Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein.


Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
14 02 2022
Historique:
received: 09 07 2021
accepted: 24 01 2022
entrez: 15 2 2022
pubmed: 16 2 2022
medline: 1 3 2022
Statut: epublish

Résumé

SARS-CoV-2 infection is a major global public health concern with incompletely understood pathogenesis. The SARS-CoV-2 spike (S) glycoprotein comprises a highly conserved free fatty acid binding pocket (FABP) with unknown function and evolutionary selection advantage

Identifiants

pubmed: 35165285
doi: 10.1038/s41467-022-28446-x
pii: 10.1038/s41467-022-28446-x
pmc: PMC8844029
doi:

Substances chimiques

Antibodies, Neutralizing 0
Antibodies, Viral 0
Fatty Acid-Binding Proteins 0
Fatty Acids 0
Spike Glycoprotein, Coronavirus 0
spike glycoprotein, SARS-CoV 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

868

Subventions

Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
ID : MaxSynBio Consortium
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB 1129
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : Gottfried-Wilhelm-Leibniz Program
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Max-Planck-Gesellschaft (Max Planck Society)
ID : Max Planck School Matter to Life
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/L01386X/1
Pays : United Kingdom

Informations de copyright

© 2022. The Author(s).

Références

Toelzer, C. et al. Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein. Science 370, 725–730 (2020).
pubmed: 32958580 pmcid: 8050947 doi: 10.1126/science.abd3255
Bangaru, S. et al. Structural analysis of full-length SARS-CoV-2 spike protein from an advanced vaccine candidate. Science 370, 1089–1094 (2020).
pubmed: 33082295 pmcid: 7857404 doi: 10.1126/science.abe1502
Shang, J. et al. Structural basis of receptor recognition by SARS-CoV-2. Nature 581, 221–224 (2020).
pubmed: 32225175 pmcid: 7328981 doi: 10.1038/s41586-020-2179-y
Benton, D. J. et al. Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion. Nature 588, 327–330 (2020).
pubmed: 32942285 pmcid: 7116727 doi: 10.1038/s41586-020-2772-0
Piccoli, L. et al. Mapping neutralizing and immunodominant sites on the SARS-CoV-2 spike receptor-binding domain by structure-guided high-resolution serology. Cell 183, 1024–1042.e1021 (2020).
pubmed: 32991844 pmcid: 7494283 doi: 10.1016/j.cell.2020.09.037
Grant, O. C., Montgomery, D., Ito, K. & Woods, R. J. Analysis of the SARS-CoV-2 spike protein glycan shield reveals implications for immune recognition. Sci. Rep. 10, 14991 (2020).
pubmed: 32929138 pmcid: 7490396 doi: 10.1038/s41598-020-71748-7
Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260–1263 (2020).
pubmed: 32075877 pmcid: 7164637 doi: 10.1126/science.abb2507
Walls, A. C. et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281–292.e286 (2020).
pubmed: 32155444 pmcid: 7102599 doi: 10.1016/j.cell.2020.02.058
Xu, C. et al. Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM. Sci. Adv. 7, eabe5575 (2021).
pubmed: 33277323 pmcid: 7775788 doi: 10.1126/sciadv.abe5575
Ke, Z. et al. Structures and distributions of SARS-CoV-2 spike proteins on intact virions. Nature 588, 498–502 (2020).
pubmed: 32805734 pmcid: 7116492 doi: 10.1038/s41586-020-2665-2
Casari, I., Manfredi, M., Metharom, P. & Falasca, M. Dissecting lipid metabolism alterations in SARS-CoV-2. Prog. Lipid Res. https://doi.org/10.1016/j.plipres.2021.101092 (2021).
Yan, B. et al. Characterization of the lipidomic profile of human coronavirus-infected cells: implications for lipid metabolism remodeling upon coronavirus replication. Viruses 11, 73 (2019).
pmcid: 6357182 doi: 10.3390/v11010073
Zheng, H. et al. Metabolomics reveals sex-specific metabolic shifts and predicts the duration from positive to negative in non-severe COVID-19 patients during recovery process. Comput. Struct. Biotechnol. J. https://doi.org/10.1016/j.csbj.2021.03.039 (2021).
Doaei, S. et al. The effect of omega-3 fatty acid supplementation on clinical and biochemical parameters of critically ill patients with COVID-19: a randomized clinical trial. J. Transl. Med. 19, 128 (2021).
pubmed: 33781275 pmcid: 8006115 doi: 10.1186/s12967-021-02795-5
Jonsson, S., Mendenhall, M. & Jonsson, C. Case Study Using Nebulized Isomerized Linoleic Acid (LA) for Outpatient Treatment of Symptomatic COVID-19. https://doi.org/10.2139/ssrn.3733231 (SSRN, 2020).
Hammock, B. D., Wang, W., Gilligan, M. M. & Panigrahy, D. Eicosanoids: The overlooked storm in coronavirus disease 2019 (COVID-19)? Am. J. Pathol. 190, 1782–1788 (2020).
pubmed: 32650004 pmcid: 7340586 doi: 10.1016/j.ajpath.2020.06.010
Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A. & Ng, L. F. P. The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 20, 363–374 (2020).
pubmed: 32346093 doi: 10.1038/s41577-020-0311-8
Kratzer, B., Hofer, S., Zabel, M. & Pickl, W. F. All the small things: how virus-like particles and liposomes modulate allergic immune responses. Eur. J. Immunol. 50, 17–32 (2020).
pubmed: 31799700 doi: 10.1002/eji.201847810
Mandala, V. S. et al. Structure and drug binding of the SARS-CoV-2 envelope protein transmembrane domain in lipid bilayers. Nat. Struct. Mol. Biol. 27, 1202–1208 (2020).
pubmed: 33177698 pmcid: 7718435 doi: 10.1038/s41594-020-00536-8
Bar-On, Y. M., Flamholz, A., Phillips, R. & Milo, R. SARS-CoV-2 (COVID-19) by the numbers. Elife https://doi.org/10.7554/eLife.57309 (2020).
Abhishek, S. et al. Electroceutical fabric lowers zeta potential and eradicates coronavirus infectivity upon contact. ChemRxiv https://doi.org/10.26434/chemrxiv.12307214.v1 (2020).
Zhang, Q. et al. ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. J. Exp. Clin. Cancer Res. 38, 173–173 (2019).
pubmed: 31023337 pmcid: 6482513 doi: 10.1186/s13046-019-1156-5
Schneider, M. et al. Severe acute respiratory syndrome coronavirus replication is severely impaired by MG132 due to proteasome-independent inhibition of M-calpain. J. Virol. 86, 10112–10122 (2012).
pubmed: 22787216 pmcid: 3446591 doi: 10.1128/JVI.01001-12
Cortese, M. et al. Integrative imaging reveals SARS-CoV-2-induced reshaping of subcellular morphologies. Cell Host Microbe 28, 853–866.e855 (2020).
pubmed: 33245857 pmcid: 7670925 doi: 10.1016/j.chom.2020.11.003
Ramanathan, M., Ferguson, I. D., Miao, W. & Khavari, P. A. SARS-CoV-2 B.1.1.7 and B.1.351 spike variants bind human ACE2 with increased affinity. bioRxiv https://doi.org/10.1101/2021.02.22.432359 (2021).
Richieri, G. V. & Kleinfeld, A. M. Unbound free fatty acid levels in human serum. J. Lipid Res. 36, 229–240 (1995).
pubmed: 7751810 doi: 10.1016/S0022-2275(20)39899-0
Archambault, A.-S. et al. Lipid storm within the lungs of severe COVID-19 patients: extensive levels of cyclooxygenase and lipoxygenase-derived inflammatory metabolites. medRxiv https://doi.org/10.1101/2020.12.04.20242115 (2020).
Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e278 (2020).
pubmed: 32142651 pmcid: 7102627 doi: 10.1016/j.cell.2020.02.052
Hoffmann, M. et al. Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity. EBioMedicine https://doi.org/10.1016/j.ebiom.2021.103255 (2021).
Jaimes, J. A., André, N. M., Chappie, J. S., Millet, J. K. & Whittaker, G. R. Phylogenetic analysis and structural modeling of SARS-CoV-2 spike protein reveals an evolutionary distinct and proteolytically sensitive activation loop. J. Mol. Biol. 432, 3309–3325 (2020).
pubmed: 32320687 pmcid: 7166309 doi: 10.1016/j.jmb.2020.04.009
Ozono, S. et al. SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity. Nat. Commun. 12, 848 (2021).
pubmed: 33558493 pmcid: 7870668 doi: 10.1038/s41467-021-21118-2
Johnson, B. A. et al. Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature 591, 293–299 (2021).
pubmed: 33494095 pmcid: 8175039 doi: 10.1038/s41586-021-03237-4
Makowski, L., Olson-Sidford, W. & W-Weisel, J. Biological and clinical consequences of integrin binding via a rogue RGD motif in the SARS CoV-2 spike protein. Viruses https://doi.org/10.3390/v13020146 (2021).
Maginnis, M. S. et al. Beta1 integrin mediates internalization of mammalian reovirus. J. Virol. 80, 2760–2770 (2006).
pubmed: 16501085 pmcid: 1395463 doi: 10.1128/JVI.80.6.2760-2770.2006
Shoemark, D. K. et al. Molecular simulations suggest vitamins, retinoids and steroids as ligands of the free Fatty acid pocket of the SARS-CoV-2 spike protein**. Angew. Chem. Int. Ed. 60, 7098–7110 (2021).
Dofferhoff, A. S. M. et al. Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa1258 (2020).
The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. N. Engl. J. Med. 384, 693–704 (2020).
Zhang, S. et al. Bat and pangolin coronavirus spike glycoprotein structures provide insights into SARS-CoV-2 evolution. Nat. Commun. 12, 1607 (2021).
pubmed: 33707453 pmcid: 7952905 doi: 10.1038/s41467-021-21767-3
Cevik, M. et al. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe 2, e13–e22 (2021).
pubmed: 33521734 doi: 10.1016/S2666-5247(20)30172-5
Hermesh, T., Moltedo, B., López, C. B. & Moran, T. M. Buying time-the immune system determinants of the incubation period to respiratory. Viruses. Viruses 2, 2541–2558 (2010).
pubmed: 21994630 doi: 10.3390/v2112541
Greaney, A. J. et al. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. Cell Host Microbe 29, 44–57.e49 (2021).
pubmed: 33259788 pmcid: 7676316 doi: 10.1016/j.chom.2020.11.007
Wrobel, A. G. et al. Antibody-mediated disruption of the SARS-CoV-2 spike glycoprotein. Nat. Commun. 11, 5337 (2020).
pubmed: 33087721 pmcid: 7577971 doi: 10.1038/s41467-020-19146-5
Atyeo, C. et al. Dissecting strategies to tune the therapeutic potential of SARS-CoV-2-specific monoclonal antibody CR3022. JCI Insight 6, e143129 https://doi.org/10.1172/jci.insight.143129 (2021).
Greaney, A. J. et al. Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies. Cell Host Microbe 29, 463–476.e466 (2021).
pubmed: 33592168 pmcid: 7869748 doi: 10.1016/j.chom.2021.02.003
Schaffitzel, C. et al. In vitro selection and evolution of protein-ligand interactions by ribosome display. in Protein-Protein Interactions: A Molecular Cloning Manual (ed. Golemis, E. Adams, P.). Ch. 27, (Cold Spring Harbor Laboratory Press, 2005).
Brash, A. R. Arachidonic acid as a bioactive molecule. J. Clin. Invest. 107, 1339–1345 (2001).
pubmed: 11390413 pmcid: 209328 doi: 10.1172/JCI13210
Adam, L. et al. Dynamics of SARS-CoV-2 host cell interactions inferred from transcriptome analyses. bioRxiv https://doi.org/10.1101/2021.07.04.450986 (2021).
Tan, H.-X. et al. Immunogenicity of prime-boost protein subunit vaccine strategies against SARS-CoV-2 in mice and macaques. Nat. Commun. 12, 1403 (2021).
pubmed: 33658497 pmcid: 7930087 doi: 10.1038/s41467-021-21665-8
Pombo, J. P. & Sanyal, S. Perturbation of intracellular cholesterol and fatty acid homeostasis during flavivirus infections. Front. Immunol. https://doi.org/10.3389/fimmu.2018.01276 (2018).
Staufer, O. et al. Microfluidic production and characterization of biofunctionalized giant unilamellar vesicles for targeted intracellular cargo delivery. Biomaterials 264, 120203 (2021).
pubmed: 32987317 doi: 10.1016/j.biomaterials.2020.120203
Staufer, O. et al. Bottom-up assembly of biomedical relevant fully synthetic extracellular vesicles. Sci. Adv. 7, eabg6666 (2021).
pubmed: 34516902 pmcid: 8442894 doi: 10.1126/sciadv.abg6666
Berger, I., Fitzgerald, D. J. & Richmond, T. J. Baculovirus expression system for heterologous multiprotein complexes. Nat. Biotechnol. 22, 1583–1587 (2004).
pubmed: 15568020 doi: 10.1038/nbt1036
Frampton, D. et al. Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(21)00170-5 .
Schaffitzel, C., Hanes, J., Jermutus, L. & Plückthun, A. Ribosome display: an in vitro method for selection and evolution of antibodies from libraries. J. Immunol. Methods 231, 119–135 (1999).
pubmed: 10648932 doi: 10.1016/S0022-1759(99)00149-0
Els Conrath, K., Lauwereys, M., Wyns, L. & Muyldermans, S. Camel single-domain antibodies as modular building units in bispecific and bivalent antibody constructs. J. Biol. Chem. 276, 7346–7350 (2001).
pubmed: 11053416 doi: 10.1074/jbc.M007734200
Staufer, O., Schroter, M., Platzman, I. & Spatz, J. P. Bottom-up assembly of functional intracellular synthetic organelles by droplet-based microfluidics. Small https://doi.org/10.1002/smll.201906424 (2020).
Staufer, O. et al. Adhesion stabilized en masse intracellular electrical recordings from multicellular assemblies. Nano Lett. 19, 3244–3255 (2019).
pubmed: 30950627 pmcid: 6727598 doi: 10.1021/acs.nanolett.9b00784
Staufer, O. et al. Functional fusion of living systems with synthetic electrode interfaces. Beilstein J. Nanotechnol. 7, 296–301 (2016).
pubmed: 26977386 pmcid: 4778514 doi: 10.3762/bjnano.7.27
Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. Elife https://doi.org/10.7554/eLife.42166 (2018).
Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).
pubmed: 28250466 pmcid: 5494038
Kremer, J. R., Mastronarde, D. N. & McIntosh, J. R. Computer visualization of three-dimensional image data using IMOD. J. Struct. Biol. 116, 71–76 (1996).
pubmed: 8742726 doi: 10.1006/jsbi.1996.0013
Keller, C. A. & Kasemo, B. Surface specific kinetics of lipid vesicle adsorption measured with a quartz crystal microbalance. Biophys. J. 75, 1397–1402 (1998).
pubmed: 9726940 pmcid: 1299813 doi: 10.1016/S0006-3495(98)74057-3
Briand, E., Zäch, M., Svedhem, S., Kasemo, B. & Petronis, S. Combined QCM-D and EIS study of supported lipid bilayer formation and interaction with pore-forming peptides. Analyst 135, 343–350 (2010).
pubmed: 20098769 doi: 10.1039/B918288H
Wintjens, R., Bifani, A. M. & Bifani, P. Impact of glycan cloud on the B-cell epitope prediction of SARS-CoV-2 Spike protein. npj Vaccines 5, 81 (2020).
pubmed: 32944295 pmcid: 7474083 doi: 10.1038/s41541-020-00237-9
Marsh, J. A. & Teichmann, S. A. Relative solvent accessible surface area predicts protein conformational changes upon binding. Structure 19, 859–867 (2011).
pubmed: 21645856 pmcid: 3145976 doi: 10.1016/j.str.2011.03.010
Sehnal, D. et al. Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res. 49, W431–W437 (2021).
pubmed: 33956157 pmcid: 8262734 doi: 10.1093/nar/gkab314
Else, P. L. The highly unnatural fatty acid profile of cells in culture. Prog. Lipid Res. 77, 101017 (2020).
pubmed: 31809755 doi: 10.1016/j.plipres.2019.101017
Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San. Diego, Calif.) 25, 402–408 (2001).
doi: 10.1006/meth.2001.1262

Auteurs

Oskar Staufer (O)

Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany. oskar.staufer@mr.mpg.de.
Institute for Molecular Systems Engineering, University of Heidelberg, Im Neuenheimer Feld 253, 69120, Heidelberg, Germany. oskar.staufer@mr.mpg.de.
Max Planck-Bristol Center for Minimal Biology, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK. oskar.staufer@mr.mpg.de.
Max Planck School Matter to Life, Jahnstraße 29, 69120, Heidelberg, Germany. oskar.staufer@mr.mpg.de.

Kapil Gupta (K)

School of Biochemistry, Biomedical Sciences, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK.
Bristol Synthetic Biology Centre BrisSynBio, University of Bristol, 4 Tyndall Ave, Bristol, BS8 1TQ, UK.

Jochen Estebano Hernandez Bücher (JE)

Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany.
Institute for Molecular Systems Engineering, University of Heidelberg, Im Neuenheimer Feld 253, 69120, Heidelberg, Germany.

Fabian Kohler (F)

Department of Physics, Technical University of Munich, 85748, Garching, Germany.

Christian Sigl (C)

Department of Physics, Technical University of Munich, 85748, Garching, Germany.

Gunjita Singh (G)

School of Biochemistry, Biomedical Sciences, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK.

Kate Vasileiou (K)

School of Biochemistry, Biomedical Sciences, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK.

Ana Yagüe Relimpio (A)

Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany.
Institute for Molecular Systems Engineering, University of Heidelberg, Im Neuenheimer Feld 253, 69120, Heidelberg, Germany.

Meline Macher (M)

Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany.
Institute for Molecular Systems Engineering, University of Heidelberg, Im Neuenheimer Feld 253, 69120, Heidelberg, Germany.
Max Planck School Matter to Life, Jahnstraße 29, 69120, Heidelberg, Germany.

Sebastian Fabritz (S)

Department for Chemical Biology, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany.

Hendrik Dietz (H)

Max Planck School Matter to Life, Jahnstraße 29, 69120, Heidelberg, Germany.
Department of Physics, Technical University of Munich, 85748, Garching, Germany.

Elisabetta Ada Cavalcanti Adam (EA)

Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany.
Max Planck School Matter to Life, Jahnstraße 29, 69120, Heidelberg, Germany.

Christiane Schaffitzel (C)

School of Biochemistry, Biomedical Sciences, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK.
Bristol Synthetic Biology Centre BrisSynBio, University of Bristol, 4 Tyndall Ave, Bristol, BS8 1TQ, UK.
Halo Therapeutics Ltd, Science Creates, Albert Road St. Philips Central, Bristol, BS2 0XJ, UK.

Alessia Ruggieri (A)

Department of Infectious Diseases, Molecular Virology, Center for Integrated Infectious Disease Research, University of Heidelberg, Im Neuenheimer Feld 344, 69120, Heidelberg, Germany.

Ilia Platzman (I)

Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany.
Institute for Molecular Systems Engineering, University of Heidelberg, Im Neuenheimer Feld 253, 69120, Heidelberg, Germany.
Max Planck-Bristol Center for Minimal Biology, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK.

Imre Berger (I)

Max Planck-Bristol Center for Minimal Biology, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK. imre.berger@bristol.ac.uk.
School of Biochemistry, Biomedical Sciences, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK. imre.berger@bristol.ac.uk.
Bristol Synthetic Biology Centre BrisSynBio, University of Bristol, 4 Tyndall Ave, Bristol, BS8 1TQ, UK. imre.berger@bristol.ac.uk.
Halo Therapeutics Ltd, Science Creates, Albert Road St. Philips Central, Bristol, BS2 0XJ, UK. imre.berger@bristol.ac.uk.

Joachim P Spatz (JP)

Department for Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstraße 29, 69120, Heidelberg, Germany. spatz@mr.mpg.de.
Institute for Molecular Systems Engineering, University of Heidelberg, Im Neuenheimer Feld 253, 69120, Heidelberg, Germany. spatz@mr.mpg.de.
Max Planck-Bristol Center for Minimal Biology, University of Bristol, 1 Tankard's Close, Bristol, BS8 1TD, UK. spatz@mr.mpg.de.
Max Planck School Matter to Life, Jahnstraße 29, 69120, Heidelberg, Germany. spatz@mr.mpg.de.

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