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  • 1.
    Aguilo, Francesca
    et al.
    Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Li, SiDe
    Balasubramaniyan, Natarajan
    Sancho, Ana
    Benko, Sabina
    Zhang, Fan
    Vashisht, Ajay
    Rengasamy, Madhumitha
    Andino, Blanca
    Chen, Chih-hung
    Zhou, Felix
    Qian, Chengmin
    Zhou, Ming-Ming
    Wohlschlegel, James A
    Zhang, Weijia
    Suchy, Frederick J
    Walsh, Martin J
    Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 3, p. 479-492Article in journal (Refereed)
    Abstract [en]

    The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism.

  • 2. Bjornson, Elias
    et al.
    Mukhopadhyay, Bani
    Asplund, Anna
    Pristovsek, Nusa
    Cinar, Resat
    Romeo, Stefano
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kunos, George
    Nielsen, Jens
    Mardinoglu, Adil
    Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 13, no 9, p. 2014-2026Article in journal (Refereed)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC.

  • 3.
    Björnson, Elias
    et al.
    Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden..
    Mukhopadhyay, Bani
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA..
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pristovsek, Nusa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cinar, Resat
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA..
    Romeo, Stefano
    Univ Gothenburg, Wallenberg Lab, Sahlgrenska Ctr Cardiovasc & Metab Res, Dept Mol & Clin Med, S-41345 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Cardiol, S-41650 Gothenburg, Sweden.;Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Clin Nutr Unit, I-88100 Catanzaro, Italy..
    Uhlen, Mathias
    KTH Royal Inst Technol, Dept Prote, S-10691 Stockholm, Sweden.;KTH Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden..
    Kunos, George
    NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA..
    Nielsen, Jens
    Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden.;KTH Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden..
    Mardinoglu, Adil
    Chalmers, Dept Biol & Biol Engn, S-41296 Gothenburg, Sweden.;KTH Royal Inst Technol, Sci Life Lab, S-17121 Stockholm, Sweden..
    Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 13, no 9, p. 2014-2026Article in journal (Refereed)
    Abstract [en]

    Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC.

  • 4.
    Boal, Frédéric
    et al.
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Puhar, Andrea
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). INSERM U1202, Unite´ de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris Cedex 15, France.
    Xuereb, Jean-Marie
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Kunduzova, Oksana
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    Sansonetti, Philippe J.
    INSERM U1202, Unite´ de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris Cedex 15, France.
    Payrastre, Bernard
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France; .
    Tronchére, Héléne
    INSERM U1048, I2MC and Universite´ Paul Sabatier, 31432 Toulouse, France.
    PI5P Triggers ICAM-1 Degradation in Shigella Infected Cells, Thus Dampening Immune Cell Recruitment2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 4, p. 750-759Article in journal (Refereed)
    Abstract [en]

    Shigella flexneri, the pathogen responsible for bacillary dysentery, has evolved multiple strategies to control the inflammatory response. Here, we show that Shigella subverts the subcellular trafficking of the intercellular adhesion molecule-1 (ICAM-1), a key molecule in immune cell recruitment, in a mechanism dependent on the injected bacterial enzyme IpgD and its product, the lipid mediator PI5P. Overexpression of IpgD, but not a phosphatase dead mutant, induced the internalization and the degradation of ICAM-1 in intestinal epithelial cells. Remarkably, addition of permeant PI5P reproduced IpgD effects and led to the inhibition of neutrophil recruitment. Finally, these results were confirmed in an in vivo model of Shigella infection where IpgD-dependent ICAM-1 internalization reduced neutrophil adhesion. In conclusion, we describe here an immune evasion mechanism used by the pathogen Shigella to divert the host cell trafficking machinery in order to reduce immune cell recruitment.

  • 5. Brattås, Per Ludvik
    et al.
    Jönsson, Marie E.
    Fasching, Liana
    Nelander Wahlestedt, Jenny
    Shahsavani, Mansoureh
    Falk, Ronny
    Falk, Anna
    Jern, Patric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Parmar, Malin
    Jakobsson, Johan
    TRIM28 Controls a Gene Regulatory Network Based on Endogenous Retroviruses in Human Neural Progenitor Cells2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Endogenous retroviruses (ERVs), which make up 8% of the human genome, have been proposed to participate in the control of gene regulatory networks. In this study, we find a region- and developmental stage-specific expression pattern of ERVs in the developing human brain, which is linked to a transcriptional network based on ERVs. We demonstrate that almost 10,000, primarily primate-specific, ERVs act as docking platforms for the co-repressor protein TRIM28 in human neural progenitor cells, which results in the establishment of local heterochromatin. Thereby, TRIM28 represses ERVs and consequently regulates the expression of neighboring genes. These results uncover a gene regulatory network based on ERVs that participates in control of gene expression of protein-coding transcripts important for brain development.

  • 6. Dang, Thanh Chung
    et al.
    Ishii, Yoko
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan;Univ Nagano, Fac Hlth & Human Dev, Dept Hlth Sci, Nagano 3808525, Japan.
    Nguyen, Van De
    Yamamoto, Seiji
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Hamashima, Takeru
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Okuno, Noriko
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Nguyen, Quang Linh
    Sang, Yang
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Ohkawa, Noriaki
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Biochem, Toyama 9300194, Japan;JST, CREST, Toyama 9300194, Japan.
    Saitoh, Yoshito
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Biochem, Toyama 9300194, Japan;JST, CREST, Toyama 9300194, Japan.
    Shehata, Mohammad
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Biochem, Toyama 9300194, Japan;JST, CREST, Toyama 9300194, Japan.
    Takakura, Nobuyuki
    Osaka Univ, Res Inst Microbial Dis, Dept Signal Transduct, Suita, Osaka 5650871, Japan.
    Fujimori, Toshihiko
    Natl Inst Basic Biol, Div Embryol, Okazaki, Aichi 4448787, Japan.
    Inokuchi, Kaoru
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Biochem, Toyama 9300194, Japan;JST, CREST, Toyama 9300194, Japan.
    Mori, Hisashi
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Mol Neurosci, Toyama 9300194, Japan.
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Integrated Cardio Metab Ctr, S-14157 Huddinge, Sweden.
    Sasahara, Masakiyo
    Univ Toyama, Grad Sch Med & Pharmaceut Sci, Dept Pathol, Toyama 9300194, Japan.
    Powerful Homeostatic Control of Oligodendroglial Lineage by PDGFR alpha in Adult Brain2019In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 27, no 4, p. 1073-1089Article in journal (Refereed)
    Abstract [en]

    Oligodendrocyte progenitor cells (OPCs) are widely distributed cells of ramified morphology in adult brain that express PDGFR alpha and NG2. They retain mitotic activities in adulthood and contribute to oligodendrogenesis and myelin turnover; however, the regulatory mechanisms of their cell dynamics in adult brain largely remain unknown. Here, we found that global Pdgfra inactivation in adult mice rapidly led to elimination of OPCs due to synchronous maturation toward oligodendrocytes. Surprisingly, OPC densities were robustly reconstituted by the active expansion of Nestin(+) immature cells activated in meninges and brain parenchyma, as well as a few OPCs that escaped from Pdgfra inactivation. The multipotent immature cells were induced in the meninges of Pdgfra-inactivated mice, but not of control mice. Our findings revealed powerful homeostatic control of adult OPCs, engaging dual cellular sources of adult OPC formation. These properties of the adult oligodendrocyte lineage and the alternative OPC source may be exploited in regenerative medicine.

  • 7.
    Darmanis, Spyros
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gallant, Caroline Julie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Marinescu, Voichita Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Flamourakis, Georgios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Fredriksson, Simon
    Olink Biosci, S-75237 Uppsala, Sweden..
    Assarsson, Erika
    Olink Biosci, S-75237 Uppsala, Sweden..
    Lundberg, Martin
    Olink Biosci, S-75237 Uppsala, Sweden..
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 2, p. 380-389Article in journal (Refereed)
    Abstract [en]

    Significant advances have been made in methods to analyze genomes and transcriptomes of single cells, but to fully define cell states, proteins must also be accessed as central actors defining a cell's phenotype. Methods currently used to analyze endogenous protein expression in single cells are limited in specificity, throughput, or multiplex capability. Here, we present an approach to simultaneously and specifically interrogate large sets of protein and RNA targets in lysates from individual cells, enabling investigations of cell functions and responses. We applied our method to investigate the effects of BMP4, an experimental therapeutic agent, on early-passage glioblastoma cell cultures. We uncovered significant heterogeneity in responses to treatment at levels of RNA and protein, with a subset of cells reacting in a distinct manner to BMP4. Moreover, we found overall poor correlation between protein and RNA at the level of single cells, with proteins more accurately defining responses to treatment.

  • 8.
    De La Fuente, Alerie Guzman
    et al.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Lange, Simona
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria..
    Silva, Maria Elena
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile.;Univ Austral Chile, Inst Pharm, Fac Sci, Valdivia, Chile..
    Gonzalez, Ginez A.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Tempfer, Herbert
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Tendon & Bone Regenerat, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    van Wijngaarden, Peter
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Univ Melbourne, Dept Surg, Royal Victorian Eye & Ear Hosp, Ctr Eye Res Australia,Ophthalmol, Melbourne, Vic, Australia..
    Zhao, Chao
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Di Canio, Ludovica
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Trost, Andrea
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Ophthalmol Optometry & Res Program Expt Ophthalmo, A-5020 Salzburg, Austria..
    Bieler, Lara
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Zaunmair, Pia
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Rotheneichner, Peter
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    O'Sullivan, Anna
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Couillard-Despres, Sebastien
    Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Inst Expt Neuroregenerat, A-5020 Salzburg, Austria..
    Errea, Oihana
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Mäe, Maarja A.
    Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    He, Liqun
    Tianjin Med Univ, Key Lab Post Neuroinjury Neuro Repair & Regenerat, Tianjin Neurol Inst, Dept Neurosurg,Gen Hosp,Minist Educ & Tianjin Cit, Tianjin 300052, Peoples R China..
    Keller, Annika
    Zurich Univ, Zurich Univ Hosp, Div Neurosurg, CH-8091 Zurich, Switzerland..
    Batiz, Luis F.
    Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Los Andes, Fac Med, CIB, Santiago, Chile..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Aigner, Ludwig
    Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Austrian Cluster Tissue Regenerat, Vienna, Austria..
    Franklin, Robin J. M.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England..
    Rivera, Francisco J.
    Univ Cambridge, Wellcome Trust & MRC Cambridge Stem Cell Inst, Cambridge CB2 0AH, England.;Paracelsus Med Univ Salzburg, Inst Mol Regenerat Med, A-5020 Salzburg, Austria.;Paracelsus Med Univ Salzburg, Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, A-5020 Salzburg, Austria.;Univ Austral Chile, Fac Med, Inst Anat Histol & Pathol, Lab Stem Cells & Neuroregenerat, Valdivia, Chile.;Univ Austral Chile, Ctr Interdisciplinary Studies Nervous Syst CISNe, Valdivia, Chile..
    Pericytes Stimulate Oligodendrocyte Progenitor Cell Differentiation during CNS Remyelination2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1755-1764Article in journal (Refereed)
    Abstract [en]

    The role of the neurovascular niche in CNS myelin regeneration is incompletely understood. Here, we show that, upon demyelination, CNS-resident pericytes (PCs) proliferate, and parenchymal non-vessel-associated PC-like cells (PLCs) rapidly develop. During remyelination, mature oligodendrocytes were found in close proximity to PCs. In Pdgfb(ret/ret) mice, which have reduced PC numbers, oligodendrocyte progenitor cell (OPC) differentiation was delayed, although remyelination proceeded to completion. PC-conditioned medium accelerated and enhanced OPC differentiation in vitro and increased the rate of remyelination in an ex vivo cerebellar slice model of demyelination. We identified Lama2 as a PC-derived factor that promotes OPC differentiation. Thus, the functional role of PCs is not restricted to vascular homeostasis but includes the modulation of adult CNS progenitor cells involved in regeneration.

  • 9.
    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, ISSN 2211-1247, 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.

  • 10. Fasching, L.
    et al.
    Kapopoulou, A.
    Sachdeva, R.
    Petri, R.
    Jönsson, M. E.
    Männe, C.
    Turelli, P.
    Jern, Patric
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cammas, F.
    Trono, D.
    Jakobsson, J.
    TRIM28 Represses Transcription of Endogenous Retroviruses in Neural Progenitor Cells2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, no 1, p. 20-28Article in journal (Refereed)
    Abstract [en]

    TRIM28 is a corepressor that mediates transcriptional silencing by establishing local heterochromatin. Here, we show that deletion of TRIM28 in neural progenitor cells (NPCs) results in high-level expression of two groups of endogenous retroviruses (ERVs): IAP1 and MMERVK10C. We find that NPCs use TRIM28-mediated histone modifications to dynamically regulate transcription and silencing of ERVs, which is in contrast to other somatic cell types using DNA methylation. We also show that derepression of ERVs influences transcriptional dynamics in NPCs through the activation of nearby genes and the expression of long noncoding RNAs. These findings demonstrate a unique dynamic transcriptional regulation of ERVs in NPCs. Our results warrant future studies on the role of ERVs in the healthy and diseased brain.

  • 11. 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, ISSN 2211-1247, 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.

  • 12.
    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, ISSN 2211-1247, 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.

  • 13.
    Fourati, Zaineb
    et al.
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Howard, Rebecca J.
    Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Heusser, Stephanie A.
    Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.;Stockholm Univ, Sci Life Lab, S-17165 Solna, Sweden..
    Hu, Haidai
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France.;UPMC Univ Paris 6, Sorbonne Univ, F-75005 Paris, France..
    Ruza, Reinis R.
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Sauguet, Ludovic
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Lindahl, Erik
    KTH, Centres, SeRC - Swedish e-Science Research Centre. KTH, Centres, Science for Life Laboratory, SciLifeLab. Stockholm Univ, Dept Biochem & Biophys, S-17165 Solna, Sweden.
    Delarue, Marc
    Inst Pasteur, Unit Struct Dynam Macromol, F-75015 Paris, France.;CNRS, UMR 3528, F-75015 Paris, France..
    Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels2018In: Cell reports, ISSN 2211-1247, 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. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it 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 they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

  • 14. 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, ISSN 2211-1247, 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.

  • 15.
    Furter, Markus
    et al.
    Swiss Fed Inst Technol, Inst Microbiol, CH-8093 Zurich, Switzerland.
    Sellin, Mikael E.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swiss Fed Inst Technol, Inst Microbiol, CH-8093 Zurich, Switzerland.
    Hansson, Gunnar C.
    Univ Gothenburg, Dept Med Biochem, S-40530 Gothenburg, Sweden.
    Hardt, Wolf-Dietrich
    Swiss Fed Inst Technol, Inst Microbiol, CH-8093 Zurich, Switzerland.
    Mucus Architecture and Near-Surface Swimming Affect Distinct Salmonella Typhimurium Infection Patterns along the Murine Intestinal Tract2019In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 27, no 9, p. 2665-26788.e1–e3Article in journal (Refereed)
    Abstract [en]

    Mucus separates gut-luminal microbes from the tissue. It is unclear how pathogens like Salmonella Typhimurium (S.Tm) can overcome this obstacle. Using live microscopy, we monitored S.Tm interactions with native murine gut explants and studied how mucus affects the infection. A dense inner mucus layer covers the distal colon tissue, limiting direct tissue access. S.Tm performs near-surface swimming on this mucus layer, which allows probing for colon mucus heterogeneities, but can also entrap the bacterium in the dense inner colon mucus layer. In the cecum, dense mucus fills only the bottom of the intestinal crypts, leaving the epithelium between crypts unshielded and prone to access by motile and non-motile bacteria alike. This explains why the cecum is highly infection permissive and represents the primary site of S.Tm enterocolitis in the streptomycin mouse model. Our findings highlight the importance of mucus in intestinal defense and homeostasis.

  • 16. 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, ISSN 2211-1247, 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.

  • 17. Georgoudaki, Anna-Maria
    et al.
    Prokopec, Kajsa E.
    Boura, Vanessa F.
    Hellqvist, Eva
    Sohn, Silke
    Ostling, Jeanette
    Dahan, Rony
    Harris, Robert A.
    Rantalainen, Mattias
    Klevebring, Daniel
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Brage, Suzanne Egyhazi
    Fuxe, Jonas
    Rolny, Charlotte
    Li, Fubin
    Ravetch, Jeffrey V.
    Karlsson, Mikael C. I.
    Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 15, no 9, p. 2000-2011Article in journal (Refereed)
    Abstract [en]

    Tumors are composed of multiple cell types besides the tumor cells themselves, including innate immune cells such as macrophages. Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells present in the tumor microenvironment (TME). Here, they contribute to immunosuppression, enabling the establishment and persistence of solid tumors as well as metastatic dissemination. We have found that the pattern recognition scavenger receptor MARCO defines a subtype of suppressive TAMs and is linked to clinical outcome. An anti-MARCO monoclonal antibody was developed, which induces anti-tumor activity in breast and colon carcinoma, as well as in melanoma models through reprogramming-TAM-populations to a pro-inflammatory phenotype and increasing tumor immunogenicity. This anti-tumor activity is dependent on the inhibitory Fc-receptor, Fc gamma RIIB, and also enhances the efficacy of checkpoint therapy. These results demonstrate that immunotherapies using antibodies designed to modify myeloid cells of the TME represent a promising mode of cancer treatment.

  • 18. Gerold, Gisa
    et al.
    Meissner, Felix
    Bruening, Janina
    Welsch, Kathrin
    Perin, Paula M
    Baumert, Thomas F
    Vondran, Florian W
    Kaderali, Lars
    Marcotrigiano, Joseph
    Khan, Abdul G
    Mann, Matthias
    Rice, Charles M
    Pietschmann, Thomas
    Quantitative Proteomics Identifies Serum Response Factor Binding Protein 1 as a Host Factor for Hepatitis C Virus Entry2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 12, no 5, p. 864-878, article id S2211-1247(15)00689-0Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) enters human hepatocytes through a multistep mechanism involving, among other host proteins, the virus receptor CD81. How CD81 governs HCV entry is poorly characterized, and CD81 protein interactions after virus binding remain elusive. We have developed a quantitative proteomics protocol to identify HCV-triggered CD81 interactions and found 26 dynamic binding partners. At least six of these proteins promote HCV infection, as indicated by RNAi. We further characterized serum response factor binding protein 1 (SRFBP1), which is recruited to CD81 during HCV uptake and supports HCV infection in hepatoma cells and primary human hepatocytes. SRFBP1 facilitates host cell penetration by all seven HCV genotypes, but not of vesicular stomatitis virus and human coronavirus. Thus, SRFBP1 is an HCV-specific, pan-genotypic host entry factor. These results demonstrate the use of quantitative proteomics to elucidate pathogen entry and underscore the importance of host protein-protein interactions during HCV invasion.

  • 19. Goldberg, Emily L.
    et al.
    Asher, Jennifer L.
    Molony, Ryan D.
    Shaw, Albert C.
    Zeiss, Caroline J.
    Wang, Chao
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Herzog, Raimund I.
    Iwasaki, Akiko
    Dixit, Vishwa Deep
    beta-Hydroxybutyrate deactivates Neutrophil NLRP3 inflammasome to relieve gout flares2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 9, p. 2077-2087Article in journal (Refereed)
    Abstract [en]

    Aging and lipotoxicity are two major risk factors for gout that are linked by the activation of the NLRP3 inflammasome. Neutrophil-mediated production of interleukin-1 beta (IL-1 beta) drives gouty flares that cause joint destruction, intense pain, and fever. However, metabolites that impact neutrophil inflammasome remain unknown. Here, we identified that ketogenic diet (KD) increases beta-hydroxybutyrate (BHB) and alleviates urate crystal-induced gout without impairing immune defense against bacterial infection. BHB inhibited NLRP3 inflammasome in S100A9 fibril-primed and urate crystal-activated macrophages, which serve to recruit inflammatory neutrophils in joints. Consistent with reduced gouty flares in rats fed a ketogenic diet, BHB blocked IL-1 beta in neutrophils in a NLRP3-dependent manner in mice and humans irrespective of age. Mechanistically, BHB inhibited the NLRP3 inflammasome in neutrophils by reducing priming and assembly steps. Collectively, our studies show that BHB, a known alternate metabolic fuel, is also an anti-inflammatory molecule that may serve as a treatment for gout.

  • 20. 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, ISSN 2211-1247, 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.

  • 21. Harms, Matthew J.
    et al.
    Li, Qian
    Lee, Sunjae
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zhang, Cheng
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kull, Bengt
    Hallen, Stefan
    Thorell, Anders
    Alexandersson, Ida
    Hagberg, Carolina E.
    Peng, Xiao-Rong
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Spalding, Kirsty L.
    Boucher, Jeremie
    Mature Human White Adipocytes Cultured under Membranes Maintain Identity, Function, and Can Transdifferentiate into Brown-like Adipocytes2019In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247Article in journal (Refereed)
  • 22.
    Hellberg, Sandra
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Eklund, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Köpsén, Mattias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Kockum, Ingrid
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Olsson, Tomas
    Karolinska Institute, Department Clin Neurosci, Neuroimmunol Unit, S-17177 Linkoping, Sweden.
    Skogh, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Kastbom, Alf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Sjöwall, Christopher
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Neurology.
    Håkansson, Irene
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    Jenmalm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Dynamic Response Genes in CD4+T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 11, p. 2928-2939Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.

  • 23.
    Hellberg, Sandra
    et al.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Eklund, Daniel
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Gawel, Danuta R.
    The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Köpsén, Mattias
    The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
    Zhang, Huan
    The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Nestor, Colm E.
    The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Kockum, Ingrid
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Linköping, Sweden.
    Olsson, Tomas
    Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Linköping, Sweden.
    Skogh, Thomas
    Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Kastbom, Alf
    Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Sjöwall, Christopher
    Department of Rheumatology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Vrethem, Magnus
    Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Håkansson, Irene
    Department of Neurology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Benson, Mikael
    The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Jenmalm, Maria C.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Gustafsson, Mika
    Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
    Ernerudh, Jan
    Department of Clinical Immunology and Transfusion Medicine and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 11, p. 2928-2939Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.

  • 24. Hilgen, Gerrit
    et al.
    Sorbaro, Martino
    KTH, School of Engineering Sciences (SCI), Physics, Theoretical & Computational Biophysics.
    Pirmoradian, Sahar
    Muthmann, Jens-Oliver
    Kepiro, Ibolya Edit
    Ullo, Simona
    Ramirez, Cesar Juarez
    Encinas, Albert Puente
    Maccione, Alessandro
    Berdondini, Luca
    Murino, Vittorio
    Sona, Diego
    Zanacchi, Francesca Cella
    Sernagor, Evelyne
    Hennig, Matthias Helge
    Unsupervised Spike Sorting for Large-Scale, High-Density Multielectrode Arrays2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 10, p. 2521-2532Article in journal (Refereed)
    Abstract [en]

    We present amethod for automated spike sorting for recordings with high-density, large-scale multielectrode arrays. Exploiting the dense sampling of single neurons by multiple electrodes, an efficient, low-dimensional representation of detected spikes consisting of estimated spatial spike locations and dominant spike shape features is exploited for fast and reliable clustering into single units. Millions of events can be sorted in minutes, and the method is parallelized and scales better than quadratically with the number of detected spikes. Performance is demonstrated using recordings with a 4,096-channel array and validated using anatomical imaging, optogenetic stimulation, and model-based quality control. A comparison with semi-automated, shape-based spike sorting exposes significant limitations of conventional methods. Our approach demonstrates that it is feasible to reliably isolate the activity of up to thousands of neurons and that dense, multi-channel probes substantially aid reliable spike sorting.

  • 25. Hillier, Charles
    et al.
    Pardo, Mercedes
    Yu, Lu
    Bushell, Ellen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sanderson, Theo
    Metcalf, Tom
    Herd, Colin
    Anar, Burcu
    Rayner, Julian C.
    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).
    Choudhary, Jyoti S.
    Landscape of the Plasmodium Interactome Reveals Both Conserved and Species-Specific Functionality2019In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 28, no 6, p. 1635-1647Article in journal (Refereed)
    Abstract [en]

    Malaria represents a major global health issue, and the identification of new intervention targets remains an urgent priority. This search is hampered by more than one-third of the genes of malaria-causing Plasmodium parasites being uncharacterized. We report a large-scale protein interaction network in Plasmodium schizonts, generated by combining blue native-polyacrylamide electrophoresis with quantitative mass spectrometry and machine learning. This integrative approach, spanning 3 species, identifies > 20,000 putative protein interactions, organized into 600 protein clusters. We validate selected interactions, assigning functions in chromatin regulation to previously unannotated proteins and suggesting a role for an EELM2 domain-containing protein and a putative microrchidia protein as mechanistic links between AP2-domain transcription factors and epigenetic regulation. Our interactome represents a high-confidence map of the native organization of core cellular processes in Plasmodium parasites. The network reveals putative functions for uncharacterized proteins, provides mechanistic and structural insight, and uncovers potential alternative therapeutic targets.

  • 26. 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, ISSN 2211-1247, 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.

  • 27.
    Holst, Mikkel Roland
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Vidal-Quadras, Maite
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundborg, Magnus
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion2017In: Cell reports, ISSN 2211-1247, 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.

  • 28. Hosp, Fabian
    et al.
    Vossfeldt, Hannes
    Heinig, Matthias
    Vasiljevic, Djordje
    Arumughan, Anup
    Wyler, Emanuel
    Landthaler, Markus
    Hubner, Norbert
    Wanker, Erich E.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lalowski, Maciej
    Voigt, Aaron
    Selbach, Matthias
    Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 11, no 7, p. 1134-1146Article in journal (Refereed)
    Abstract [en]

    Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's disease (AD), Huntingtin (HTT) for Huntington's disease, Parkin (PARK2) for Parkinson's disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

  • 29.
    Jahn, Michael
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab. K.
    Vialas, Vital
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Karlsen, Jan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Maddalo, Gianluca
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Edfors, Fredrik
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Forsström, Björn
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Uhlén, Mathias
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Käll, Lukas
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hudson, Elton P.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Growth of Cyanobacteria Is Constrained by the Abundance of Light and Carbon Assimilation Proteins2018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 25, no 2, p. 478-+Article in journal (Refereed)
    Abstract [en]

    Cyanobacteria must balance separate demands for energy generation, carbon assimilation, and biomass synthesis. We used shotgun proteomics to investigate proteome allocation strategies in the model cyanobacterium Synechocystis sp. PCC 6803 as it adapted to light and inorganic carbon (C-i) limitation. When partitioning the proteome into seven functional sectors, we find that sector sizes change linearly with growth rate. The sector encompassing ribosomes is significantly smaller than in E. coli, which may explain the lower maximum growth rate in Synechocystis. Limitation of light dramatically affects multiple proteome sectors, whereas the effect of C-i limitation is weak. Carbon assimilation proteins respond more strongly to changes in light intensity than to C-i. A coarse-grained cell economy model generally explains proteome trends. However, deviations from model predictions suggest that the large proteome sectors for carbon and light assimilation are not optimally utilized under some growth conditions and may constrain the proteome space available to ribosomes.

  • 30.
    Jiang, Yiwen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Marinescu, Voichita Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Maturi, Naga Prathyusha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Olofsson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindberg, Nanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olofsson, Tommie
    Natl Board Forens Med, Dept Forens Med, Box 1024, S-75140 Uppsala, Sweden..
    Leijonmarck, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 4, p. 977-990Article in journal (Refereed)
    Abstract [en]

    The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

  • 31.
    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, ISSN 2211-1247, 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.

  • 32. 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, ISSN 2211-1247, 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.

  • 33. Krypotou, Emilia
    et al.
    Scortti, Mariela
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Oelker, Melanie
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Luisi, Ben F.
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Vazquez-Boland, Jose
    Control of Bacterial Virulence through the Peptide Signature of the Habitat2019In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 26, no 7, p. 1815-1827Article in journal (Refereed)
    Abstract [en]

    To optimize fitness, pathogens selectively activate their virulence program upon host entry. Here, we report that the facultative intracellular bacterium Listeria monocytogenes exploits exogenous oligopeptides, a ubiquitous organic N source, to sense the environment and control the activity of its virulence transcriptional activator, PrfA. Using a genetic screen in adsorbent- treated ( PrfA-inducing) medium, we found that PrfA is functionally regulated by the balance between activating and inhibitory nutritional peptides scavenged via the Opp transport system. Activating peptides provide essential cysteine precursor for the PrfA-inducing cofactor glutathione ( GSH). Non-cysteine-containing peptides cause promiscuous PrfA inhibition. Biophysical and co-crystallization studies reveal that peptides inhibit PrfA through steric blockade of the GSH binding site, a regulation mechanism directly linking bacterial virulence and metabolism. L. monocytogenes mutant analysis in macrophages and our functional data support a model in which changes in the balance of antagonistic Oppimported oligopeptides promote PrfA induction intra-cellularly and PrfA repression outside the host.

  • 34.
    Kurylo, Chad M.
    et al.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Parks, Matthew M.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Juette, Manuel F.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Zinshteyn, Boris
    Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA;Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA.
    Altman, Roger B.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Thibado, Jordana K.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA.
    Vincent, C. Theresa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA;Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Blanchard, Scott C.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA;Weill Cornell Med, Triinst Training Program Chem Biol, New York, NY 10065 USA.
    Endogenous rRNA Sequence Variation Can Regulate Stress Response Gene Expression and Phenotype2018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 25, no 1, p. 236-248.e6Article in journal (Refereed)
    Abstract [en]

    Prevailing dogma holds that ribosomes are uniform in composition and function. Here, we show that nutrient limitation-induced stress in E. coli changes the relative expression of rDNA operons to alter the rRNA composition within the actively translating ribosome pool. The most upregulated operon encodes the unique 16S rRNA, rrsH, distinguished by conserved sequence variation within the small ribosomal subunit. rrsH-bearing ribosomes affect the expression of functionally coherent gene sets and alter the levels of the RpoS sigma factor, the master regulator of the general stress response. These impacts are associated with phenotypic changes in antibiotic sensitivity, biofilm formation, and cell motility and are regulated by stress response proteins, ReIA and ReIE, as well as the metabolic enzyme and virulence-associated protein, AdhE. These findings establish that endogenously encoded, naturally occurring rRNA sequence variation can modulate ribosome function, central aspects of gene expression regulation, and cellular physiology.

  • 35.
    Kuzhandaivel, Anujaianthi
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Schultz, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Alkhori, Liza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Alenius, Mattias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cilia-Mediated Hedgehog Signaling in Drosophila2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 7, no 3, p. 672-680Article in journal (Refereed)
    Abstract [en]

    Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates.

  • 36.
    Kuzhandaivel, Anujaianthi
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Schultz, Sebastian W.
    Linköpings universitet, Avdelningen för cellbiologi.
    Alkhori, Liza
    Linköpings universitet, Avdelningen för cellbiologi.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    Cilia-Mediated Hedgehog Signaling in Drosophila2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 7, no 3, p. 672-680Article in journal (Refereed)
    Abstract [en]

    Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia-mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates.

  • 37. Leitner, Johannes
    et al.
    Retzer, Katarzyna
    Malenica, Nenad
    Bartkeviciute, Rasa
    Lucyshyn, Doris
    Jäger, Gunilla
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Korbei, Barbara
    Byström, Anders
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Luschnig, Christian
    Meta-regulation of Arabidopsis Auxin Responses Depends on tRNA Maturation2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 11, no 4, p. 516-526Article in journal (Refereed)
    Abstract [en]

    Polar transport of the phytohormone auxin throughout plants shapes morphogenesis and is subject to stringent and specific control. Here, we identify basic cellular activities connected to translational control of gene expression as sufficient to specify auxin-mediated development. Mutants in subunits of Arabidopsis Elongator, a protein complex modulating translational efficiency via maturation of tRNAs, exhibit defects in auxin-controlled developmental processes, associated with reduced abundance of PIN-formed (PIN) auxin transport proteins. Similar anomalies are observed upon interference with tRNA splicing by downregulation of RNA ligase (AtRNL), pointing to a general role of tRNA maturation in auxin signaling. Elongator Protein 6 (ELP6) and AtRNL expression patterns underline an involvement in adjusting PIN protein levels, whereas rescue of mutant defects by auxin indicates rate-limiting activities in auxin-controlled organogenesis. This emphasizes mechanisms in which auxin serves as a bottleneck for plant morphogenesis, translating common cellular activities into defined developmental readouts.

  • 38.
    Lesurf, Robert
    et al.
    McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, McGill Ctr Bioinformat, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada..
    Aure, Miriam Ragle
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0318 Oslo, Norway..
    Mörk, Hanne Haberg
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway..
    Vitelli, Valeria
    Univ Oslo, Oslo Ctr Biostat & Epidemiol, N-0317 Oslo, Norway.;Univ Oslo, Dept Biostat, N-0317 Oslo, Norway. St Olavs Univ Hosp, Dept Oncol, N-7006 Trondheim, Norway..
    Lundgren, Steinar
    Department of Oncology, St. Olav’s University Hospital, 7006 Trondheim, Norway.; Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.
    Börresen-Dale, Anne-Lise
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0318 Oslo, Norway..
    Kristensen, Vessela
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0318 Oslo, Norway.;Akershus Univ Hosp, Dept Clin Mol Biol & Lab Sci EpiGen, Div Med, N-1478 Lorenskog, Norway..
    Wämberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hallett, Michael
    McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, McGill Ctr Bioinformat, Montreal, PQ H3G 1Y6, Canada.;McGill Univ, Sch Comp Sci, Montreal, PQ H3A 0E9, Canada..
    Sörlie, Therese
    Norwegian Radium Hosp, Oslo Univ Hosp, Inst Canc Res, N-0424 Oslo, Norway.;Norwegian Radium Hosp, Oslo Univ Hosp, Dept Canc Genet, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0318 Oslo, Norway..
    Molecular Features of Subtype-Specific Progression from Ductal Carcinoma In Situ to Invasive Breast Cancer2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 4, p. 1166-1179Article in journal (Refereed)
    Abstract [en]

    Breast cancer consists of at least five main molecular "intrinsic'' subtypes that are reflected in both pre-invasive and invasive disease. Although previous studies have suggested that many of the molecular features of invasive breast cancer are established early, it is unclear what mechanisms drive progression and whether the mechanisms of progression are dependent or independent of subtype. We have generated mRNA, miRNA, and DNA copy-number profiles from a total of 59 in situ lesions and 85 invasive tumors in order to comprehensively identify those genes, signaling pathways, processes, and cell types that are involved in breast cancer progression. Our work provides evidence that there are molecular features associated with disease progression that are unique to the intrinsic subtypes. We additionally establish subtype-specific signatures that are able to identify a small proportion of pre-invasive tumors with expression profiles that resemble invasive carcinoma, indicating a higher likelihood of future disease progression.

  • 39. Liew, Li Phing
    et al.
    Lim, Zun Yi
    Cohen, Matan
    Kong, Ziqing
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bell, Stephen D
    Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, no 6, p. 1657-1670Article in journal (Refereed)
    Abstract [en]

    In many organisms, hydroxyurea (HU) inhibits class I ribonucleotide reductase, leading to lowered cellular pools of deoxyribonucleoside triphosphates. The reduced levels for DNA precursors is believed to cause replication fork stalling. Upon treatment of the hyperthermophilic archaeon Sulfolobus solfataricus with HU, we observe dose-dependent cell cycle arrest, accumulation of DNA double-strand breaks, stalled replication forks, and elevated levels of recombination structures. However, Sulfolobus has a HU-insensitive class II ribonucleotide reductase, and we reveal that HU treatment does not significantly impact cellular DNA precursor pools. Profiling of protein and transcript levels reveals modulation of a specific subset of replication initiation and cell division genes. Notably, the selective loss of the regulatory subunit of the primase correlates with cessation of replication initiation and stalling of replication forks. Furthermore, we find evidence for a detoxification response induced by HU treatment.

  • 40.
    Liin, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Yazdi, Samira
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramentol, Rosamary
    Univ Miami, FL 33136 USA.
    Barro-Soria, Rene
    Univ Miami, FL 33136 USA.
    Larsson, H. Peter
    Univ Miami, FL 33136 USA.
    Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.12018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 24, no 11, p. 2908-2918Article in journal (Refereed)
    Abstract [en]

    Polyunsaturated fatty acid (PUFA) analogs represent a new class of potential anti-arrhythmic K(V)7.1 and K(V)7.1+KCNE1 channel activators. In this study, we describe dual independent activating effects of negatively charged PUFA analogs on K(V)7.1 and K(V)7.1+KCNE1 that are dependent on discrete channel motifs. PUFA analogs are critically dependent on K326 in S6 of K(V)7.1 to increase the maximum conductance and critically dependent on specific S4 arginines in K(V)7.1 to shift the voltage dependence of channel opening toward negative voltages. Our findings provide insights into how K(V)7.1+KCNE1 activators may interact electrostatically both with the pore domain and the voltage-sensing domain to augment channel activity. We believe that the molecular understanding of how PUFA analogs induce dual independent activating effects is an important step toward the development of effective anti-arrhythmic drugs that target K(V)7.1 channels.

  • 41.
    Lim, Sharon
    et al.
    Karolinska Institute, Sweden.
    Zhang, Yin
    Karolinska Institute, Sweden.
    Zhang, Danfang
    Karolinska Institute, Sweden; Tianjin Medical University, Peoples R China.
    Chen, Fang
    Karolinska Institute, Sweden; Zhejiang Chinese Medical University, Peoples R China.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Feng, Ninghan
    Karolinska Institute, Sweden; Second Hospital Wuxi, Peoples R China.
    Seki, Takahiro
    Karolinska Institute, Sweden.
    Andersson, Patrik
    Karolinska Institute, Sweden.
    Li, Jingrong
    Simcere Pharmaceut RandD, Peoples R China.
    Zang, Jingwu
    Simcere Pharmaceut RandD, Peoples R China.
    Sun, Baocun
    Tianjin Medical University, Peoples R China.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden; University of Leicester, England.
    VEGFR2-Mediated Vascular Dilation as a Mechanism of VEGF-Induced Anemia and Bone Marrow Cell Mobilization2014In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 9, no 2, p. 569-580Article in journal (Refereed)
    Abstract [en]

    Molecular mechanisms underlying tumor VEGF-induced host anemia and bone marrow cell (BMC) mobilization remain unknown. Here, we report that tumor VEGF markedly induced sinusoidal vasculature dilation in bone marrow (BM) and BMC mobilization to tumors and peripheral tissues in mouse and human tumor models. Unexpectedly, anti-VEGFR2, but not anti-VEGFR1, treatment completely blocked VEGF-induced anemia and BMC mobilization. Genetic deletion of Vegfr2 in endothelial cells markedly ablated VEGF-stimulated BMC mobilization. Conversely, deletion of the tyrosine kinase domain from Vegfr1 gene (Vegfr1(TK-/-)) did not affect VEGF-induced BMC mobilization. Analysis of VEGFR1(+)/VEGFR2(+) populations in peripheral blood and BM showed no significant ratio difference between VEGF-and control tumor-bearing animals. These findings demonstrate that vascular dilation through the VEGFR2 signaling is the mechanism underlying VEGF-induced BM mobilization and anemia. Thus, our data provide mechanistic insights on VEGF-induced BMC mobilization in tumors and have therapeutic implications by targeting VEGFR2 for cancer therapy.

  • 42.
    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, ISSN 2211-1247, 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.

  • 43. 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, ISSN 2211-1247, 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.

  • 44. 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, ISSN 2211-1247, 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.

  • 45.
    Munk, Anne Sofie
    et al.
    Univ Rochester, Ctr Translat Neuromed, Rochester, NY 14642 USA;Univ Copenhagen, Ctr Basic & Translat Neurosci, DK-2200 Copenhagen, Denmark.
    Wang, Wei
    Univ Rochester, Ctr Translat Neuromed, Rochester, NY 14642 USA.
    Bechet, Nicholas Burdon
    Lund Univ, Dept Expt Med Sci, S-22184 Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, S-22184 Lund, Sweden.
    Eltanahy, Ahmed M.
    Lund Univ, Dept Expt Med Sci, S-22184 Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, S-22184 Lund, Sweden;Mansoura Univ, Mansoura Univ Hosp, Fac Med, Mansoura 35516, Egypt.
    Cheng, Anne Xiaoan
    Univ Rochester, Ctr Translat Neuromed, Rochester, NY 14642 USA.
    Sigurdsson, Bjorn
    Univ Copenhagen, Ctr Basic & Translat Neurosci, DK-2200 Copenhagen, Denmark.
    Benraiss, Abdellatif
    Univ Rochester, Ctr Translat Neuromed, Rochester, NY 14642 USA.
    Mäe, Maarja Andaloussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Kress, Benjamin Travis
    Univ Rochester, Ctr Translat Neuromed, Rochester, NY 14642 USA;Univ Copenhagen, Ctr Basic & Translat Neurosci, DK-2200 Copenhagen, Denmark.
    Kelley, Douglas H.
    Univ Rochester, Dept Mech Engn, Rochester, NY 14627 USA.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, ICMC, S-14157 Huddinge, Sweden.
    Mollgard, Kjeld
    Univ Copenhagen, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark.
    Meissner, Anja
    Lund Univ, Dept Expt Med Sci, S-22184 Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, S-22184 Lund, Sweden.
    Nedergaard, Maiken
    Univ Rochester, Ctr Translat Neuromed, Rochester, NY 14642 USA;Univ Copenhagen, Ctr Basic & Translat Neurosci, DK-2200 Copenhagen, Denmark.
    Lundgaard, Iben
    Univ Rochester, Ctr Translat Neuromed, Rochester, NY 14642 USA;Lund Univ, Dept Expt Med Sci, S-22184 Lund, Sweden;Lund Univ, Wallenberg Ctr Mol Med, S-22184 Lund, Sweden.
    PDGF-B Is Required for Development of the Glymphatic System2019In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 26, no 11, p. 2955-+Article in journal (Refereed)
    Abstract [en]

    The glymphatic system is a highly polarized cerebro-spinal fluid (CSF) transport system that facilitates the clearance of neurotoxic molecules through a brain-wide network of perivascular pathways. Herein we have mapped the development of the glymphatic system in mice. Perivascular CSF transport first emerges in hippocampus in newborn mice, and a mature glymphatic system is established in the cortex at 2 weeks of age. Formation of astrocytic endfeet and polarized expression of aquaporin 4 (AQP4) consistently co-incided with the appearance of perivascular CSF transport. Deficiency of platelet-derived growth factor B (PDGF-B) function in the PDGF retention motif knockout mouse line Pdgfb(ret/ret) suppressed the development of the glymphatic system, whose functions remained suppressed in adulthood compared with wild-type mice. These experiments map the natural development of the glymphatic system in mice and define a critical role of PDGF-B in the development of perivascular CSF transport.

  • 46. Mönnich, M.
    et al.
    Borgeskov, L.
    Breslin, L.
    Jakobsen, L.
    Rogowski, M.
    Doganli, C.
    Schrøder, J. M.
    Mogensen, J. B.
    Blinkenkjær, L.
    Harder, L. M.
    Lundberg, Emma
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Cellular and Clinical Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Geimer, S.
    Christensen, S. T.
    Andersen, J. S.
    Larsen, L. A.
    Pedersen, L. B.
    CEP128 Localizes to the Subdistal Appendages of the Mother Centriole and Regulates TGF-β/BMP Signaling at the Primary Cilium2018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 22, no 10, p. 2601-2614Article in journal (Refereed)
    Abstract [en]

    The centrosome is the main microtubule-organizing center in animal cells and comprises a mother and daughter centriole surrounded by pericentriolar material. During formation of primary cilia, the mother centriole transforms into a basal body that templates the ciliary axoneme. Ciliogenesis depends on mother centriole-specific distal appendages, whereas the role of subdistal appendages in ciliary function is unclear. Here, we identify CEP128 as a centriole subdistal appendage protein required for regulating ciliary signaling. Loss of CEP128 did not grossly affect centrosomal or ciliary structure but caused impaired transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) signaling in zebrafish and at the primary cilium in cultured mammalian cells. This phenotype is likely the result of defective vesicle trafficking at the cilium as ciliary localization of RAB11 was impaired upon loss of CEP128, and quantitative phosphoproteomics revealed that CEP128 loss affects TGF-β1-induced phosphorylation of multiple proteins that regulate cilium-associated vesicle trafficking. Mönnich et al. show that CEP128 localizes to the subdistal appendages of the mother centriole and basal body of the primary cilium. CEP128 regulates vesicular trafficking and targeting of RAB11 to the primary cilium. CEP128 loss leads to impaired TGF-β/BMP signaling, which, in zebrafish, is associated with defective organ development.

  • 47. Nehme, Ralda
    et al.
    Zuccaro, Emanuela
    Ghosh, Sulagna Dia
    Li, Chenchen
    Sherwood, John L.
    Pietilainen, Olli
    Barrett, Lindy E.
    Limone, Francesco
    Worringer, Kathleen A.
    Kommineni, Sravya
    Zang, Ying
    Cacchiarelli, Davide
    Meissner, Alex
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Haggarty, Stephen
    Madison, Jon
    Muller, Matthias
    Arlotta, Paola
    Fu, Zhanyan
    Feng, Guoping
    Eggan, Kevin
    Combining NGN2 Programming with Developmental Patterning Generates Human Excitatory Neurons with NMDAR-Mediated Synaptic Transmission2018In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 23, no 8, p. 2509-2523Article in journal (Refereed)
    Abstract [en]

    Transcription factor programming of pluripotent stem cells (PSCs) has emerged as an approach to generate human neurons for disease modeling. However, programming schemes produce a variety of cell types, and those neurons that are made often retain an immature phenotype, which limits their utility in modeling neuronal processes, including synaptic transmission. We report that combining NGN2 programming with SMAD and WNT inhibition generates human patterned induced neurons (hpiNs). Single-cell analyses showed that hpiN cultures contained cells along a developmental continuum, ranging from poorly differentiated neuronal progenitors to well-differentiated, excitatory glutamatergic neurons. The most differentiated neurons could be identified using a CAMK2A::GFP reporter gene and exhibited greater functionality, including NMDAR-mediated synaptic transmission. We conclude that utilizing single-cell and reporter gene approaches for selecting successfully programmed cells for study will greatly enhance the utility of hpiNs and other programmed neuronal populations in the modeling of nervous system disorders.

  • 48.
    Nestor, Colm
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Lentini, Antonio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Hägg Nilsson, Cathrine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Gawel, Danuta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Mattson, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Wang, Hui
    MD Anderson Cancer Centre, TX 77030 USA.
    Rundquist, Olof
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Meehan, Richard R.
    University of Edinburgh, Scotland.
    Klocke, Bernward
    Genomatix Software GmbH, Germany.
    Seifert, Martin
    Genomatix Software GmbH, Germany.
    Hauck, Stefanie M.
    German Research Centre Environm Health GmbH, Germany.
    Laumen, Helmut
    Technical University of Munich, Germany; Technical University of Munich, Germany; Helmholtz Zentrum Munchen, Germany; Technical University of Munich, Germany; Technical University of Munich, Germany.
    Zhang, Huan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Benson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Allergy Center.
    5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 2, p. 559-570Article in journal (Refereed)
    Abstract [en]

    5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by the TET family of enzymes as part of a recently discovered active DNA de-methylation pathway. 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity. Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function. We observe similar DNA de-methylation in CD4(+) memory T cells in vivo, indicating that early remodeling events persist long term in differentiated cells. Underscoring their important function, 5hmC loci were highly enriched for genetic variants associated with T cell diseases and T-cell-specific chromosomal interactions. Extensive functional validation of 22 risk variants revealed potentially pathogenic mechanisms in diabetes and multiple sclerosis. Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment.

  • 49.
    Nilsson, Ola B.
    et al.
    Stockholm Univ, Ctr Biomembrane Res, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    Hedman, Rickard
    Stockholm Univ, Ctr Biomembrane Res, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    Marino, Jacopo
    Univ Munich, CiPS M, Gene Ctr, D-81377 Munich, Germany.;Univ Munich, CiPS M, Ctr Integrated Prot Sci Munich, D-81377 Munich, Germany..
    Wickles, Stephan
    Univ Munich, CiPS M, Gene Ctr, D-81377 Munich, Germany.;Univ Munich, CiPS M, Ctr Integrated Prot Sci Munich, D-81377 Munich, Germany..
    Bischoff, Lukas
    Univ Munich, CiPS M, Gene Ctr, D-81377 Munich, Germany.;Univ Munich, CiPS M, Ctr Integrated Prot Sci Munich, D-81377 Munich, Germany..
    Johansson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Mueller-Lucks, Annika
    Stockholm Univ, Ctr Biomembrane Res, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    Trovato, Fabio
    Penn State Univ, Dept Chem, University Pk, PA 16802 USA..
    Puglisi, Joseph D.
    Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA.;Stanford Univ, Sch Med, Stanford Magnet Resonance Lab, Stanford, CA 94305 USA..
    O'Brien, Edward P.
    Penn State Univ, Dept Chem, University Pk, PA 16802 USA..
    Beckmann, Roland
    Univ Munich, CiPS M, Gene Ctr, D-81377 Munich, Germany.;Univ Munich, CiPS M, Ctr Integrated Prot Sci Munich, D-81377 Munich, Germany..
    von Heijne, Gunnar
    Stockholm Univ, Ctr Biomembrane Res, Dept Biochem & Biophys, S-10691 Stockholm, Sweden.;Stockholm Univ, Sci Life Lab, S-17121 Solna, Sweden..
    Cotranslational Protein Folding inside the Ribosome Exit Tunnel2015In: Cell reports, ISSN 2211-1247, 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.

  • 50.
    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, ISSN 2211-1247, 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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