Refine
Has Fulltext
- yes (267)
Is part of the Bibliography
- yes (267)
Year of publication
Document Type
- Journal article (176)
- Doctoral Thesis (84)
- Preprint (5)
- Master Thesis (1)
- Report (1)
Language
- English (267) (remove)
Keywords
- Thrombozyt (18)
- platelets (17)
- ischemic stroke (10)
- Maus (9)
- Thrombose (8)
- gephyrin (7)
- platelet (7)
- platelet activation (6)
- GPVI (5)
- Microscopy (5)
- blood (5)
- glycoprotein VI (5)
- platelet aggregation (5)
- thrombo-inflammation (5)
- Biologie (4)
- Drosophila melanogaster (4)
- Fluoreszenzmikroskopie (4)
- Mice (4)
- Mikroskopie (4)
- Platelets (4)
- Rezeptor (4)
- Signaltransduktion (4)
- Staphylococcus aureus (4)
- Taufliege (4)
- Thrombosis (4)
- X-ray crystallography (4)
- expression (4)
- integrins (4)
- megakaryocytes (4)
- thrombosis (4)
- Arteriosklerose (3)
- Arzneimitteldesign (3)
- DNS-Reparatur (3)
- Dendritische Zelle (3)
- Diabetes mellitus (3)
- Drosophila (3)
- Fettsäurestoffwechsel (3)
- GPCR (3)
- HUWE1 (3)
- Hämostase (3)
- Inflammation (3)
- Megakaryozyt (3)
- Metalloproteinasen (3)
- NRF2 (3)
- Platelet (3)
- Proteinkinase D (3)
- Rac1 (3)
- Typ 1 (3)
- Ubiquitin (3)
- actin (3)
- cell wall (3)
- crystal structure (3)
- escherichia coli (3)
- flow cytometry (3)
- lipid bilayer (3)
- macrophages (3)
- mechanisms (3)
- phosphorylation (3)
- protein (3)
- thrombin (3)
- ATF4 (2)
- Agent (2)
- Aorta (2)
- Blut-Hirn-Schranke (2)
- Breast-tumors (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)
- Einzelmolekülmikroskopie (2)
- Entzündung (2)
- Expansion Microscopy (2)
- FRET (2)
- Fettsäurebiosynthese (2)
- Fluorescence (2)
- Fluoreszenz (2)
- G protein-coupled receptors (2)
- GABA (2)
- GABAA receptors (2)
- Genexpression (2)
- Gephyrin (2)
- Helicasen (2)
- Hirnhautentzündung (2)
- Inhibitorische Synapse (2)
- Inhibitory synapse (2)
- Interleukin 6 (2)
- Kollagen (2)
- Kristallstruktur (2)
- LASP1 (2)
- Learning and memory (2)
- Lung cancer (2)
- MIZ1 (2)
- Megakaryocyte (2)
- Megakaryopoese (2)
- Meningitis (2)
- Metabolism (2)
- Molekulargenetik (2)
- Nude-mice (2)
- OSMR (2)
- Obesity (2)
- Oncostatin M (2)
- PIP2 (2)
- Peptidsynthese (2)
- Plättchen (2)
- Pneumolysin (2)
- Protein (2)
- Regulation (2)
- Rho GTPase (2)
- SOCE (2)
- Schlaganfall (2)
- Smad (2)
- T-Lymphozyt (2)
- T-cells (2)
- TFIIH (2)
- Therapy (2)
- Toxin (2)
- Transkriptionsfaktor (2)
- Type 1 Diabetes (2)
- Zelle (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)
- chloroquine (2)
- coagulation (2)
- collagens (2)
- collybistin (2)
- dendritic cells (2)
- diazepam (2)
- differentiation (2)
- domain (2)
- extracellular domain (2)
- factor XII (2)
- fluorescence imaging (2)
- fluorescence microscopy (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)
- 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)
- pathway (2)
- phospholipase D (2)
- platelet receptors (2)
- porin (2)
- recognition (2)
- rheumatoid arthritis (2)
- signaling (2)
- stroke (2)
- structural basis (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)
- AFM (1)
- AGT (1)
- AKT1 (1)
- AMP-activated protein kinase (AMPK) (1)
- AMP‐activated protein kinase (1)
- ATGL (1)
- Acetylation (1)
- Acetylierung (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)
- Antikörper (1)
- Antithrombotics (1)
- Antithrombotika (1)
- Antithrombotikum (1)
- Apoptosis (1)
- Archaea (1)
- Archaebakterien (1)
- Arp2/3 complex (1)
- Art (1)
- Arterial water (1)
- Arterielles Blut (1)
- Astrozyt (1)
- Atherosclerosis (1)
- Autoantigen (1)
- Autoinhibition (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)
- Bcl-2 (1)
- Behavior (1)
- Beige adipocytes (1)
- Bericht (1)
- Bildbearbeitung (1)
- Bildgebung intakten Knochens (1)
- Bildverarbeitung (1)
- Bindungsprozess (1)
- Biochemie (1)
- Biochemistry (1)
- Biology (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)
- C. elegans (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)
- 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)
- Cluster (1)
- Coefficient (1)
- Collaborative Research Center (1)
- Collagen (1)
- Combination therapy (1)
- Component selectivity (1)
- Conditioning (1)
- Contactin 1 (1)
- Cortactin (1)
- Corynebacterium urealyticum (1)
- Cranial window (1)
- Crystal structure of MTR1 (1)
- CyaA (1)
- Cyclophosphamide (1)
- Cys-loop receptor (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)
- Darm (1)
- Deletion (1)
- Dendritic cells (1)
- Diabetes (1)
- Diabetes Typ 1 (1)
- Differentiation (1)
- Differenzierung (1)
- Diphenylether (1)
- Disulfidbrücken (1)
- Diversifikation <Biologie> (1)
- Dopamine (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)
- Einzelpartikelverfolgung (1)
- Enoyl-Reduktase (1)
- Enoyl-acyl-carrier-protein-Reductase (1)
- Entwicklung (1)
- Enzyme Regulation (1)
- Epitop (1)
- Erlernte Hilflosigkeit (1)
- EsaA (1)
- Escherichia coli (1)
- Escherichia coli AlkA (1)
- Experimental Biomedicine (1)
- Experimental stroke (1)
- Extracellular Vesicles (1)
- FANCM (1)
- FAS-II (1)
- FAT10ylation (1)
- FIONA (1)
- FMMs (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)
- FoxO3 (1)
- Foxo1 (1)
- Fragiles X Syndrom (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)
- 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)
- Glycoprotein GPV (1)
- Glycoprotein VI (1)
- Glycoprotein hormone (1)
- Glykoprotein VI (1)
- Glykoprotein-Shedding (1)
- Glykoproteine (1)
- Gram-positive bacteria (1)
- Guanine nucleotide exchange factor (GEF) (1)
- Gα\(_{i1}\), Gα\(_{i2}\) and Gα\(_{i3}\) activation (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)
- Herzhypertrophie (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)
- Inhibition (1)
- Inhibitor (1)
- Inhibitory-postsynapse (1)
- Insulin (1)
- Insulinsekretion (1)
- Integrine (1)
- Interleukin 17 (1)
- Intravascular coagulation (1)
- Intrazellulärraum (1)
- Invasion (1)
- Invertebrate vision (1)
- Iron-uptake (1)
- Ischemic stroke (1)
- JAQ1 (1)
- KEA (1)
- KEAP1 (1)
- KIT (1)
- Kardial Hypertrophy (1)
- Kardiovaskulär (1)
- Kationen-Homöostase (1)
- Knochen-Morphogenese-Proteine (1)
- Knockout <Molekulargenetik> (1)
- Koagulation (1)
- Kollektive Invasion (1)
- Konditionierung (1)
- Kraftmikroskopie (1)
- Krebsforschung (1)
- Krebszelle (1)
- Kristallographie (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)
- Leukaemia-inhibitory factor (1)
- Lichtblattmikroskopie (1)
- Lichtscheibenmikroskopie (1)
- Lipid Rafts (1)
- Lipide (1)
- Lipolysis (1)
- LpxC inhibitors (1)
- Lungenkrebs (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)
- Mast cells (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)
- 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)
- Muskelzelle (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)
- Parkinsons disease (1)
- Peptidase inhibitor 16 (PI16) (1)
- Peptide (1)
- Perforine (1)
- Perfusion (1)
- Phagozytose (1)
- Phospholipase D (1)
- Phosphorylation (1)
- Phosphorylierung (1)
- Pilzkörper (1)
- Plasmamembran (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)
- Protein p53 (1)
- Protein p73 (1)
- Proteinfaltung (1)
- Proteinkinase C (1)
- Proteins (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)
- ROK-alpha (1)
- RSK (1)
- RTX-Toxins (1)
- Rats (1)
- Ratte (1)
- RecQ4 (1)
- Receptor Preference (1)
- Receptor internalization (1)
- Receptor signaling (1)
- Recombinant vaccinia (1)
- Registrierung <Bildverarbeitung> (1)
- Regression (1)
- Rho GTPasen (1)
- Rho GTPasw (1)
- RhoGTPase (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)
- Secretion (1)
- Serotonin (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 lymphocyte (1)
- T-Zellaktivierung (1)
- T-Zellhomöostase (1)
- TGN1412 (1)
- TIG2 (1)
- TRRAP (1)
- Tagesrhythmus (1)
- Tfb4 (1)
- Thrombopoese (1)
- Thrombopoiesis (1)
- Thrombozytenaggregation (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)
- 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)
- Ube2S (1)
- Ubiquitin-PA (1)
- Ubiquitin-Protein-Ligase (1)
- Ubiquitin-conjugating (E2) enzymes (1)
- Ubiquitin-conjugating enzyme (1)
- Ubiquitinierung (1)
- Ubiquitylation (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)
- Zellkern (1)
- Zelllinie (1)
- Zellmigration (1)
- Zelltransport (1)
- Zellwand (1)
- Zentralnervensystem (1)
- Zielstruktur (1)
- Zinc (1)
- Zink-Finger-Proteine (1)
- Zytoskelett (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-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)
- 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)
- 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)
- carcinoma (1)
- cardiovascular (1)
- cardiovascular disease (1)
- cascade (1)
- cell (1)
- cell membranes (1)
- cell proliferation (1)
- cell signalling (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 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)
- 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)
- crystallography (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)
- dSTORM (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 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)
- 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)
- 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)
- 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)
- mRNA (1)
- magnetic resonance imaging (1)
- marcophages (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)
- metastases (1)
- miR-17~92 (1)
- miR-30 (1)
- miRNA expression (1)
- miRNA processing (1)
- miRNS (1)
- microenvironment (1)
- microglia (1)
- microscopy (1)
- microvascular complications (1)
- microvascular density (1)
- microvasculature (1)
- migration (1)
- mismatch recognition (1)
- mismatches (1)
- mitochondria (1)
- mitochondrial transport (1)
- mitogenic signaling (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)
- 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)
- 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)
- p63 (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)
- phagocytosis (1)
- phagosome maturation (1)
- phosphatidic acid (1)
- phosphatidylethanolamine (1)
- phosphatidylserine (1)
- phosphoglycolate phosphatase (1)
- phospholipase C gamma 2 (1)
- photo-cross-linking (1)
- pkd (1)
- planar cell polarity (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)
- 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)
- scaffold protein (1)
- scaffolding protein gephyryrin (1)
- screening (1)
- secondary lung tumors (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)
- 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)
- 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 (SRM) (1)
- surgery (1)
- swiss model (1)
- synapse (1)
- synapse formation (1)
- system (1)
- systemic micro-inflammation oxidative stress (1)
- tMCAO (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 (267) (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)
The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.
Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a thus far unknown cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the lytic-latent switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily drugable master regulator of the herpesvirus lytic-latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.
The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.
Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the life-threatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. Patient histories show variability in symptoms and responses to therapeutic treatments. A better understanding of the autoantibody pathology is required to develop improved therapeutic strategies. So far, the underlying molecular pathomechanisms include enhanced receptor internalization and direct receptor blocking altering GlyR function. A common epitope of autoantibodies against the GlyRα1 has been previously defined to residues 1A-33G at the N-terminus of the mature GlyR extracellular domain. However, if other autoantibody binding sites exist or additional GlyR residues are involved in autoantibody binding is yet unknown. The present study investigates the importance of receptor glycosylation for binding of anti-GlyR autoantibodies. The glycine receptor α1 harbors only one glycosylation site at the amino acid residue asparagine 38 localized in close vicinity to the identified common autoantibody epitope. First, non-glycosylated GlyRs were characterized using protein biochemical approaches as well as electrophysiological recordings and molecular modeling. Molecular modeling of non-glycosylated GlyRα1 did not show major structural alterations. Moreover, non-glycosylation of the GlyRα1N38Q did not prevent the receptor from surface expression. At the functional level, the non-glycosylated GlyR demonstrated reduced glycine potency, but patient GlyR autoantibodies still bound to the surface-expressed non-glycosylated receptor protein in living cells. Efficient adsorption of GlyR autoantibodies from patient samples was possible by binding to native glycosylated and non-glycosylated GlyRα1 expressed in living not fixed transfected HEK293 cells. Binding of patient-derived GlyR autoantibodies to the non-glycosylated GlyRα1 offered the possibility to use purified non-glycosylated GlyR extracellular domain constructs coated on ELISA plates and use them as a fast screening readout for the presence of GlyR autoantibodies in patient serum samples. Following successful adsorption of patient autoantibodies by GlyR ECDs, binding to primary motoneurons and transfected cells was absent. Our results indicate that the glycine receptor autoantibody binding is independent of the receptor’s glycosylation state. Purified non-glycosylated receptor domains harbouring the autoantibody epitope thus provide, an additional reliable experimental tool besides binding to native receptors in cell-based assays for detection of autoantibody presence in patient sera.
Introduction
Pro-thrombotic events are one of the prevalent causes of intensive care unit (ICU) admissions among COVID-19 patients, although the signaling events in the stimulated platelets are still unclear.
Methods
We conducted a comparative analysis of platelet transcriptome data from healthy donors, ICU, and non-ICU COVID-19 patients to elucidate these mechanisms. To surpass previous analyses, we constructed models of involved networks and control cascades by integrating a global human signaling network with transcriptome data. We investigated the control of platelet hyperactivation and the specific proteins involved.
Results
Our study revealed that control of the platelet network in ICU patients is significantly higher than in non-ICU patients. Non-ICU patients require control over fewer proteins for managing platelet hyperactivity compared to ICU patients. Identification of indispensable proteins highlighted key subnetworks, that are targetable for system control in COVID-19-related platelet hyperactivity. We scrutinized FDA-approved drugs targeting indispensable proteins and identified fostamatinib as a potent candidate for preventing thrombosis in COVID-19 patients.
Discussion
Our findings shed light on how SARS-CoV-2 efficiently affects host platelets by targeting indispensable and critical proteins involved in the control of platelet activity. We evaluated several drugs for specific control of platelet hyperactivity in ICU patients suffering from platelet hyperactivation. The focus of our approach is repurposing existing drugs for optimal control over the signaling network responsible for platelet hyperactivity in COVID-19 patients. Our study offers specific pharmacological recommendations, with drug prioritization tailored to the distinct network states observed in each patient condition. Interactive networks and detailed results can be accessed at https://fostamatinib.bioinfo-wuerz.eu/.
Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5’-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small molecule screening, protein crystallography and biolayer interferometry, we discover and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.
DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O\(^6\)-alkylguanine and O\(^4\)-alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the base out of the DNA helix into the active site pocket in the protein. Alkyltransferases then directly and irreversibly transfer the alkyl group from the base to the active site cysteine residue. In contrast, alkyltransferase-like proteins recruit nucleotide excision repair components for O\(^6\)-alkylguanine elimination. One or more of these proteins are found in all kingdoms of life, and where this has been determined, their overall DNA repair mechanism is strictly conserved between organisms. Nevertheless, between species, subtle as well as more extensive differences that affect target lesion preferences and/or introduce additional protein functions have evolved. Examining these differences and their functional consequences is intricately entwined with understanding the details of their DNA repair mechanism(s) and their biological roles. In this review, we will present and discuss various aspects of the current status of knowledge on this intriguing protein family.
The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma. xCT activity was abolished by genetic depletion in the Tyr::CreER; Braf\(^{CA}\); Pten\(^{lox/+}\) melanoma model and by acute cystine withdrawal in melanoma cell lines. Both interventions profoundly impacted melanoma glutathione levels, but they were surprisingly well tolerated by murine melanomas in vivo and by most human melanoma cell lines in vitro. RNA sequencing of human melanoma cells revealed a strong adaptive upregulation of NRF2 and ATF4 pathways, which orchestrated the compensatory upregulation of genes involved in antioxidant defence and de novo cysteine biosynthesis. In addition, the joint activation of ATF4 and NRF2 triggered a phenotypic switch characterized by a reduction of differentiation genes and induction of pro-invasive features, which was also observed after erastin treatment or the inhibition of glutathione synthesis. NRF2 alone was capable of inducing the phenotypic switch in a transient manner. Together, our data show that cystine or glutathione levels regulate the phenotypic plasticity of melanoma cells by elevating ATF4 and NRF2.
Highlights
• The integrated stress response leads to a general ATF4-dependent activation of NRF2
• ATF4 causes a CHAC1-dependent GSH depletion, resulting in NRF2 stabilization
• An elevation of NRF2 transcript levels fosters this effect
• NRF2 supports the ISR/ATF4 pathway by improving cystine and antioxidant supply
Summary
The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.
Besides their central role in haemostasis and thrombosis, platelets are increasingly recognised as versatile effector cells in inflammation, the innate and adaptive immune response, extracellular matrix reorganisation and fibrosis, maintenance of barrier and organ integrity, and host response to pathogens. These platelet functions, referred to as thrombo-inflammation and immunothrombosis, have gained major attention in the COVID-19 pandemic, where patients develop an inflammatory disease state with severe and life-threatening thromboembolic complications. In the CRC/TR 240, a highly interdisciplinary team of basic, translational and clinical scientists explored these emerging roles of platelets with the aim to develop novel treatment concepts for cardiovascular disorders and beyond. We have i) unravelled mechanisms leading to life-threatening thromboembolic complica-tions following vaccination against SARS-CoV-2 with adenoviral vector-based vaccines, ii) identified unrecognised functions of platelet receptors and their regulation, offering new potential targets for pharmacological intervention and iii) developed new methodology to study the biology of megakar-yocytes (MKs), the precursor cells of platelets in the bone marrow, which lay the foundation for the modulation of platelet biogenesis and function. The projects of the CRC/TR 240 built on the unique expertise of our research network and focussed on the following complementary fields: (A) Cell bi-ology of megakaryocytes and platelets and (B) Platelets as regulators and effectors in disease. To achieve this aim, we followed a comprehensive approach starting out from in vitro systems and animal models to clinical research with large prospective patient cohorts and data-/biobanking. Despite the comparably short funding period the CRC/TR 240 discovered basic new mechanisms of platelet biogenesis, signal transduction and effector function and identified potential MK/platelet-specific molecular targets for diagnosis and therapy of thrombotic, haemorrhagic and thrombo-inflammatory disease states.
Xiphophorus fish exhibit a clear phenotypic polymorphism in puberty onset and reproductive strategies of males. In X. nigrensis and X. multilineatus, puberty onset is genetically determined and linked to a melanocortin 4 receptor (Mc4r) polymorphism of wild-type and mutant alleles on the sex chromosomes. We hypothesized that Mc4r mutant alleles act on wild-type alleles by a dominant negative effect through receptor dimerization, leading to differential intracellular signaling and effector gene activation. Depending on signaling strength, the onset of puberty either occurs early or is delayed. Here, we show by Förster Resonance Energy Transfer (FRET) that wild-type Xiphophorus Mc4r monomers can form homodimers, but also heterodimers with mutant receptors resulting in compromised signaling which explains the reduced Mc4r signaling in large males. Thus, hetero- vs. homo- dimerization seems to be the key molecular mechanism for the polymorphism in puberty onset and body size in male fish.
The pancreas is the key organ for the maintenance of euglycemia. This is regulated in particular by α-cell-derived glucagon and β-cell-derived insulin, which are released in response to nutrient deficiency and elevated glucose levels, respectively. Although glucose is the main regulator of insulin secretion, it is significantly enhanced by various potentiators.
Platelets are anucleate cell fragments in the bloodstream that are essential for hemostasis to prevent and stop bleeding events. Besides their classical role, platelets were implemented to be crucial for other physiological and pathophysiological processes, such as cancer progression, immune defense, and angiogenesis. Platelets from diabetic patients often present increased reactivity and basal activation. Interestingly, platelets store and release several substances that have been reported to potentiate insulin secretion by β-cells. For these reasons, the impact of platelets on β-cell functioning was investigated in this thesis.
Here it was shown that both glucose and a β-cell-derived substance/s promote platelet activation and binding to collagen. Additionally, platelet adhesion specifically to the microvasculature of pancreatic islets was revealed, supporting the hypothesis of their influence on glucose homeostasis. Genetic or pharmacological ablation of platelet functioning and platelet depletion consistently resulted in reduced insulin secretion and associated glucose intolerance. Further, the platelet-derived lipid fraction was found to enhance glucose-stimulated insulin secretion, with 20-hydroxyeicosatetraenoic acid (20-HETE) and possibly also lyso-precursor of platelet-activating factor (lysoPAF) being identified as crucial factors. However, the acute platelet-stimulated insulin secretion was found to decline with age, as did the levels of platelet-derived 20-HETE. In addition to their direct stimulatory effect on insulin secretion, specific defects in platelet activation have also been shown to affect glucose homeostasis by potentially influencing islet vascular development. Taking together, the results of this thesis suggest a direct and indirect mechanism of platelets in the regulation of insulin secretion that ensures glucose homeostasis, especially in young individuals.
Ferroptosis is a form of cell death characterized by phospholipid peroxidation, where numerous studies have suggested that the induction of ferroptosis is a therapeutic strategy to target therapy refractory cancer entities. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone reductase, is a key determinant of ferroptosis vulnerability, and its pharmacological inhibition was shown to strongly sensitize cancer cells to ferroptosis. A first generation of FSP1 inhibitors, exemplified by the small molecule iFSP1, has been reported; however, the molecular mechanisms underlying inhibition have not been characterized in detail. In this study, we explore the species-specific inhibition of iFSP1 on the human isoform to gain insights into its mechanism of action. Using a combination of cellular, biochemical, and computational methods, we establish a critical contribution of a species-specific aromatic architecture that is essential for target engagement. The results described here provide valuable insights for the rational development of second-generation FSP1 inhibitors combined with a tracer for screening the druggable pocket. In addition, we pose a cautionary notice for using iFSP1 in animal models, specifically murine models.
Glycine receptor β–targeting autoantibodies contribute to the pathology of autoimmune diseases
(2024)
Background and Objectives
Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit–binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology.
Methods
In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings.
Results
Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy.
Discussion
Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.
Platelets play an important role in haemostasis by mediating blood clotting at sites of blood vessel damage. Platelets, also participate in pathological conditions including thrombosis and inflammation. Upon vessel damage, two glycoprotein receptors, the GPIb-IX-V complex and GPVI, play important roles in platelet capture and activation.
GPIb-IX-V binds to von Willebrand factor and GPVI to collagen. This initiates a signalling cascade resulting in platelet shape change and spreading, which is dependent on the actin cytoskeleton. This thesis aimed to develop and implement different super-resolution microscopy techniques to gain a deeper understanding of the conformation and location of these receptors in the platelet plasma membrane, and to provide insights into their signalling pathways. We suggest direct stochastic optical reconstruction microscopy (dSTORM) and structured illumination microscopy (SIM) as the best candidates for imaging single platelets, whereas expansion microscopy (ExM) is ideal for imaging platelets aggregates.
Furthermore, we highlighted the role of the actin cytoskeleton, through Rac in GPVI signalling pathway. Inhibition of Rac, with EHT1864 in human platelets induced GPVI and GPV, but not GPIbα shedding. Furthermore, EHT1864 treatment did not change GPVI dimerisation or clustering, however, it decreased phospholipase Cγ2 phosphorylation levels, in human, but not murine platelets, highlighting interspecies differences. In summary, this PhD thesis demonstrates that; 1) Rac alters GPVI signalling pathway in human but not mouse platelets; 2) our newly developed ExM protocol can be used to image platelet aggregates labelled with F(ab’) fragments
Kef couples the potassium efflux with proton influx in gram-negative bacteria. The resulting acidification of the cytosol efficiently prevents the killing of the bacteria by reactive electrophilic compounds. While other degradation pathways for electrophiles exist, Kef is a short-term response that is crucial for survival. It requires tight regulation since its activation comes with the burden of disturbed homeostasis. Electrophiles, entering the cell, react spontaneously or catalytically with glutathione, which is present at high concentrations in the cytosol. The resulting glutathione conjugates bind to the cytosolic regulatory domain of Kef and trigger activation while the binding of glutathione keeps the system closed. Furthermore, nucleotides can bind to this domain for stabilization or inhibition. The binding of an additional ancillary subunit, called KefF or KefG, to the cytosolic domain is required for full activation. The regulatory domain is termed K+ transport–nucleotide binding (KTN) or regulator of potassium conductance (RCK) domain, and it is also found in potassium uptake systems or channels in other oligomeric arrangements. Bacterial RosB-like transporters and K+ efflux antiporters (KEA) of plants are homologs of Kef but fulfill different functions. In summary, Kef provides an interesting and well-studied example of a highly regulated bacterial transport system.
Monoglyceride lipase (MGL) hydrolyzes monoacylglycerols (MG) to glycerol and one fatty acid. Among the various MG species, MGL also degrades 2-arachidonoylglycerol, the most abundant endocannabinoid and potent activator of the cannabinoid receptors 1 and 2. We investigated the consequences of MGL deficiency on platelet function using systemic (Mgl\(^{−/−}\)) and platelet-specific Mgl-deficient (platMgl\(^{−/−}\)) mice. Despite comparable platelet morphology, loss of MGL was associated with decreased platelet aggregation and reduced response to collagen activation. This was reflected by reduced thrombus formation in vitro, accompanied by a longer bleeding time and a higher blood volume loss. Occlusion time after FeCl\(_3\)-induced injury was markedly reduced in Mgl\(^{−/−}\) mice, which is consistent with contraction of large aggregates and fewer small aggregates in vitro. The absence of any functional changes in platelets from platMgl\(^{−/−}\) mice is in accordance with lipid degradation products or other molecules in the circulation, rather than platelet-specific effects, being responsible for the observed alterations in Mgl\(^{−/−}\) mice. We conclude that genetic deletion of MGL is associated with altered thrombogenesis.
Platelets have a key physiological role in haemostasis however, inappropriate thrombus formation can lead to cardiovascular diseases such as myocardial infarction or stroke. Although, such diseases are common worldwide there are comparatively few anti-platelet drugs, and these are associated with an increased risk of bleeding. Platelets also have roles in thrombo-inflammation, immuno-thrombosis and cancer, in part via C-type lectin-like receptor 2 (CLEC-2) and its ligand podoplanin. Although CLEC-2 contributes to these diseases in mice, as well as to thrombus stability, it is unclear whether CLEC-2 has similar roles in humans, particularly as human CLEC-2 (hCLEC-2) cannot be investigated experimentally in vivo.
To investigate hCLEC-2 in vivo, we generated a humanised CLEC-2 mouse (hCLEC-2KI) model, as well as a novel monoclonal antibody, HEL1, that binds to a different site than an existing antibody, AYP1. Using these antibodies, we have provided proof of principle for the use of hCLEC-2KI mice to test potential therapeutics targeting hCLEC-2, and shown for the first time that hCLEC-2 can be immunodepleted, with little effect on haemostasis. However, our results have also suggested that there are species differences in the role of CLEC-2 in arterial thrombosis. We further confirmed this using human blood where blocking CLEC-2 ligand binding had no effect on thrombosis, whereas we confirmed a minor role for mouse CLEC-2 in thrombus stability. We also investigated the effect of blocking CLEC-2 signalling using the Bruton’s tyrosine kinase inhibitor PRN473 on CLEC-2 mediated immuno-thrombosis in a Salmonella typhimurium infection model. However, no effect on thrombosis was observed suggesting that CLEC-2 signalling is not involved.
Overall, our results suggest that there may be differences in the role of human and mouse CLEC-2, at least in arterial thrombosis, which could limit the potential of CLEC-2 as an anti-thrombotic target. However, it appears that the interaction between CLEC-2 and podoplanin is conserved and therefore CLEC-2 could still be a therapeutic target in immuno-thrombosis, thrombo-inflammation and cancer. Furthermore, any potential human specific therapeutics could be investigated in vivo using hCLEC-2KI mice.
Clostridioides bacteria are responsible for life threatening infections. Here, we show that in addition to actin, the binary toxins CDT, C2I, and Iota from Clostridioides difficile, botulinum, and perfrigens, respectively, ADP-ribosylate the actin-related protein Arp2 of Arp2/3 complex and its additional components ArpC1, ArpC2, and ArpC4/5. The Arp2/3 complex is composed of seven subunits and stimulates the formation of branched actin filament networks. This activity is inhibited after ADP-ribosylation of Arp2. Translocation of the ADP-ribosyltransferase component of CDT toxin into human colon carcinoma Caco2 cells led to ADP-ribosylation of cellular Arp2 and actin followed by a collapse of the lamellipodial extensions and F-actin network. Exposure of isolated mouse colon pieces to CDT toxin induced the dissolution of the enterocytes leading to luminal aggregation of cellular debris and the collapse of the mucosal organization. Thus, we identify the Arp2/3 complex as hitherto unknown target of clostridial ADP-ribosyltransferases.