Refine
Has Fulltext
- yes (290)
Is part of the Bibliography
- yes (290)
Year of publication
Document Type
- Journal article (181)
- Doctoral Thesis (102)
- Preprint (5)
- Master Thesis (1)
- Report (1)
Keywords
- Thrombozyt (19)
- platelets (17)
- ischemic stroke (10)
- Maus (9)
- Thrombose (8)
- gephyrin (7)
- platelet (7)
- platelet activation (6)
- GPVI (5)
- Microscopy (5)
- Signaltransduktion (5)
- blood (5)
- glycoprotein VI (5)
- platelet aggregation (5)
- thrombo-inflammation (5)
- Biologie (4)
- DNS-Reparatur (4)
- Drosophila melanogaster (4)
- Fluoreszenzmikroskopie (4)
- Mice (4)
- Mikroskopie (4)
- Platelets (4)
- Rezeptor (4)
- Staphylococcus aureus (4)
- Taufliege (4)
- Thrombosis (4)
- X-ray crystallography (4)
- expression (4)
- integrins (4)
- megakaryocytes (4)
- phosphorylation (4)
- thrombosis (4)
- Arteriosklerose (3)
- Arzneimitteldesign (3)
- Dendritische Zelle (3)
- Diabetes mellitus (3)
- Drosophila (3)
- Entzündung (3)
- Fettsäurestoffwechsel (3)
- GPCR (3)
- Genexpression (3)
- HUWE1 (3)
- Hämostase (3)
- Inflammation (3)
- Megakaryozyt (3)
- Metalloproteinasen (3)
- NRF2 (3)
- Platelet (3)
- Proteinkinase D (3)
- Rac1 (3)
- Transkriptionsfaktor (3)
- Typ 1 (3)
- Ubiquitin (3)
- actin (3)
- cell wall (3)
- crystal structure (3)
- differentiation (3)
- escherichia coli (3)
- flow cytometry (3)
- fluorescence microscopy (3)
- lipid bilayer (3)
- macrophages (3)
- mechanisms (3)
- protein (3)
- thrombin (3)
- AFM (2)
- ATF4 (2)
- Agent (2)
- Aorta (2)
- Apoptosis (2)
- Blut-Hirn-Schranke (2)
- Breast-tumors (2)
- C. elegans (2)
- C/EBP (2)
- CML (2)
- CXCR4 (2)
- Caenorhabditis elegans (2)
- Calcium (2)
- Cancer (2)
- Cryo-EM (2)
- Cytomegalie-Virus (2)
- Cytoskeleton (2)
- DNA repair (2)
- Differenzierung (2)
- Einzelmolekülmikroskopie (2)
- Expansion Microscopy (2)
- FRET (2)
- Fettsäurebiosynthese (2)
- Fluorescence (2)
- Fluoreszenz (2)
- G protein-coupled receptors (2)
- GABA (2)
- GABAA receptors (2)
- Gephyrin (2)
- Helicasen (2)
- Herzhypertrophie (2)
- Hirnhautentzündung (2)
- Inhibition (2)
- Inhibitorische Synapse (2)
- Inhibitory synapse (2)
- Interleukin 6 (2)
- Invasion (2)
- Kollagen (2)
- Kristallographie (2)
- Kristallstruktur (2)
- LASP1 (2)
- Learning and memory (2)
- Lung cancer (2)
- MIZ1 (2)
- Megakaryocyte (2)
- Megakaryopoese (2)
- Meningitis (2)
- Metabolism (2)
- Molekulargenetik (2)
- Muskelzelle (2)
- Nude-mice (2)
- OSMR (2)
- Obesity (2)
- Oncostatin M (2)
- PIP2 (2)
- Peptidsynthese (2)
- Phagozytose (2)
- Phosphorylierung (2)
- Plasmamembran (2)
- Plättchen (2)
- Pneumolysin (2)
- Protein (2)
- Protein p53 (2)
- Protein p73 (2)
- Regulation (2)
- Rhabdomyosarkom (2)
- Rho GTPase (2)
- SOCE (2)
- Schlaganfall (2)
- Smad (2)
- T-Lymphozyt (2)
- T-cells (2)
- TFIIH (2)
- Therapy (2)
- Toxin (2)
- Type 1 Diabetes (2)
- Zelle (2)
- Zellmigration (2)
- Zellskelett (2)
- Zelltod (2)
- activation (2)
- artemisinin (2)
- atherosclerosis (2)
- atomic-force microscopy (2)
- binding (2)
- biosensors (2)
- blood coagulation (2)
- bone marrow (2)
- breast-tumors (2)
- cancer (2)
- cell biology (2)
- cell signalling (2)
- chloroquine (2)
- coagulation (2)
- collagens (2)
- collybistin (2)
- crystallography (2)
- dSTORM (2)
- dendritic cells (2)
- diazepam (2)
- domain (2)
- extracellular domain (2)
- factor XII (2)
- fluorescence imaging (2)
- fluorescence resonance energy transfer (FRET) (2)
- gene expression (2)
- glycine receptor (2)
- gp130 (2)
- human (2)
- hydrodynamics (2)
- inflammation (2)
- inhibitory neurotransmission (2)
- inhibitory postsynapse (2)
- interactome (2)
- ischemic penumbra (2)
- isothermal titration calorimetry (2)
- lipid bilayer membrane (2)
- matrix protein porin (2)
- melanoma (2)
- membrane (2)
- membrane potential (2)
- meningitis (2)
- metastasis (2)
- miRNS (2)
- mice (2)
- middle cerebral artery occlusion (2)
- mouse (2)
- mouse model (2)
- murine (2)
- neuronal dendrites (2)
- neurons (2)
- nucleotide excision repair (2)
- nucleotide excision-repair (2)
- nude-mice (2)
- oncolytic viruses (2)
- p34 (2)
- p44 (2)
- p53 (2)
- p63 (2)
- p73 (2)
- pathway (2)
- phagocytosis (2)
- phospholipase D (2)
- platelet receptors (2)
- porin (2)
- recognition (2)
- rheumatoid arthritis (2)
- signaling (2)
- stroke (2)
- structural basis (2)
- structure based drug design (2)
- sulfur (2)
- synapses (2)
- synaptic plasticity (2)
- therapy (2)
- thermodynamics (2)
- thrombopoiesis (2)
- translocation (2)
- tumorigenesis (2)
- tumors (2)
- type VII secretion system (2)
- vision (2)
- vitamin B6 (2)
- 1,25-dihydroxyvitamin D\(_{3}\) (1)
- 2-photon microscopy (1)
- 3D printing (1)
- 7,8-dihydroxyflavone (7,8-DHF) (1)
- 7-Dehydrocholesterol (1)
- 8-oxoguanine (1)
- AAA (1)
- AAA+ ATPase p97 (1)
- ADAM10 (1)
- ADP-ribosyltransferases (1)
- AGT (1)
- AKT1 (1)
- AMP-activated protein kinase (AMPK) (1)
- AMP‐activated protein kinase (1)
- ATGL (1)
- Abszission (1)
- Acetylation (1)
- Acetylierung (1)
- Ackerschmalwand (1)
- Actin (1)
- Actin binding proteins (1)
- Actin cytoskeleton-related protein (1)
- Actin-bindende Proteine (1)
- Activation (1)
- Active zone (1)
- Adapterprotein (1)
- Adipokine (1)
- Adipositas (1)
- Adrenalin (1)
- Affinity probe (1)
- Aktive Zone (1)
- Allgemeine Zelle (1)
- Anthrax Toxin (1)
- Anti-Gehirn Autoantikörper (1)
- Antikörper (1)
- Antithrombotics (1)
- Antithrombotika (1)
- Antithrombotikum (1)
- Archaea (1)
- Archaebakterien (1)
- Arp2/3 complex (1)
- Art (1)
- Arterial water (1)
- Arterielles Blut (1)
- Aspergillus fumigatus (1)
- Astrozyt (1)
- Atherosclerosis (1)
- Atriales natriuretisches Hormon (1)
- Autoantigen (1)
- Autoantikörper (1)
- Autoinhibition (1)
- Automatische Biegewinkelmessung (1)
- Autophagie (1)
- BCR‐ABL (1)
- BIN2 (1)
- BMP (1)
- BRAF (1)
- BTB domain (1)
- BV-2 (1)
- Bacillus anthracis (1)
- Bacillus subtilis (1)
- Bacterial Toxins (1)
- Bakteriengift (1)
- Basen-Exzisionsreparatur (1)
- Bcl-2 (1)
- Behavior (1)
- Beige adipocytes (1)
- Bericht (1)
- Biegewinkel (1)
- Bildbearbeitung (1)
- Bildgebung intakten Knochens (1)
- Bildverarbeitung (1)
- Bindungsprozess (1)
- Biochemie (1)
- Biochemistry (1)
- Biology (1)
- Biomarker (1)
- Black-lipid-bilayer (1)
- Blood-brain barrier (1)
- Blutgefäßsystem (1)
- Blutplättchen (1)
- Bone morphogenetic proteins (1)
- Bordetella pertussis (1)
- Brain (1)
- Burkholderia (1)
- Burkholderia pseudomallei (1)
- C2-toxin (1)
- CCR2 (1)
- CD coreceptors (1)
- CD11b+ myeloid cells (1)
- CD84 (1)
- CHAC1 (1)
- CIB1 (1)
- CLEC-2 (1)
- CLEC-2 ITAM (1)
- COVID-19 (1)
- COX-2 (1)
- COX2 expression (1)
- CVT (1)
- CXCL12-abundant reticular (CAR)-cells (1)
- CXCL4 (1)
- CXCL7 (1)
- Calcium signalling (1)
- Calcium-bindende Proteine (1)
- Carboxy-Terminus (1)
- Carcinogenese (1)
- Carcinoma (1)
- Caspr1 (1)
- Cation Homeostasis (1)
- Cell (1)
- Cell line (1)
- Cells (1)
- Central nervous system (1)
- Cerebral-ischemia (1)
- ChIP-sequencing (1)
- Chaetomium thermophilum (1)
- Chemerin (1)
- Chemerin processing (1)
- Chemotherapy (1)
- Chlamydia trachomatis (1)
- Cholesterin (1)
- Cholesterol (1)
- Chylomicron (1)
- Chylomicrons (1)
- Circadian rhythms (1)
- Clec16a (1)
- Clostridioides binary toxins (1)
- Clostridium-botulinum (1)
- Cluster (1)
- Coefficient (1)
- Collaborative Research Center (1)
- Collagen (1)
- Combination therapy (1)
- Component selectivity (1)
- Computerprogramm (1)
- Conditioning (1)
- Contactin 1 (1)
- Cortactin (1)
- Corynebacterium urealyticum (1)
- Cranial window (1)
- Crystal structure of MTR1 (1)
- Crystal-structure (1)
- Current noise-analysis (1)
- CyaA (1)
- Cyclophosphamide (1)
- Cys-loop receptor (1)
- Cytokine (1)
- DAMGO (1)
- DAPI staining (1)
- DHCR7 (1)
- DNA Repair (1)
- DNA damage (1)
- DNA metabolism (1)
- DNA origami (1)
- DNA structures (1)
- DNA-Reparatur (1)
- DNA-based nanostructures (1)
- DNA-processing enzymes (1)
- DNS-Bindung (1)
- Darm (1)
- Deletion (1)
- Dendritic cells (1)
- Diabetes (1)
- Diabetes Typ 1 (1)
- Differentiation (1)
- Diphenylether (1)
- Disulfidbrücken (1)
- Diversifikation <Biologie> (1)
- Dopamine (1)
- Durchflusscytometrie (1)
- Dynamik (1)
- Dynamik von Membranrezeptoren (1)
- E1 (1)
- E2 (1)
- E3 enzyme (1)
- EHT1864 (1)
- ERK map kinease (1)
- ERK1/2 (1)
- ESAT‐6‐like secretion system (1)
- ESS (1)
- Edema factor (1)
- Einzelpartikelverfolgung (1)
- Enoyl-Reduktase (1)
- Enoyl-acyl-carrier-protein-Reductase (1)
- Entwicklung (1)
- Enzym (1)
- Enzyme Regulation (1)
- Epitop (1)
- Erlernte Hilflosigkeit (1)
- EsaA (1)
- Escherichia coli (1)
- Escherichia coli AlkA (1)
- Escherichia-coli (1)
- Experimental Biomedicine (1)
- Experimental stroke (1)
- Extracellular Vesicles (1)
- FANCM (1)
- FAS-II (1)
- FAT10ylation (1)
- FIONA (1)
- FMMs (1)
- FRAP (1)
- FRET sensors (1)
- FabI (1)
- FabV (1)
- FeS cluster (1)
- Ferroptose (1)
- Ferroptosis (1)
- Fettsäure-Synthase (1)
- Fgf-signalling (1)
- Fibroblast (1)
- Flippase (1)
- Flotillin (1)
- Fluorescence Microscopy (1)
- Fluorescence Resonance Energy Transfer (1)
- Fluorescence correlation spectroscopy (1)
- Fluorescence imaging with one nanometer accuracy (1)
- Fluorescence microscopy (1)
- Fluorescence resonance energy transfer (1)
- Fluorescent probes (1)
- Fluoreszenzsonde (1)
- Fluoreszmikroskopie (1)
- FoxO3 (1)
- Foxo1 (1)
- Fragiles X Syndrom (1)
- Frühdiagnostik (1)
- Förster Resonance Energy Transfer (1)
- Förster resonance energy transfer (1)
- G Protein-Coupled Receptors (1)
- G protein-coupled receptor (1)
- G-Protein gekoppelte Rezeptoren (1)
- G-protein coupled receptors (1)
- G-protein-coupled receptors (1)
- GABA(A) receptors (1)
- GABA-A receptor (1)
- GABAA (1)
- GBM (1)
- GFAP (1)
- GI-101A tumor xenografts (1)
- GIST (1)
- GLV-1 h153 (1)
- GLV-1H68 (1)
- GPCRs (1)
- GPVI shedding (1)
- GPX4 (1)
- GSH (1)
- GapN (1)
- Gelernte Hilflosigkeit (1)
- Genanalyse (1)
- Gene-expression (1)
- General Transcription Factor II H (1)
- Gerinnungsfaktor (1)
- Geruchswahrnehmung (1)
- Gleiten (1)
- Gliafaserprotein (1)
- Glycoprotein GPV (1)
- Glycoprotein VI (1)
- Glycoprotein hormone (1)
- Glykoprotein VI (1)
- Glykoprotein-Shedding (1)
- Glykoproteine (1)
- Glykosylasen (1)
- Gram-positive bacteria (1)
- Guanine nucleotide exchange factor (GEF) (1)
- Guanylatcyclase (1)
- Guanylyl cyclase A (1)
- Gα\(_{i1}\), Gα\(_{i2}\) and Gα\(_{i3}\) activation (1)
- H1 helix (1)
- H1-Helix (1)
- H2A histone family member X (H2AX) (1)
- HECT Ligase (1)
- HHV-6A (1)
- HIF1alpha (1)
- Head-injury (1)
- Heart (1)
- Helicase (1)
- Hemodynamic depression (1)
- Hemostasis (1)
- Hepatitis B Virus (1)
- Herpesvirus (1)
- Heubacillus (1)
- Hic-5 (1)
- High-throughput screening (1)
- Hirschsprung disease (1)
- Homöostase (1)
- Hypothalamus (1)
- Hypoxia (1)
- Hypoxie (1)
- IMA2.1 (1)
- ITAM (1)
- Identification (1)
- Immune Thrombocytopenia (1)
- Immunologische Synapse (1)
- Immunthrombozytopenie (1)
- In vivo (1)
- In vivo imaging (1)
- In-vivo (1)
- Inhibitor (1)
- Inhibitory-postsynapse (1)
- Insulin (1)
- Insulinsekretion (1)
- Integrine (1)
- Interleukin 17 (1)
- Intravascular coagulation (1)
- Intrazellulärraum (1)
- Invertebrate vision (1)
- Ion-channel (1)
- Iron-uptake (1)
- Ischemic stroke (1)
- JAQ1 (1)
- KEA (1)
- KEAP1 (1)
- KIT (1)
- Kardial Hypertrophy (1)
- Kardiovaskulär (1)
- Karzinomzellen (1)
- Kationen-Homöostase (1)
- Knochen-Morphogenese-Proteine (1)
- Knockout <Molekulargenetik> (1)
- Koagulation (1)
- Kollektive Invasion (1)
- Konditionierung (1)
- Kraftmikroskopie (1)
- Krebsforschung (1)
- Krebszelle (1)
- L-3,4-Dihydroxyphenylalanine-induced dyskinesia (1)
- LC-MS (1)
- LC3-assoziierte Phagozytose (1)
- LIFR (1)
- Latrophilin (1)
- Learned Helplessness (1)
- Lebenszyklus (1)
- Leber-Metabolismus (1)
- Lentiviral transgenesis (1)
- Lernen und Gedächtnis (1)
- Lethal factor (1)
- Leukaemia-inhibitory factor (1)
- Lichtblattmikroskopie (1)
- Lichtscheibenmikroskopie (1)
- Lipid Rafts (1)
- Lipid bilayer-membranes (1)
- Lipide (1)
- Lipolysis (1)
- LpxC inhibitors (1)
- Lungenkrebs (1)
- Lymphom (1)
- M14 carboxypeptidasses (1)
- MAPK signaling (1)
- MAX (1)
- MGL (1)
- MRI reporter (1)
- MYC (1)
- MYCN (1)
- MYCNv (1)
- Magnetic-resonance (1)
- Malignant effusion (1)
- Maligne Transformation (1)
- Mass Spectrometry (1)
- Massenspektrometrie (1)
- Mast cells (1)
- Matrix protein porin (1)
- Mc4r (1)
- Mcl-1 (1)
- Mechanismus (1)
- Medicine (1)
- Medizin (1)
- Megakaryozytopoese (1)
- Membrane Receptor Dynamics (1)
- Membranglykoproteine (1)
- Membranrezeptor (1)
- Metabolismus (1)
- Metabotropic glutamate receptor (1)
- Metalloproteases (1)
- Metalloproteinase (1)
- Methyltransferase Ribozyme MTR1 (1)
- Microarray (1)
- Microvesicle (1)
- Mitose (1)
- Mittelkörper (1)
- Model (1)
- Molecular Biophysics (1)
- Molecular-weight heparin (1)
- Molekularbiologie (1)
- Molekulare Marker (1)
- Mouse (1)
- Mouse model (1)
- Multidrug-Resistenz (1)
- Multiphotonenmikroskopie (1)
- Multiproteinkomplex (1)
- Mushroom body (1)
- Muskelkontraktion (1)
- Myomesin (1)
- NADPH (1)
- NAP-2 (1)
- NF-KAPPA-B (1)
- NFκB-activation (1)
- NOD (1)
- Nanofabrication (1)
- Nanofabrikation (1)
- Ndrg1 (1)
- Neurobiologie (1)
- Neurofascin (1)
- Neurogenetik (1)
- Neurons (1)
- Neuroscience (1)
- Neurowissenschaften (1)
- Neutralisation <Chemie> (1)
- Nrf2 (1)
- Nuclease (1)
- Nucleasen (1)
- Nucleotide-Excision-Repair (1)
- Nukleotid-Exzisions-Reparatur (1)
- O6-alkylguanine-DNA alkyltransferase (1)
- OSC (1)
- Obscurin (1)
- Odor-feeding-time memory (1)
- Olig2 (1)
- Oncolytic vaccinia virus (1)
- Oncolytic virotherapy (1)
- OprO (1)
- OprP (1)
- Orai2 (1)
- P14ARF (1)
- P4-ATPase (1)
- PDE (1)
- PDI (1)
- PDXP inhibitors (1)
- PF4 (1)
- PKA signaling (1)
- PKD1 (1)
- PKR (1)
- PNA (peptide nucleic acid) (1)
- PTMs (1)
- PTPN22 (1)
- Parkinson Disease (1)
- Parkinson-Krankheit (1)
- Parkinsons disease (1)
- Peptidase inhibitor 16 (PI16) (1)
- Peptide (1)
- Perforine (1)
- Perfusion (1)
- Phenylalanine clamp (1)
- Phospholipase D (1)
- Phosphorylation (1)
- Pilzkörper (1)
- Plasmonic (1)
- Platelet activating Factor (1)
- Platelet activation (1)
- Platelet-Membranglykoprotein p62 (1)
- Plätchen aktivierung (1)
- Polkörper (1)
- Pore (1)
- Pore formation (1)
- Pore-formation (1)
- Porenbildung (1)
- Posttranslationale Änderung (1)
- Primärtumor (1)
- Profilierung (1)
- Protease inhibition (1)
- Protective antigen (1)
- Protein Disulfid Isomerase (1)
- Protein Kinase C (1)
- Protein Kinase D (1)
- Protein Kinase D 1 (1)
- Protein Kinase D2 (1)
- Protein kinase D1 (PKD1) (1)
- Protein kinase D3 (PKD3) (1)
- Proteinfaltung (1)
- Proteinkinase C (1)
- Proteins (1)
- Protoplasten (1)
- Ptpn22 (1)
- Purification (1)
- Quantifizierung (1)
- Quantitation (1)
- Quergestreifte Muskulatur (1)
- RARRES2 (1)
- RCK domain (1)
- RHO (1)
- RHO-associated kinease (1)
- RKIP (1)
- RNA (1)
- RNA interference (1)
- RNA splicing (1)
- RNA structures (1)
- RNA-catalyzed RNA methylation (1)
- RNAi (1)
- RNS-Interferenz (1)
- ROCK (1)
- ROK-alpha (1)
- RSK (1)
- RTX-Toxins (1)
- Rac (1)
- Ranvier-Schnürring (1)
- Rasterkraftmikroskop (1)
- Rats (1)
- Ratte (1)
- RecQ4 (1)
- Receptor Preference (1)
- Receptor internalization (1)
- Receptor signaling (1)
- Recombinant vaccinia (1)
- Registrierung <Bildverarbeitung> (1)
- Regression (1)
- Remorin (1)
- Rheumatoide Arthritis (1)
- Rho GTPasen (1)
- Rho GTPasw (1)
- RhoGTPase (1)
- Rhodesain (1)
- Ribosom (1)
- Röntgenkristallographie (1)
- S-layer protein (1)
- S6KII RSK (1)
- SARS-CoV-2 (1)
- SDS polyacrylamide gel electrophoresis (1)
- SLC7A11 (1)
- SOC (1)
- STIM2 (1)
- Salmonella-typhimurium (1)
- Schlafkrankheit (1)
- Secretion (1)
- Sepsis (1)
- Serotonin (1)
- Sezernierte Faktoren (1)
- Signaling (1)
- Single Particle Tracking (1)
- Sinusthrombose (1)
- Solid-phase peptide synthesis (1)
- Sonderforschungsbereich Transregio 240 (1)
- Spezifität (1)
- Spleen tyrosine kinase (1)
- Src family (1)
- Ssl1 (1)
- Staphylococcus aureus USA300 (1)
- Store-Operated (1)
- Streptococcus pneumoniae (1)
- Stress (1)
- Structural Biology (1)
- Struktur-basiertes Wirkstoff Design (1)
- Sugar-transport (1)
- Super-Resolution Microscopy (1)
- Super-resolution microsopy (1)
- Superhochauflösende Mikroskopie (1)
- Synapse (1)
- T cell (1)
- T cell development (1)
- T cell rezeptor transfer (1)
- T lymphocyte (1)
- T-Lymphozyten-Rezeptor (1)
- T-Zell-Rezeptor Transfer (1)
- T-Zellaktivierung (1)
- T-Zellhomöostase (1)
- T-Zellrezeptor (1)
- TGN1412 (1)
- TIG2 (1)
- TPp73 (1)
- TRRAP (1)
- Tagesrhythmus (1)
- Telomerase (1)
- Tfb4 (1)
- Thrombopoese (1)
- Thrombopoiesis (1)
- Thrombozytenaggregation (1)
- Thrombozytenfunktionsanalyse (1)
- Thrombozytopathie (1)
- Thrombozytopoese (1)
- Thrombus (1)
- Thrombus formation (1)
- Tissue (1)
- Tissue staining (1)
- Titin (1)
- Transcription (1)
- Transkription (1)
- Translokation (1)
- Transparent motion (1)
- Triclosan (1)
- Triton X 100 (1)
- Trypanosoma brucei (1)
- Trypanosomiasis (1)
- TspanC8 (1)
- Tuberkelbakterium (1)
- Tumorigenese (1)
- Tumorzelle (1)
- Type 1 diabetes (1)
- Type VIIb secretion system (1)
- UBA6 (1)
- UBE2S (1)
- UBE2Z (1)
- UBE3A (1)
- US22 gene family (1)
- USP (1)
- Ube2S (1)
- Ubiquitin-PA (1)
- Ubiquitin-Protein-Ligase (1)
- Ubiquitin-conjugating (E2) enzymes (1)
- Ubiquitin-conjugating enzyme (1)
- Ubiquitinierung (1)
- Ubiquitylation (1)
- Unique Selling Proposition (1)
- VACV (1)
- VEGF (1)
- VSMC (1)
- Vaccinia virus (1)
- Vascular endothelial Growth Factor (1)
- Vaskuläre Integrität (1)
- Verhalten (1)
- Verweildauer (1)
- Vesikelbildung (1)
- Visual attention (1)
- Visuelle Aufmerksamkeit (1)
- Von-Willebrand-factor (1)
- WDR5 (1)
- Warsaw breakage syndrome (1)
- Wilms tumor (1)
- Wirkstoff (1)
- X-Ray Chrystallography (1)
- X-ray Crystallography (1)
- XPD (1)
- XPD helicase (1)
- Xeroderma pigmentosum (1)
- Xiphophorus (1)
- X‐ray crystallography (1)
- Yersinia (1)
- Yersinia pestis (1)
- Zebrabärbling (1)
- Zebrafisch (1)
- Zebrafish (1)
- Zelldifferenzierung (1)
- Zellkern (1)
- Zelllinie (1)
- Zelltransport (1)
- Zellwand (1)
- Zentralnervensystem (1)
- Zielstruktur (1)
- Zinc (1)
- Zink-Finger-Proteine (1)
- Zytoskelett (1)
- abscission (1)
- accelerated atherosclerosis (1)
- accumulation (1)
- acetylsalicylic acid (1)
- actins (1)
- activating transcription factor 4 (ATF4) (1)
- active zone (1)
- acute graft-versus host disease (1)
- acute myeloid leukemia (1)
- acute slices (1)
- adaptor protein Swiprosin-1/EFhd2 (1)
- additive manufacturing (1)
- adenylate cyclase toxin (1)
- adenylyl cyclase (1)
- adhesion GPCR (1)
- adipocyte (1)
- adipocytes (1)
- adipose (1)
- adrenergic receptor (1)
- adsorption (1)
- aggregation (1)
- alkene-alkyne [2+2] photocycloaddition (1)
- alkylation damage (1)
- alloreactive T cells (1)
- allosterism (1)
- amino acid sequence (1)
- aminoquinolinium salts (1)
- ampa receptors (1)
- ancistrocladinium A (1)
- angiogenesis (1)
- animal behavior (1)
- animal models (1)
- animal-model (1)
- animals (1)
- anions (1)
- antagonists (1)
- anthrax (1)
- anti-brain autoantibodies (1)
- anti-inflammatory (1)
- antibacterial activity (1)
- antibiotics (1)
- antibody (1)
- antibody/autoantibody (1)
- antigen processing and recognition (1)
- antioxidant function (1)
- aorta (1)
- apolipoprotein E (1)
- apoptose (1)
- apoptosis (1)
- arachidonic acid metabolic network (1)
- aspergillus fumigatus (1)
- astrocytes (1)
- ataxia teleagiectasia mutated (ATM) (1)
- atheriosclerotic lesions (1)
- atomic force microscopy (1)
- atomic force microscopy (AFM) (1)
- atopic dermatitis (1)
- atrial natriuretic peptide (1)
- attention (1)
- autoantibodies (1)
- autoantibody (aAb) (1)
- autoantigen (1)
- autoimmunity (1)
- autoinhibition (1)
- axonal transport (1)
- bacteria (1)
- bacterial fatty-acid biosynthesis (1)
- bacterial meningitis (1)
- base excision repair (1)
- base pairs (1)
- bead models (1)
- behavioral conditioning (1)
- beige adipocytes (1)
- beta (1)
- beta cell function (1)
- biased signaling (1)
- binding components (1)
- binding mode (1)
- biochemical characterization (1)
- bioconjugation (1)
- biological techniques (1)
- biomarkers (1)
- biomedicine (1)
- biopharmaceuticals (1)
- biosensor (1)
- black lipid bilayer (1)
- blood brain barrier (1)
- blood flow (1)
- blood platelets (1)
- blue native polyacrylamide gel electrophoresis (1)
- bone morphogenetic protein (1)
- bone-marrow (1)
- borrelia burgdorferi (1)
- boundary cap (1)
- brain (1)
- brain damage (1)
- breast cancer (1)
- bulky damages recognition (1)
- cAMP (1)
- cAMP signaling (1)
- calcitonin gene-related peptide (1)
- calcium (1)
- calmodulin (1)
- cancer biology (1)
- cancer therapy (1)
- cancer treatment (1)
- carboxy terminus (1)
- carcinoma (1)
- carcinoma cells (1)
- cardiac hypertrophy (1)
- cardiovascular (1)
- cardiovascular disease (1)
- cascade (1)
- cell (1)
- cell membranes (1)
- cell migration (1)
- cell proliferation (1)
- cell staining (1)
- cell wall channel (1)
- cell walls (1)
- cell-autonomous defense (1)
- cell-cycle arrest (1)
- cell-line (1)
- cells (1)
- cellular neuroscience (1)
- cellular stress response (1)
- cellular-trafficking (1)
- cerebellum (1)
- cerebrovascular diseases (1)
- cerebrovascular disorders (1)
- channel (1)
- chemical libraries (1)
- chemokine (1)
- chemokines (1)
- chemotherapy (1)
- cholesterol (1)
- cholesterol-dependent cytolysin (1)
- cholinergic interneurons (1)
- chronic heart failure (1)
- chronic kidney disease (1)
- chronophin (1)
- chylomicron (1)
- ciliary neurotrophic factor (1)
- click-chemistry (1)
- clinical neurology (1)
- coagulation system (1)
- coffin-lowry-syndrome (1)
- collective invasion (1)
- combinatorial libraries (1)
- complex (1)
- complex stability (1)
- computational docking (1)
- conditioned response (1)
- conformational activation (1)
- conformational auto-epitope (1)
- conjugation (1)
- conservation (1)
- conserving surgery (1)
- containing GABA(A) receptors (1)
- controllability (1)
- convergent extension movements (1)
- corticosteroids and cyclophosphamide (1)
- corynebacteria (1)
- corynebacterium diphtheriae (1)
- cultured hippocampal-neurons (1)
- cyclic AMP (1)
- cyclic peptides/cyclopeptides (1)
- cyclopeptide therapy (1)
- cysteine (1)
- cytokine release (1)
- cytomegaloviren (1)
- cytomegalovirus (1)
- cytoskeleton (1)
- cytotoxic T cells (1)
- dCIRL (1)
- damage responses (1)
- damaged DNA (1)
- deficient mice (1)
- demography (1)
- dendric cells (1)
- dendritic cell (1)
- dendritic growth (1)
- dendritic spines (1)
- dentate gyrus (1)
- detergents (1)
- deubiquitinase (1)
- developmental cycle (1)
- diabetes (1)
- diacylglycerol (DAG) (1)
- diet (1)
- dimeric peptide (1)
- dimerization (1)
- direct muss spectrometric profiling (1)
- disulfide bonds (1)
- dogs (1)
- domain swapping (1)
- dominant (1)
- dopa-induced dyskinesia (1)
- dopamine (1)
- dopamine transporters (1)
- dopaminergics (1)
- double knockout mice (1)
- drosophila melanogaster (1)
- drug development (1)
- drug discovery (1)
- drug repurposing (1)
- drug target (1)
- dunce (1)
- ectodomain cleavage (1)
- electrohydrodynamics (1)
- electron cryo microscopy (1)
- electron cryo-microscopy (1)
- electron microscopy (1)
- embryos (1)
- end-stage renal failure (1)
- endocannabinoid release (1)
- endothelial cell (1)
- endothelial cell interactions (1)
- endothelial growth-factor (1)
- enoyl reductase (1)
- enoyl-ACP reductase (1)
- enoyl-ACP reductase inhibitors (1)
- envelopment (1)
- enzyme (1)
- enzyme activator (1)
- enzyme mechanism (1)
- enzyme mechanisms (1)
- enzymes (1)
- epithelial-mesenchymal transition (1)
- epitope (1)
- essential genes (1)
- exchange factor collybistin (1)
- experimental autoimmune encephalomyelitis (1)
- extracellular vesicle (1)
- eye movements (1)
- eyes (1)
- factor Sox10 (1)
- factor-I (1)
- fat absorption (1)
- fatty acid biosynthesis (1)
- fatty acid synthesis (1)
- fentanyl (1)
- ferroptosis (1)
- fetal liver (1)
- fibrin (1)
- fibrinogen (1)
- field flow fractionation (1)
- fine-mapping (1)
- flippase (1)
- flotillin (1)
- fluorescence (1)
- fluorescence lifetime imaging microscopy (1)
- fluorescence resonance energy transfer (1)
- fluorescence-detected sedimentation (1)
- fluorescent probes (1)
- fluorescent protein (1)
- fosmidomycin (1)
- fostamatinib (1)
- fractalkine (1)
- fragment screening (1)
- friut fly behaviour (1)
- fusion and fission (1)
- gamma-aminobutyric-acid (1)
- gastric cancer (1)
- gel electrophoresis (1)
- gene (1)
- gene therapy (1)
- general transcription factor IIH (TFIIH) (1)
- genetic code expansion (1)
- genome integrity (1)
- genomic stability (1)
- germline mutation (1)
- glutamate (1)
- glutamate receptor (1)
- glv-1h68 (1)
- glycine (1)
- glycine receptor (GlyR) (1)
- glycine transporter 2 (1)
- glycolytic flux control (1)
- glycoprotein GPV (1)
- glycoprotein Ib (1)
- glycoprotein Ibα (1)
- glycoprotein receptor Ib (1)
- glycoprotein receptor Ibα (1)
- glycoprotein-shedding (1)
- glycosylation (1)
- glyvine uptake (1)
- gram negative bacteria (1)
- gram-negative bacteria (1)
- granule cells (1)
- growth regulator (1)
- guanine nucleotide exchange factor (GEF) (1)
- gut microbiome (1)
- hTERT (1)
- haemostasis (1)
- haloacid dehalogenase (1)
- helicase (1)
- hematopoiesis (1)
- hemodialysis (1)
- hemostasis (1)
- hemostasis, (1)
- hepatitis B core protein (1)
- hepatitis B virus (1)
- hippocampus (1)
- histologic diversity (1)
- histology (1)
- homeostasisIon channels (1)
- homoFRET (1)
- homology modeling (1)
- hormone receptors (1)
- human cells (1)
- human interleukin-4 (1)
- human sodium iodide symporter (hNIS) (1)
- humanized tumor (1)
- humans (1)
- hybrid imaging (1)
- hybridomas (1)
- hypercholeterolemia (1)
- hyperekplexia (1)
- hyperlipedemic mice (1)
- hypertonic solution (1)
- identification (1)
- imaging and sensing (1)
- immune cell function (1)
- immune cell recruitment (1)
- immune evasion (1)
- immunohistochemistry techniques (1)
- immunological synapse (1)
- immunoprecipitation (1)
- in vitro (1)
- in vitro and in vivo thrombus formation (1)
- in vivo (1)
- in vivo Modelle (1)
- in vivo imaging (1)
- in vivo models (1)
- in-vitro (1)
- in-vitro propagation (1)
- in-vivo (1)
- inactivation (1)
- increases atherosclersosis (1)
- indoleamine 2,3-dioxygenase (1)
- indoxyl sulfate (1)
- inflammatory sites (1)
- inhibition (1)
- inhibitor residence time (1)
- inhibitory synapse (1)
- innate immune response (1)
- insect flight (1)
- insulin (1)
- intact bone imaging (1)
- integrated stress response (1)
- integrin α2 (1)
- interleukin-6-type cytokines (1)
- internalization (1)
- interspecies comparison (1)
- intestine (1)
- intoxication (1)
- intracranial bleeding (1)
- intrahelical lesion (1)
- intrinsic metabolism (1)
- invasion (1)
- ion channels in the nervous system (1)
- ionic selectivity (1)
- iota-toxin (1)
- kidneys (1)
- kinase Syk (1)
- kinease (1)
- kinetics (1)
- knockout (1)
- laminin receptor (1)
- latency (1)
- learning (1)
- lesion formation (1)
- leukemia-inhibitory factor (1)
- leukocyte adhesion (1)
- ligand potencies (1)
- ligases (1)
- light pulses (1)
- light-induced interstrand DNA crosslinking (1)
- lightsheet microscopy (1)
- lines (1)
- lipid asymmetry (1)
- lipid bilayer membranes (1)
- lipidomics (1)
- listeriolysin O (1)
- liver (1)
- localization (1)
- locomotion (1)
- long-term depression (1)
- long-term potentation (1)
- loop B (1)
- loss of function (1)
- low-secretion phenotype mutants (1)
- lung and intrathoracic tumors (1)
- lymph node stromal cells (1)
- lymph node transplantation (1)
- lymph nodes (1)
- lymphoma (1)
- mRNA (1)
- magnetic resonance imaging (1)
- marcophages (1)
- mass spectrometry (1)
- mast cells (1)
- mastectomy (1)
- mastocytosis (1)
- mathematical modeling (1)
- matrix metalloproteinase (1)
- maturation signal (1)
- maus (1)
- mechanotransduction (1)
- medicine (1)
- medium spiny neurons (1)
- megakaryopoiesis (1)
- melanoma malignancy (1)
- melt electrowriting (1)
- membrane interaction (1)
- mesenteric lymph node (1)
- metabolism (1)
- metabotropic signalling (1)
- metalloproteinase (1)
- metals (1)
- metastases (1)
- miR-17~92 (1)
- miR-30 (1)
- miRNA (1)
- miRNA expression (1)
- miRNA processing (1)
- microenvironment (1)
- microglia (1)
- microscopy (1)
- microvascular complications (1)
- microvascular density (1)
- microvasculature (1)
- midbody (1)
- migration (1)
- mismatch recognition (1)
- mismatches (1)
- mitochondria (1)
- mitochondrial transport (1)
- mitogenic signaling (1)
- mitosis (1)
- mobilization (1)
- model (1)
- modulation of virus replication (1)
- molecular basis (1)
- molecular biology (1)
- molecular mass (1)
- molecular mobility (1)
- molecular structure (1)
- molybdenum cofactor biosynthesis (1)
- monoclonal antibodies (1)
- monocyte (1)
- monocytes (1)
- monovalent cation:proton antiporter-2 (CPA2) family (1)
- morphogenesis (1)
- motion (1)
- motoneuron (1)
- mouse models (1)
- movement disorders (1)
- mrsk2 KO mouse (1)
- multi-drug-resistance (1)
- multiphoton microscopy (1)
- multiple myeloma (1)
- multiple sclerosis (1)
- murine cytomegalovirus (1)
- muscle (1)
- mutant p53 (1)
- mutation screening (1)
- mutation triggers (1)
- mutations (1)
- mycobacterium smegmatis (1)
- mycolic acid (1)
- myogenic differentiation (1)
- myomesin (1)
- nanoelectronics (1)
- nanolithography (1)
- nanomedicine (1)
- nanorobot (1)
- nanotechnology (1)
- naphthylisoquinoline alkaloids (1)
- neddylation (1)
- neocortex (1)
- network (1)
- neural networks (1)
- neurite outgrowth (1)
- neuroblastoma cell (1)
- neuroinflammation (1)
- neurologin-2 (1)
- neurology (1)
- neuromuscular junction (1)
- neuronal differentiation (1)
- neuropil (1)
- neurotransmitters (1)
- neurotrophic factor (1)
- neutralization (1)
- neutrophils (1)
- nilotinib (1)
- nitric oxide synthase (1)
- noncooperative binding (1)
- nuclear envelope (1)
- nuclear export (1)
- nuclear receptors (1)
- obesity (1)
- object segmentation (1)
- obscurin (1)
- octopamine (1)
- oncolytic viral therapy (1)
- oncolytic virotherapy (1)
- opioid peptides (1)
- opioid receptors (1)
- outer membrane proteins (1)
- oxazolone colitis (1)
- oxidation (1)
- oxidative stress (1)
- p-cresyl sulfate (1)
- p53-dependent apoptosis (1)
- p53-inducible regulator (1)
- pain behavior (1)
- pancreas (1)
- parathyroid hormone 1 receptor (1)
- pathway analysis (1)
- peptide (1)
- peptide inhibitor design (1)
- peptide inhibitor of envelopment (1)
- peptide microarray (1)
- peptides (1)
- peptidomoics (1)
- peripheral nerve (1)
- peripheral nervous system (1)
- permeability (1)
- pet dogs (1)
- phagosome maturation (1)
- phosphatidic acid (1)
- phosphatidylethanolamine (1)
- phosphatidylserine (1)
- phosphoglycolate phosphatase (1)
- phospholipase C gamma 2 (1)
- phosphorylation sites (1)
- photo-cross-linking (1)
- pkd (1)
- planar cell polarity (1)
- plasma membrane (1)
- plasticity (1)
- platelet adhesion (1)
- platelet degranulation (1)
- platelet factor 4 (1)
- platelet inhibition (1)
- platelet receptor (1)
- pneumolysin (1)
- pocket factor (1)
- podoplanin (1)
- polarization (1)
- popliteal aneurysm (1)
- pore formation (1)
- pore-forming toxin (1)
- post-translational modification (1)
- post-translational modifications (1)
- potassium homeostasis (1)
- precursor cells (1)
- presynaptic hyperekplexia (1)
- progressive encephalitis with rigidity and myoclonus (PERM) (1)
- proliferating cell nuclear antigen (PCNA) (1)
- promoter affinity (1)
- propionic acid (1)
- proteasome inhibitor resistance (1)
- proteasome subunit beta type-5 (PSMB5) (1)
- proteasome system (1)
- protective antigen (1)
- protein NEDD8 (1)
- protein RSK2 (1)
- protein disulfide isomerase (1)
- protein folding (1)
- protein kinase (1)
- protein kinase C (1)
- protein kinase D1 (1)
- protein kinase D2/PKD2/PRKD2 (1)
- protein processing (1)
- protein structures (1)
- protein synthesis shut down (1)
- protein transport (1)
- protein ubiquitination (1)
- protein-DNA interaction (1)
- protein-DNA interactions (1)
- protein-protein interaction (1)
- protein-protein interaction (PPI) (1)
- proteins (1)
- protein–protein interaction (1)
- proteome (1)
- proteomics (1)
- protochlamydia amoebophila (1)
- protoplasts (1)
- pseudomonas aeruginosa (1)
- puberty (1)
- purification (1)
- pyridoxal phosphatase (1)
- pyridoxal phosphatase (PDXP) (1)
- radiation-therapy (1)
- radii (1)
- radioiodine therapy (1)
- rat spinal-cord (1)
- receptor (1)
- receptor clustering (1)
- receptor signaling (1)
- receptor-beta subunits (1)
- recombinant tissue-type plasminogen activator (1)
- recruitment (1)
- regulation (1)
- regulatory T cells (1)
- regulatory circuit downstream (1)
- renal cancer (1)
- repair (1)
- repair and replication (1)
- replication (1)
- replication fork (1)
- resolvin (1)
- responses (1)
- restoration (1)
- restricition enzymes (1)
- rhabdomyosarcoma (1)
- rhabdomyosarcoma development (1)
- scaffold protein (1)
- scaffolding protein gephyryrin (1)
- screening (1)
- secondary lung tumors (1)
- secreted factors (1)
- selective channel (1)
- seminoma (1)
- senescence (1)
- sensitive amine oxidase (1)
- sensory cues (1)
- sensory physiology (1)
- serotonin (1)
- serum 25-hydroxyvitamin D (1)
- sex addiction (1)
- shedding (1)
- side chain properties (1)
- signal peptides (1)
- signal transduction (1)
- signal transduction pathway (1)
- signaling microdomain (1)
- signaling network (1)
- signalling pathways (1)
- silver staining (1)
- single channel analysis (1)
- single channel recording (1)
- single molecule (1)
- single strand blocking (1)
- site (1)
- size exclusion chromatography (1)
- skin autofluorescence (1)
- sleeping sickness (1)
- sliding (1)
- sodium-iodide symporter (1)
- sorafenib (1)
- spatiotemporal thrombus (1)
- species specificity (1)
- spinal-cord (1)
- spinco ultracentrifuge (1)
- stage-i (1)
- startle (1)
- stem cells (1)
- stiff-person syndrome (SPS) (1)
- stomach (1)
- storage-pool diseases (1)
- store-operated calcium entry (1)
- stranded DNAs (1)
- stress response (1)
- structural biology (1)
- structural disruption (1)
- structural mechanism (1)
- structure-based drug design (1)
- subcutaneous human tumors (1)
- subpopulation (1)
- subsets (1)
- substrate recognition (1)
- substrate specificity (1)
- subthreshold IKK activation (1)
- subunit (1)
- sulfates (1)
- sulfides (1)
- sulfites (1)
- super resolution microscopy (1)
- super-resolution microscopy (1)
- super-resolution microscopy (SRM) (1)
- surgery (1)
- swiss model (1)
- synapse (1)
- synapse formation (1)
- synaptic development (1)
- system (1)
- systemic micro-inflammation oxidative stress (1)
- tMCAO (1)
- telomerase (1)
- temporal range (1)
- temporal-lobe epilepsy (1)
- tetraspanin (1)
- thiol starvation (1)
- thiosulfates (1)
- thromboxane (1)
- thymine (1)
- thyroid-cancer (1)
- time-correlated single photon counting (TCSPC) (1)
- time-resolved anisotropy (1)
- titin (1)
- torque (1)
- torque meter (1)
- toxin (1)
- toxins (1)
- trafficking (1)
- trans-Golgi network (1)
- transactivation (1)
- transcription factors (1)
- transcriptome (1)
- transient middle cerebral artery occlusion (1)
- transient receptor potential channels (1)
- translesion synthesis (1)
- transmission (1)
- trypanosomes (1)
- tuberculosis (1)
- tumor microenvironment (1)
- tumour-necrosis factors (1)
- type 1 diabetes (1)
- type I interferon (1)
- tyrosine-protein kinase (1)
- ubiquitin (1)
- ubiquitin ligase (1)
- ubiquitylation (ubiquitination) (1)
- ultrastructure (1)
- undamaged DNA (1)
- uracil binding (1)
- variocosities (1)
- vascular adhesion protein-1 (1)
- vascular system (1)
- vaskuläre glatte Muskelzelle (1)
- vasp (1)
- velocity (1)
- vibration (1)
- virotherapy (1)
- virus reactivation (1)
- walking (1)
- x-ray crystallography (1)
- xeroderma-pigmentosum (1)
- µ-Opioid receptor (1)
- Übergewicht (1)
- β cell (1)
- β1-adrenoceptor/β1-adrenergic receptor (1)
- β3 adrenergic receptor (1)
- β3 adrenergic receptor (ADRB3) (1)
Institute
- Rudolf-Virchow-Zentrum (290) (remove)
Sonstige beteiligte Institutionen
- Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg (2)
- Center for Nanosystems Chemistry (CNC), University of Würzburg (1)
- Eberhard Karls Universität Tübingen (1)
- Genelux Corporation, San Diego Science Center, 3030 Bunker Hill Street, Suite 310, San Diego, California 92109, USA (1)
- MRB Forschungszentrum für Magnet-Resonanz-Bayern e.V., Am Hubland, D-97074 Würzburg (1)
- Research Center for Infectious Diseases, University of Wuerzburg, Wuerzburg 97080, Germany (1)
- Rudolf-Virchow-Zentrum für Experimentelle Biomedizin der Universität Würzburg (1)
Abstract
Streptococcus pneumoniae (pneumococcal) meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.
Author Summary
Bacterial meningitis is one of the most devastating brain diseases. Among the bacteria that cause meningitis, Streptococcus pneumoniae is the most common. Meningitis predominantly affects children, especially in the Third World, and most of them do not survive. Those that do survive often suffer permanent brain damage and hearing problems. The exact morphological substrates of brain damage in Streptococcus pneumoniae meningitis remain largely unknown. In our experiments, we found that the brain cortex of patients with meningitis demonstrated a loss of synapses (the contact points among neurons, responsible for the processes of learning and memory), and we identified the major pneumococcal neurotoxin pneumolysin as a sufficient cause of this loss. The effect was not direct but was mediated by the brain neurotransmitter glutamate, which was released upon toxin binding by one of the non-neuronal cell types of the brain – the astrocytes. Pneumolysin initiated calcium influx in astrocytes and subsequent glutamate release. Glutamate damaged the synapses via NMDA-receptors – a mechanism similar to the damage occurring in brain ischemia. Thus, we show that synaptic loss is present in pneumococcal meningitis, and we identify the toxic bacterial protein pneumolysin as the major factor in this process. These findings alter our understanding of bacterial meningitis and establish new therapeutic strategies for this fatal disease.
Background
Oncolytic virotherapy of tumors is an up-coming, promising therapeutic modality of cancer therapy. Unfortunately, non-invasive techniques to evaluate the inflammatory host response to treatment are rare. Here, we evaluate \(^{19}\)F magnetic resonance imaging (MRI) which enables the non-invasive visualization of inflammatory processes in pathological conditions by the use of perfluorocarbon nanoemulsions (PFC) for monitoring of oncolytic virotherapy.
Methodology/Principal Findings
The Vaccinia virus strain GLV-1h68 was used as an oncolytic agent for the treatment of different tumor models. Systemic application of PFC emulsions followed by \(^1H\)/\(^{19}\)F MRI of mock-infected and GLV-1h68-infected tumor-bearing mice revealed a significant accumulation of the \(^{19}\)F signal in the tumor rim of virus-treated mice. Histological examination of tumors confirmed a similar spatial distribution of the \(^{19}\)F signal hot spots and \(CD68^+\)-macrophages. Thereby, the \(CD68^+\)-macrophages encapsulate the GFP-positive viral infection foci. In multiple tumor models, we specifically visualized early inflammatory cell recruitment in Vaccinia virus colonized tumors. Furthermore, we documented that the \(^{19}\)F signal correlated with the extent of viral spreading within tumors.
Conclusions/Significance
These results suggest \(^{19}\)F MRI as a non-invasive methodology to document the tumor-associated host immune response as well as the extent of intratumoral viral replication. Thus, \(^{19}\)F MRI represents a new platform to non-invasively investigate the role of the host immune response for therapeutic outcome of oncolytic virotherapy and individual patient response.
Ablation of BRaf Impairs Neuronal Differentiation in the Postnatal Hippocampus and Cerebellum
(2013)
This study focuses on the role of the kinase BRaf in postnatal brain development. Mice expressing truncated, non-functional BRaf in neural stem cell-derived brain tissue demonstrate alterations in the cerebellum, with decreased sizes and fuzzy borders of the glomeruli in the granule cell layer. In addition we observed reduced numbers and misplaced ectopic Purkinje cells that showed an altered structure of their dendritic arborizations in the hippocampus, while the overall cornus ammonis architecture appeared to be unchanged. In male mice lacking BRaf in the hippocampus the size of the granule cell layer was normal at postnatal day 12 (P12) but diminished at P21, as compared to control littermates. This defect was caused by a reduced ability of dentate gyrus progenitor cells to differentiate into NeuN positive granule cell neurons. In vitro cell culture of P0/P1 hippocampal cells revealed that BRaf deficient cells were impaired in their ability to form microtubule-associated protein 2 positive neurons. Together with the alterations in behaviour, such as autoaggression and loss of balance fitness, these observations indicate that in the absence of BRaf all neuronal cellular structures develop, but neuronal circuits in the cerebellum and hippocampus are partially disturbed besides impaired neuronal generation in both structures.
Background
Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric \(PA_{63}\) binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the \(PA_{63}\)-channel in a dose dependent way.
Methodology/Principal Findings
Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the \(PA_{63}\)-channel in the µM range, when both, inhibitor and \(PA_{63}\) are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of \(PA_{63}\)-channel function also efficiently block intoxication of the cells by the combination lethal factor and \(PA_{63}\) in the same concentration range as they block the channels in vitro.
Conclusions/Significance
These results strongly argue in favor of a transport of lethal factor through the \(PA_{63}\)-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax.
Corynebacterium jeikeium, a resident of human skin, is often associated with multidrug resistant nosocomial infections in immunodepressed patients. C. jeikeium K411 belongs to mycolic acid-containing actinomycetes, the mycolata and contains a channel-forming protein as judged from reconstitution experiments with artificial lipid bilayer experiments. The channel-forming protein was present in detergent treated cell walls and in extracts of whole cells using organic solvents. A gene coding for a 40 amino acid long polypeptide possibly responsible for the pore-forming activity was identified in the known genome of C. jeikeium by its similar chromosomal localization to known porH and porA genes of other Corynebacterium strains. The gene jk0268 was expressed in a porin deficient Corynebacterium glutamicum strain. For purification temporarily histidine-tailed or with a GST-tag at the N-terminus, the homogeneous protein caused channel-forming activity with an average conductance of 1.25 nS in 1M KCl identical to the channels formed by the detergent extracts. Zero-current membrane potential measurements of the voltage dependent channel implied selectivity for anions. This preference is according to single-channel analysis caused by some excess of cationic charges located in the channel lumen formed by oligomeric alpha-helical wheels. The channel has a suggested diameter of 1.4 nm as judged from the permeability of different sized hydrated anions using the Renkin correction factor. Surprisingly, the genome of C. jeikeium contained only one gene coding for a cell wall channel of the PorA/PorH type found in other Corynebacterium species. The possible evolutionary relationship between the heterooligomeric channels formed by certain Corynebacterium strains and the homooligomeric pore of C. jeikeium is discussed.
In the Lyme disease spirochete Borrelia burgdorferi, the outer membrane protein P66 is capable of pore formation with an atypical high single-channel conductance of 11 nS in 1 M KCl, which suggested that it could have a larger diameter than ‘normal’ Gram-negative bacterial porins. We studied the diameter of the P66 channel by analyzing its single-channel conductance in black lipid bilayers in the presence of different nonelectrolytes with known hydrodynamic radii. We calculated the filling of the channel with these nonelectrolytes and the results suggested that nonelectrolytes (NEs) with hydrodynamic radii of 0.34 nm or smaller pass through the pore, whereas neutral molecules with greater radii only partially filled the channel or were not able to enter it at all. The diameter of the entrance of the P66 channel was determined to be \(\leq\)1.9 nm and the channel has a central constriction of about 0.8 nm. The size of the channel appeared to be symmetrical as judged from one-sidedness of addition of NEs. Furthermore, the P66-induced membrane conductance could be blocked by 80–90% by the addition of the nonelectrolytes PEG 400, PEG 600 and maltohexaose to the aqueous phase in the low millimolar range. The analysis of the power density spectra of ion current through P66 after blockage with these NEs revealed no chemical reaction responsible for channel block. Interestingly, the blockage of the single-channel conductance of P66 by these NEs occurred in about eight subconductance states, indicating that the P66 channel could be an oligomer of about eight individual channels. The organization of P66 as a possible octamer was confirmed by Blue Native PAGE and immunoblot analysis, which both demonstrated that P66 forms a complex with a mass of approximately 460 kDa. Two dimension SDS PAGE revealed that P66 is the only polypeptide in the complex.
Nanotechnological applications increasingly exploit the selectivity and processivity of biological molecules. Integration of biomolecules such as proteins or DNA into nano-systems typically requires their conjugation to surfaces, for example of carbon-nanotubes or fluorescent quantum dots. The bioconjugated nanostructures exploit the unique strengths of both their biological and nanoparticle components and are used in diverse, future oriented research areas ranging from nanoelectronics to biosensing and nanomedicine. Atomic force microscopy imaging provides valuable, direct insight for the evaluation of different conjugation approaches at the level of the individual molecules. Recent technical advances have enabled high speed imaging by AFM supporting time resolutions sufficient to follow conformational changes of intricately assembled nanostructures in solution. In addition, integration of AFM with different spectroscopic and imaging approaches provides an enhanced level of information on the investigated sample. Furthermore, the AFM itself can serve as an active tool for the assembly of nanostructures based on bioconjugation. AFM is hence a major workhorse in nanotechnology; it is a powerful tool for the structural investigation of bioconjugation and bioconjugation-induced effects as well as the simultaneous active assembly and analysis of bioconjugation-based nanostructures.
The eukaryotic actin cytoskeleton is an evolutionarily well-established pathogen target, as a large number of bacterial factors disturb its dynamics to alter the function of the host cells. These pathogenic factors modulate or mimic actin effector proteins or they modify actin directly, leading to an imbalance of the precisely regulated actin turnover. Here, we show that the pore-forming, cholesterol-dependent cytolysin pneumolysin (PLY), a major neurotoxin of Streptococcus pneumoniae, has the capacity to bind actin directly and to enhance actin polymerisation in vitro. In cells, the toxin co-localised with F-actin shortly after exposure, and this direct interaction was verified by Förster resonance energy transfer. PLY was capable of exerting its effect on actin through the lipid bilayer of giant unilamellar vesicles, but only when its pore competence was preserved. The dissociation constant of G-actin binding to PLY in a biochemical environment was 170–190 nM, which is indicative of a high-affinity interaction, comparable to the affinity of other intracellular actin-binding factors. Our results demonstrate the first example of a direct interaction of a pore-forming toxin with cytoskeletal components, suggesting that the cross talk between pore-forming cytolysins and cells is more complex than previously thought.
The Chlamydiae constitute an evolutionary well separated group of intracellular bacteria comprising important pathogens of humans as well as symbionts of protozoa. The amoeba symbiont Protochlamydia amoebophila lacks a homologue of the most abundant outer membrane protein of the Chlamydiaceae, the major outer membrane protein MOMP, highlighting a major difference between environmental chlamydiae and their pathogenic counterparts. We recently identified a novel family of putative porins encoded in the genome of P. amoebophila by in silico analysis. Two of these Protochlamydia outer membrane proteins, PomS (pc1489) and PomT (pc1077), are highly abundant in outer membrane preparations of this organism. Here we show that all four members of this putative porin family are toxic when expressed in the heterologous host Escherichia coli. Immunofluorescence analysis using antibodies against heterologously expressed PomT and PomS purified directly from elementary bodies, respectively, demonstrated the location of both proteins in the outer membrane of P. amoebophila. The location of the most abundant protein PomS was further confirmed by immuno-transmission electron microscopy. We could show that pomS is transcribed, and the corresponding protein is present in the outer membrane throughout the complete developmental cycle, suggesting an essential role for P. amoebophila. Lipid bilayer measurements demonstrated that PomS functions as a porin with anion-selectivity and a pore size similar to the Chlamydiaceae MOMP. Taken together, our results suggest that PomS, possibly in concert with PomT and other members of this porin family, is the functional equivalent of MOMP in P. amoebophila. This work contributes to our understanding of the adaptations of symbiotic and pathogenic chlamydiae to their different eukaryotic hosts.
Profiling the Cross Reactivity of Ubiquitin with the Nedd8 Activating Enzyme by Phage Display
(2013)
The C-terminal peptides of ubiquitin (UB) and UB-like proteins (UBLs) play a key role in their recognition by the specific activating enzymes (E1s) to launch their transfer through the respective enzymatic cascades thus modifying cellular proteins. UB and Nedd8, a UBL regulating the activity of cullin-RING UB ligases, only differ by one residue at their C-termini; yet each has its specific E1 for the activation reaction. It has been reported recently that UAE can cross react with Nedd8 to enable its passage through the UB transfer cascade for protein neddylation. To elucidate differences in UB recognition by UAE and NAE, we carried out phage selection of a UB library with randomized C-terminal sequences based on the catalytic formation of UB similar to NAE thioester conjugates. Our results confirmed the previous finding that residue 72 of UB plays a "gate-keeping" role in E1 selectivity. We also found that diverse sequences flanking residue 72 at the UB C-terminus can be accommodated by NAE for activation. Furthermore heptameric peptides derived from the C-terminal sequences of UB variants selected for NAE activation can function as mimics of Nedd8 to form thioester conjugates with NAE and the downstream E2 enzyme Ubc12 in the Nedd8 transfer cascade. Once the peptides are charged onto the cascade enzymes, the full-length Nedd8 protein is effectively blocked from passing through the cascade for the critical modification of cullin. We have thus identified a new class of inhibitors of protein neddylation based on the profiles of the UB C-terminal sequences recognized by NAE.