP1 protein thermogenically competent in these brite/beige-fat mitochondria? We found that, in mitochondria isolated from the inguinal white adipose depot of cold-acclimated mice, UCP1 protein levels almost reached those in brown-fat mitochondria. The UCP1 was thermogenically functional, in that these mitochondria exhibited UCP1-dependent thermogenesis with lipid or carbohydrate substrates with canonical guanosine diphosphate (GDP) sensitivity and loss of thermogenesis in UCP1 knockout (KO) mice. Obesogenic mouse strains had a lower thermogenic potential than obesity-resistant strains. The thermogenic density (UCP1-dependent oxygen consumption per g tissue) of inguinal white adipose tissue was maximally one-fifth of interscapular brown adipose tissue, and the total quantitative contribution of all inguinal mitochondria was maximally one-third of all interscapular brown-fat mitochondria, indicating that the classical brown adipose tissue depots would still predominate in thermogenesis.

  • 25. Sighel, Denise
    et al.
    Notarangelo, Michela
    Aibara, Shintaro
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Re, Angela
    Ricci, Gianluca
    Guida, Marianna
    Soldano, Alessia
    Adami, Valentina
    Ambrosini, Chiara
    Broso, Francesca
    Rosatti, Emanuele Filiberto
    Longhi, Sara
    Buccarelli, Mariachiara
    D'Alessandris, Quintino G.
    Giannetti, Stefano
    Pacioni, Simone
    Ricci-Vitiani, Lucia
    Rorbach, Joanna
    Pallini, Roberto
    Roulland, Sandrine
    Amunts, Alexey
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Mancini, Ines
    Modelska, Angelika
    Quattrone, Alessandro
    Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth2021In: Cell Reports, E-ISSN 2211-1247, Vol. 35, no 4, article id 109024Article in journal (Refereed)
    Abstract [en]

    Glioblastoma stem cells (GSCs) resist current glioblastoma (GBM) therapies. GSCs rely highly on oxidative phosphorylation (OXPHOS), whose function requires mitochondrial translation. Here we explore the therapeutic potential of targeting mitochondrial translation and report the results of high-content screening with putative blockers of mitochondrial ribosomes. We identify the bacterial antibiotic quinupristin/dalfopristin (Q/D) as an effective suppressor of GSC growth. Q/D also decreases the clonogenicity of GSCs in vitro, consequently dysregulating the cell cycle and inducing apoptosis. Cryoelectron microscopy (cryo-EM) reveals that Q/D binds to the large mitoribosomal subunit, inhibiting mitochondrial protein synthesis and functionally dysregulating OXPHOS complexes. These data suggest that targeting mitochondrial translation could be explored to therapeutically suppress GSC growth in GBM and that Q/D could potentially be repurposed for cancer treatment.

  • 26. Spaethling, Jennifer M.
    et al.
    Na, Young-Ji
    Lee, Jaehee
    Ulyanova, Alexandra V.
    Baltuch, Gordon H.
    Bell, Thomas J.
    Brem, Steven
    Chen, H. Isaac
    Dueck, Hannah
    Fisher, Stephen A.
    Garcia, Marcela P.
    Khaladkar, Mugdha
    Kung, David K.
    Lucas, Timothy H.
    O'Rourke, Donald M.
    Stefanik, Derek
    Wang, Jinhui
    Wolf, John A.
    Bartfai, Tamas
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Grady, M. Sean
    Sul, Jai-Yoon
    Kim, Junhyong
    Eberwine, James H.
    Primary Cell Culture of Live Neurosurgically Resected Aged Adult Human Brain Cells and Single Cell Transcriptomics2017In: Cell Reports, E-ISSN 2211-1247, Vol. 18, no 3, p. 791-803Article in journal (Refereed)
    Abstract [en]

    Investigation of human CNS disease and drug effects has been hampered by the lack of a system that enables single-cell analysis of live adult patient brain cells. We developed a culturing system, based on a papain-aided procedure, for resected adult human brain tissue removed during neurosurgery. We performed single-cell transcriptomics on over 300 cells, permitting identification of oligodendrocytes, microglia, neurons, endothelial cells, and astrocytes after 3 weeks in culture. Using deep sequencing, we detected over 12,000 expressed genes, including hundreds of cell-type-enriched mRNAs, IncRNAs and pri-miRNAs. We describe cell-type-and patient-specific transcriptional hierarchies. Single-cell transcriptomics on cultured live adult patient derived cells is a prime example of the promise of personalized precision medicine. Because these cells derive from subjects ranging in age into their sixties, this system permits human aging studies previously possible only in rodent systems.

  • 27.
    Tosal-Castano, Sergi
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Peselj, Carlotta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kohler, Verena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Larsson Berglund, Lisa
    Ebrahimi, Mahsa
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Vögtle, F.-Nora
    Höög, Johanna
    Andréasson, Claes
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Snd3 controls nucleus-vacuole junctions in response to glucose signaling2021In: Cell Reports, E-ISSN 2211-1247, Vol. 34, no 3, article id 108637Article in journal (Refereed)
    Abstract [en]

    Membrane contact sites facilitate the exchange of metabolites between organelles to support interorganellar communication. The nucleus-vacuole junctions (NVJs) establish physical contact between the perinuclear endoplasmic reticulum (ER) and the vacuole. Although the NVJ tethers are known, how NVJ abundance and composition are controlled in response to metabolic cues remains elusive. Here, we identify the ER protein Snd3 as central factor for NVJ formation. Snd3 interacts with NVJ tethers, supports their targeting to the contacts, and is essential for NVJ formation. Upon glucose exhaustion, Snd3 relocalizes from the ER to NVJs and promotes contact expansion regulated by central glucose signaling pathways. Glucose replenishment induces the rapid dissociation of Snd3 from the NVJs, preceding the slow disassembly of the junctions. In sum, this study identifies a key factor required for formation and regulation of NVJs and provides a paradigm for metabolic control of membrane contact sites.

1 - 27 of 27
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