Refine
Is part of the Bibliography
- yes (501)
Year of publication
- 2017 (501) (remove)
Document Type
- Journal article (366)
- Doctoral Thesis (113)
- Preprint (12)
- Conference Proceeding (6)
- Book article / Book chapter (1)
- Master Thesis (1)
- Report (1)
- Review (1)
Language
- English (501) (remove)
Keywords
- Hadron-Hadron scattering (experiments) (27)
- High energy physics (25)
- medicine (14)
- physics (12)
- Medicine (11)
- biology (10)
- inflammation (9)
- gene expression (8)
- high energy physics (8)
- PET (7)
- Higgs physics (5)
- boron (5)
- multiple myeloma (5)
- Apis mellifera (4)
- Asthma (4)
- B cells (4)
- Beyond Standard Model (4)
- CXCR4 (4)
- Candida albicans (4)
- DNA methylation (4)
- Drosophila melanogaster (4)
- Leistungsbewertung (4)
- MRI (4)
- NLO computations (4)
- Top physics (4)
- Trypanosoma (4)
- ants (4)
- blood (4)
- chemistry (4)
- fungi (4)
- geography (4)
- learning (4)
- metabolism (4)
- monocytes (4)
- mouse model (4)
- regulatory T cells (4)
- social systems (4)
- theranostics (4)
- Biology (3)
- Drosophila (3)
- Large Hadron Collider (3)
- Latrophilin (3)
- Magnetic resonance imaging (3)
- Motoneuron (3)
- Parkinson’s disease (3)
- Physics (3)
- Topologischer Isolator (3)
- alkaloids (3)
- animal sociality (3)
- antifungals (3)
- apoptosis (3)
- borylation (3)
- breast cancer (3)
- cell differentiation (3)
- dendritic cells (3)
- genetics (3)
- heart (3)
- hyperexpression techniques (3)
- ischemic stroke (3)
- lung cancer (3)
- metagenomics (3)
- molecular medicine (3)
- mouse models (3)
- mutation (3)
- positron emission tomography (3)
- psychiatry (3)
- psychology (3)
- symbiosis (3)
- 18F-FDG (2)
- Ackerschmalwand (2)
- AdS-CFT Correspondence (2)
- Aspergillus fumigatus (2)
- B7-H1 (2)
- BMP-2 (2)
- Bacterial pathogens (2)
- Bioinformatics (2)
- Boron (2)
- Burkina Faso (2)
- CNS (2)
- China (2)
- Chlamydia trachomatis (2)
- DNA damage (2)
- EAE (2)
- Electroweak interaction (2)
- FDG (2)
- Fabry disease (2)
- GPCR (2)
- Higgs boson (2)
- IL-2 (2)
- Immunotherapy (2)
- Ligand <Biochemie> (2)
- Metagenom (2)
- Metakognition (2)
- NLO Computations (2)
- Neisseria (2)
- Neisseria meningitidis (2)
- Netzwerk (2)
- Nigeria (2)
- Optimale Kontrolle (2)
- Oxygen (2)
- P300 (2)
- PET/CT (2)
- PRRT (2)
- Photoelektronenspektroskopie (2)
- Positronen-Emissions-Tomografie (2)
- Pulmonary imaging (2)
- Quality of life (2)
- RNA-sequencing (2)
- Robotik (2)
- Salmonellosis (2)
- Selbstgesteuertes Lernen (2)
- Soziale Insekten (2)
- Spinale Muskelatrophie (2)
- Spintronics (2)
- Spintronik (2)
- Staphylococcus aureus (2)
- Synapse (2)
- T cells (2)
- Tanzania (2)
- Taufliege (2)
- Thrombozyt (2)
- Transkriptionsfaktor (2)
- Trypanosoma brucei (2)
- Value (2)
- actinomycetes (2)
- amygdala (2)
- amyotrophic lateral sclerosis (2)
- antibacterial activity (2)
- antibiotics (2)
- anxiety (2)
- athletes (2)
- attention (2)
- autophagy (2)
- biomarker (2)
- biophysics (2)
- brain (2)
- cancer (2)
- cancer risk factors (2)
- cancer treatment (2)
- carbon dioxide (2)
- case report (2)
- cell cycle and cell division (2)
- ceramide (2)
- chemotherapy (2)
- chronic kidney disease (2)
- colorectal cancer (2)
- comparative genomics (2)
- condensed matter physics (2)
- coronary heart disease (2)
- cortisol (2)
- cytotoxic T cells (2)
- depression (2)
- diborene (2)
- diborenes (2)
- elderly (2)
- electronic properties and materials (2)
- epigenetics (2)
- evaluation (2)
- exciton dynamics (2)
- experimental autoimmune encephalomyelitis (2)
- fibroblasts (2)
- fibrosis (2)
- fluorescence imaging (2)
- foraging (2)
- fullerenes (2)
- fungal infection (2)
- gene regulation (2)
- genetic loci (2)
- genetic variation (2)
- genotoxicity (2)
- guideline adherence (2)
- hearing loss (2)
- histology (2)
- holography and condensed matter physics (AdS/CMT) (2)
- humans (2)
- humidity (2)
- hydration dynamics (2)
- immune evasion (2)
- immune system (2)
- immunomodulation (2)
- in vitro (2)
- infection (2)
- infrared-spectra (2)
- macrophages (2)
- marine sponges (2)
- mechanotransduction (2)
- megakaryocytes (2)
- melanoma (2)
- memory (2)
- messenger RNA (2)
- metastasis (2)
- methylation (2)
- miR-21 (2)
- miRNA (2)
- mice (2)
- microRNAs (2)
- microbiology (2)
- monitoring (2)
- multiple sclerosis (2)
- mushroom bodies (2)
- nanophotonics and plasmonics (2)
- near-infrared spectroscopy (2)
- nesting habits (2)
- neuropathic pain (2)
- optimal control (2)
- osteoarthritis (2)
- p34 (2)
- p44 (2)
- pancreatic cancer (2)
- pediatric (2)
- pollen (2)
- protected areas (2)
- protein hydration (2)
- pyrene dimer (2)
- quantum wells (2)
- regulation (2)
- regulator genes (2)
- remote sensing (2)
- semiconductors (2)
- serotonin (2)
- signaling (2)
- small interfering RNAs (2)
- social features (2)
- social interaction (2)
- structure elucidation (2)
- team sport (2)
- tight junctions (2)
- trans-formanilide (2)
- transcription factors (2)
- transcriptome (2)
- transition radiation (2)
- treatment (2)
- two-dimensional materials (2)
- validation (2)
- water migration (2)
- yellow fluorescent protein (2)
- 177Lu-DOTATATE (1)
- 177Lu-DOTATOC (1)
- 18F-DCFPL (1)
- 18F-LMI1195 (1)
- 1D transport (1)
- 3-coordinate boron (1)
- 3D Ko-kulture (1)
- 3D Pointcloud (1)
- 3D Punktwolke (1)
- 3D cell culture (1)
- 3D collation (1)
- 3D viewer (1)
- 4D flow cardiovascular magnetic resonance (1)
- 5-fluorouracil (1)
- A53T (1)
- ADAMTS (1)
- ALOS (1)
- ALOS-2 (1)
- ALS (1)
- ARIA (1)
- ARPES (1)
- ATLAS <Teilchendetektor> (1)
- ATLAS New Small Wheel (1)
- ATLAS detector (1)
- Abschlussprüfung (1)
- Abwärmenutzung (1)
- Accidental coincidence (1)
- Acetylation (1)
- Acetylierung (1)
- Actin (1)
- Actin Dynamics (1)
- Actinomyces (1)
- Actinomycetes (1)
- Acute lymphoblastic leukemia (1)
- Acute myeloid leukemia (1)
- Acyrthosiphon pisum (1)
- AdS-CFT correspondence (1)
- Adaptive Video Streaming (1)
- Adaptives System (1)
- Adaptives Videostreaming (1)
- Addukt (1)
- Adhesion-GPCR (1)
- Adipogenesis (1)
- Adrenocortical Carcinoma (1)
- Adults (1)
- Afghanistan (1)
- Africa (1)
- Agricultural soil science (1)
- Akutes Nierenversagen (1)
- Allergic rhinitis (1)
- Alpen (1)
- Alterung (1)
- Alzheimer's disease (1)
- Alzheimer’s disease (1)
- Ancistrocladus ealaensis (1)
- Ancistrocladus likoko (1)
- Angeregter Zustand (1)
- Angiogenese (1)
- Anorexia nervosa (1)
- Antiangiogenese (1)
- Antibacterial therapy (1)
- Antibacterials (1)
- Antibiotic resistance (1)
- Antibiotics (1)
- Antimikrobieller Wirkstoff (1)
- Antisense (1)
- Aorta (1)
- Apicomplexan (1)
- Aplysina aerophoba (1)
- ApoE\(^{(-/-)}\) (1)
- Apoptosis (1)
- Arabidopsis thaliana (1)
- Arbeit (1)
- Arbeitsmarkt (1)
- Arbeitsteilung (1)
- Archaikum <Geologie> (1)
- Archean (1)
- Arctic (1)
- Aristeas (1)
- Atherosclerosis (1)
- Atomphysik (1)
- Attitude Heading Reference System (AHRS) (1)
- Aufsichtsrat (1)
- Autoimmunity (1)
- Autonomic Computing (1)
- Autotransporter (1)
- Aviophobia (1)
- Axon (1)
- Axon Branching (1)
- B cell receptors (1)
- B physics (1)
- BBC3 (1)
- BCI (1)
- BDNF (1)
- BIRC7 (1)
- BMP (1)
- BRAF inhibition (1)
- Backscattering (1)
- Bacteria (1)
- Bacteriaophage AR9 (1)
- Bakterien (1)
- Barberton Supergroup (1)
- Basalmembran (1)
- Basement membrane (1)
- Batf3 (1)
- Bauchspeicheldrüsenkrebs (1)
- Becker naevus (1)
- Becker naevus syndrome (1)
- Benchmark (1)
- Benutzeroberfläche (1)
- Berchtesgaden NP (1)
- Beruf (1)
- Beschäftigtenmobilität (1)
- Beschäftigung (1)
- Bestäubung (1)
- Bestäubung Pollination Honigbiene Hummel (1)
- Betrieb (1)
- Bewegung (1)
- Beyond the Standard Model (1)
- Biene (1)
- Bienen Dressur Lernen (1)
- Bioinformatik (1)
- Bipolar (1)
- Birds (1)
- Body composition (1)
- Bone health (1)
- Bone marrow stromal cell (1)
- Bone marrow transplantation (1)
- Bor-Stickstoff-Verbindungen (1)
- Boron-Nitrogen Dative Bond (1)
- Bovine Mastitis (1)
- Brain μ-opioid receptors (1)
- Breathing (1)
- Bruchpilot (1)
- Burmese Days (1)
- C-H activation (1)
- CBF (1)
- CCN2 (1)
- CD28 (1)
- CD4\(^{+}\) T cells (1)
- CDN-Netzwerk (1)
- CH activation (1)
- CHO cell culture (1)
- CHO-Zelle (1)
- CHRODIS (1)
- CLIP-seq (1)
- CLN3 (1)
- CMV (1)
- CNBP (1)
- CNV (1)
- CO activation (1)
- CTGF (1)
- Ca\(_{v}\)2.2 (1)
- Caenorhabditis elegans (1)
- Cage (1)
- Calciumphosphate (1)
- Cancer (1)
- Cancer risk factors (1)
- Candida (1)
- Cardiovascular disease (1)
- Cataglyphis (1)
- Cell binding (1)
- Cell surface proteomics (1)
- ChIP-seq (1)
- Chaetomium thermophilum (1)
- Characterizing New Photoreceptors to Expand the Optogenetic Toolbox (1)
- Chemistry (1)
- Childhood cancer survivors (1)
- Chiralität <Chemie> (1)
- Chlamydia (1)
- Cholinesteraseinhibitor (1)
- Chronic lymphoblastic leukemia (1)
- Chronic myeloid leukemia (1)
- Chronic obstrusive pulmonary disease (1)
- Chronic rhino‑sinusitis (1)
- Circadian rhythms (1)
- Circadian rhythms and sleep (1)
- Circular dichroism spectroscopy (1)
- Cirl (1)
- Clay mineralogy (1)
- Cloud Computing (1)
- CoA (1)
- Coherent 2D spectroscopy (1)
- Collagen gels (1)
- Complexin (1)
- Compression (1)
- Computer Vision (1)
- Computer software (1)
- Consensus Control (1)
- Content Delivery Network (1)
- Cooperating UAVs (1)
- Cooperative Development (1)
- Coordinated Regional Climate Downscaling Experiment (CORDEX)-South Asia (1)
- Correlated electron effects (1)
- Correlation effects (1)
- Crisis (1)
- Cys-loop receptor (1)
- Cystic fibrosis (1)
- DExD/H-Box RNA helicase (1)
- DFT+U (1)
- DNA repair (1)
- DNA traps (1)
- DNA-Reparatur (1)
- DOTATOC (1)
- DREAM complex (1)
- Dark matter (1)
- Database searching (1)
- De-novo (1)
- Deep sequencing (1)
- Deflection routing (1)
- Deformation (1)
- Dentistry (1)
- Depression (1)
- Depression treatment (1)
- Depressive symptomatology (1)
- Dereplicaiton (1)
- Deutschland (1)
- Dezentrale Steuerung (1)
- Diagnostic medicine (1)
- Diaphragmatic breathing (1)
- Diborane (1)
- Diboranes (1)
- Diboron(4) Compounds (1)
- Dichtefunktionalformalismus (1)
- Dickdarmkrebs (1)
- Differentialgeometrie (1)
- Diffusion (1)
- Dignity (1)
- Dimension 1 (1)
- Dimere (1)
- Disease network (1)
- Distributed Control (1)
- Distributed computing (1)
- Diversifikation (1)
- Dunce isoforms (1)
- Durchflusscytometrie (1)
- Dünnschichttechnik (1)
- E. coli (1)
- EEG (1)
- ERP (1)
- ERP CSF (1)
- ERP Implementation (1)
- ESBL (1)
- ESTARFM framework (1)
- EUROASPIRE survey (1)
- EW (1)
- EZH2 (1)
- Early-onset (1)
- Echtzeitsystem (1)
- Electron Transfer (1)
- Electron Transparency (1)
- Elektronenkorrelation (1)
- Elektronentransfer (1)
- Elektronischer Transport (1)
- Elementarteilchen (1)
- EndoVAC and small bowel (1)
- Energietransfer (1)
- Energieübertragung (1)
- Energy Transfer (1)
- Enrichment analysis (1)
- Enterobacteriaceae (1)
- Entwicklungstheorie (1)
- Entzündung (1)
- Enzyme Regulation (1)
- Enzyme kinetics (1)
- Enzyme metabolism (1)
- Enzyme regulation (1)
- Enzymes (1)
- Epicardium-derived cells (1)
- Epigenetics (1)
- Epithelial-mesenchymale Transition (1)
- Erwachsener (1)
- Erweiterte Realität (1)
- Escherichia coli (1)
- Euler equations (1)
- Eulersche Differentialgleichung (1)
- Europe (1)
- European Property Law (1)
- Evolution (1)
- Evolutionäre Optimierung (1)
- Exciton coupling (1)
- Exercens (1)
- Exercise intervention (1)
- Exotics (1)
- Experimental study (1)
- Explosion (1)
- Exposure Risk (1)
- Exposure therapy (1)
- Exziton (1)
- Exzitonenkopplung (1)
- F-actin (1)
- FTY720 (1)
- Fahrsimulator (1)
- Faltungscode (1)
- Farbenpsychologie (1)
- Farbensehen (1)
- Feature Based Registration (1)
- Feldstärkemessung (1)
- Fernerkundung (1)
- Fernwartung (1)
- Ferromagnet (1)
- Ferromagnetikum (1)
- Festkörperphysik (1)
- Fettzelle (1)
- Feynman diagrams (1)
- Fibroblasten (1)
- Fibroblastenwachstumsfaktor (1)
- Ficaria ambigua (1)
- Ficaria calthifolia (1)
- Ficaria verna (1)
- First G-APD Cherenkov Telescope (1)
- Fks1 (1)
- Flavour changing neutral currents (1)
- Fokker-Planck (1)
- Fokker-Planck-Gleichung (1)
- Fokker–Planck equation (1)
- Forecasting (1)
- Formation Flight (1)
- Formulation development (1)
- Framework <Informatik> (1)
- Framework Develpment (1)
- Fruits (1)
- Functional magnetic resonance imaging (1)
- G protein-coupled receptors (1)
- G-Protein gekoppelte Rezeptor (1)
- GABA\(_{A}\) (1)
- GABBR1 (1)
- GA\(^2\)LEN (1)
- GM-CSF (1)
- GPS (1)
- GPS tracking (1)
- GTP-bindende Proteine (1)
- Galerkin-Methode (1)
- Galliumarsenid (1)
- Gamma-ray bursts (1)
- Ganglia (1)
- Gasionisationsdetektor (1)
- Gasphase (1)
- Gauge-gravity correspondence (1)
- Geldpolitik (1)
- Gene expression (1)
- Gene regulation (1)
- General Transcription Factor II H (1)
- Genetic causes of cancer (1)
- Genetics (1)
- Genexpression (1)
- Genexpression <Molekulargenetik> (1)
- Genom (1)
- Genomics (1)
- Genossenschaftsbanken (1)
- Geophysik (1)
- Georgre Orwell (1)
- German consumers (1)
- German translation (1)
- Geruchswahrnehmung (1)
- Geschlechtsbestimmung (1)
- Geschlechtsdifferenzierung (1)
- Geschwindigkeitswahrnehmung (1)
- Gestaltungsrichtlinien (1)
- Gestik (1)
- Gitterbaufehler (1)
- Gletscher (1)
- Glycin Peptide (1)
- Glycinrezeptor (1)
- Glycoprotein hormone (1)
- Gold (1)
- Golgi apparatus (1)
- Golgi-Apparat (1)
- Good Practices (1)
- Graph Theory (1)
- Graphen (1)
- Graphene (1)
- Guanylyl Cyclase (1)
- H441 (1)
- HECT Ligase (1)
- HLA-E matching (1)
- HNSCC (1)
- HPA axis (1)
- HRXRD (1)
- HSTC outcome (1)
- HUWE1 (1)
- Hadron Hadron scattering (experiments) (1)
- Halbleiterphysik (1)
- HeLa cells (1)
- Healthcare research (1)
- Heart failure (1)
- Heat Wave Magnitude Index (HWMI) (1)
- Heißes Elektron (1)
- Hematopoietic stem cell transplantation (1)
- Hemostasis (1)
- Herpes (1)
- Herz (1)
- High-energy jets (1)
- Himmelskompass (1)
- Hittitology (1)
- Hitzestress (1)
- Hoffa (1)
- Hofmeister (1)
- Hofmeister-Serie (1)
- Holography and condensed matter physics (AdS/CMT) (1)
- Homologische Algebra (1)
- Host cells (1)
- Hot electron (1)
- Housing markets (1)
- Human atrial stromal cells (1)
- Humangenetik (1)
- Hyaliner Knorpel (1)
- Hypertonic (1)
- Hyrtios (1)
- ICD-coding of CKD (1)
- ICP4 (1)
- IEG (1)
- IFN-γ (1)
- IL-10 (1)
- IL1RA (1)
- IMR-90 (1)
- Ibo (1)
- Igbo (1)
- Illumina HiSeq (1)
- Imaging Air Cherenkov Telescope (1)
- Imaging pitfalls (1)
- Imatinib (1)
- Immersion <Virtuelle Realität> (1)
- Immobilienmarkt (1)
- Immune Escape (1)
- Immune receptor signaling (1)
- IncRNA (1)
- Individualität (1)
- Industrial Organization (1)
- Industrial internet (1)
- Industrie 4.0 (1)
- Inelastische Röntgenstreuung (1)
- Inflammation (1)
- Inflammatory bowel disease (1)
- Instructional Support (1)
- Intelligent Real-time Interactive System (1)
- Interaktion (1)
- International IT Projects (1)
- Irritable bowel syndrome (1)
- Isomer (1)
- Japankärpfling (1)
- Java <Programmiersprache> (1)
- Jet physics (1)
- Josephson junctions (1)
- K-Ras (1)
- KFZA (1)
- Kaapvaal Craton (1)
- Kaapvaal Kraton (1)
- Karriere (1)
- Katholische Theologie (1)
- Kenya (1)
- Kernphysik (1)
- Kernspintomografie (1)
- Killer cell immunoglobulin-like receptors (1)
- Knochenbildung (1)
- Knochenmarkzelle (1)
- Knochenzement (1)
- Kohlenmonoxid (1)
- Kohärente 2D Spektroskopie (1)
- Kohärente Optik (1)
- Konditionierung (1)
- Krise (1)
- Kulturvergleich (1)
- Käfigverbindungen (1)
- L-typ Calciumkanal Antagonist (1)
- LC-ESI/MS/MS (1)
- LC-MS (1)
- LDOS (1)
- LFA-1 (1)
- LOGIC study (1)
- Laborem (1)
- Ladungsträgererzeugung (1)
- Landsat (1)
- Landschaftsstruktur (1)
- Langerhans cells (1)
- Langzeitgedächtnis (1)
- Larvae (1)
- Laserspektroskopie (1)
- Late-effects (1)
- Lautes Denken (1)
- Learning and memory (1)
- Lebensmittelchemie (1)
- Lernen (1)
- Letter of Aristeas (1)
- Lewis acids (1)
- Lewis-Base Adducts (1)
- Lewy-like pathology (1)
- Lineares System (1)
- Lipidumbau (1)
- Lithium-Ionen-Akkumulator (1)
- Lithium-Plating (1)
- Lizenzvertrag (1)
- Logic Programming (1)
- Logische Programmierung (1)
- Low-dimensional molecular metals (1)
- Lung (1)
- Lunge (1)
- Lungenkrebs (1)
- Luttinger-Flüssigkeit (1)
- Lysis (medicine) (1)
- MAP-Kinase (1)
- MASI (1)
- MASK (1)
- MDSC (1)
- MEMS IMU (1)
- MHD (1)
- MIBG (1)
- MICA (1)
- MICB (1)
- MITE (1)
- MMB (1)
- MODIS (1)
- MPFL (1)
- MPO (1)
- MR angiography (1)
- MS (1)
- MYC (1)
- Machine learning (1)
- Main-group chemistry (1)
- Manganese (1)
- Marfan syndrome (1)
- Marine natural products (1)
- Marine sponges (1)
- Marrakech (1)
- Mass Spectrometry (1)
- Massenspektrometrie (1)
- Matrixpolynom (1)
- Matrizenpolynom (1)
- Mcl-1 (1)
- Measurement (1)
- Medaka (1)
- Medical implants (1)
- Medical journals (1)
- Meeresschwämme (1)
- Megakaryopoese (1)
- Megalobrama amblycephala (1)
- Megaponera analis (1)
- Meiose (1)
- Meiosis (1)
- Melanom (1)
- Meliponini (1)
- Mena (1)
- Mensch-Maschine Interaktion (1)
- Mensch-Maschine-Schnittstelle (1)
- Menschenwürde (1)
- Merkel cell carcinoma (1)
- Merkel-Zellkarzinom (1)
- Merocyanine (1)
- Merocyanine dyes (1)
- Mesoskopisches System (1)
- Meta-modeling (1)
- Metabolic pathways (1)
- Metabolomics (1)
- Metabolomik (1)
- Metacognitive Prompting (1)
- Metagenomics (1)
- Metaiodobenzylguanidine (1)
- Meta‑analysis (1)
- Methanol (1)
- Micro Air Vehicle (1)
- Micromegas (1)
- Mikroorganismus (1)
- Mini Unmanned Aerial Vehicle (1)
- Mitose (1)
- Mixed Reality (1)
- Model extraction (1)
- Model transformation (1)
- Modellierung (1)
- Molecular Biophysics (1)
- Molecular biology (1)
- Molekulargenetik (1)
- Molekularphysik (1)
- Molekularstrahlepitaxie (1)
- Monetary policy (1)
- Monomere (1)
- Monozytendifferenzierung (1)
- Motoneurons (1)
- Mouse models (1)
- Multi-Paradigm Programming (1)
- Multi-Paradigm Programming Framework (1)
- Multimodal Processing (1)
- Multimodal System (1)
- Multimodales System (1)
- Multimorbidity (1)
- Multiple Myeloma (1)
- Multiple Sklerose (1)
- Multiple bonding (1)
- Multivariate analysis (1)
- Muscarinrezeptor (1)
- Muster (1)
- Myokarditis (1)
- N-heterocyclic carbenes (1)
- N-terminal domain (1)
- NAD (1)
- NADPH oxidase 2 (NOX2) (1)
- NF-\(\kappa\)B pathway (1)
- NFATc1 (1)
- NFKB (1)
- NK-cells (1)
- NLO QCD (1)
- NP-hard (1)
- NPC1 gene (1)
- NPC2 gene (1)
- NSG (1)
- NSG-UC (1)
- Nahfeldoptik (1)
- Nano-Optik (1)
- Nano-optics (1)
- Nash equilibrium (1)
- Natural products (1)
- Ndrg1 (1)
- Neisseria gonorrhoeae (1)
- Neolithic agriculture (1)
- Nervensystem (1)
- Network Functions Virtualisation (1)
- Network routing (1)
- Network-on-Chip (1)
- Neuroendocrine Tumor (1)
- Neuroethologie (1)
- Neuromodulation (1)
- Neuromuscular junctions (1)
- Neuronale Plastizität (1)
- Neuropeptide (1)
- Neuropeptidom (1)
- Neutrino data (1)
- Neutrino emission (1)
- Neutrino telescope (1)
- Next-Generation Sequenzierung (1)
- Nicht-kleinzelliges Bronchialkarzinom (NSCLC) (1)
- Niederdimensionale Molekulare Metalle (1)
- Niederdimensionales System (1)
- Niemann–Pick disease type C (1)
- Nimodipin (1)
- Non-coding RNAs (1)
- Nonadiabatic dynamics (1)
- Nonverbal (1)
- Nucleus (1)
- Numerical analysis (1)
- Numerisches Verfahren (1)
- Nährboden (1)
- OCD (1)
- ODMR-Spektroskopie (1)
- OLED (1)
- OMICS (1)
- Oberflächenplasmonresonanz (1)
- Object-Oriented Programming (1)
- Objektorientierte Programmierung (1)
- Observational study (1)
- Odor-feeding-time memory (1)
- Oilseed Rape (1)
- Oncolytic vaccinia virus (1)
- One-loop corrections (1)
- Ontologie <Wissensverarbeitung> (1)
- Optik (1)
- Optimierung (1)
- Optische Antennen (1)
- Optische Spektroskopie (1)
- Optogenetics (1)
- Optogenetik (1)
- Organic field-effect transistor (1)
- Organic semiconductors (1)
- Organik (1)
- Organische Halbleiter (1)
- Organische Solarzelle (1)
- Organischer Feldeffekttransistor (1)
- Organoboron chemistry (1)
- Osmunda regalis (1)
- Osseointegration (1)
- Osteogenesis (1)
- Osteology (1)
- P. aeruginosa (1)
- P14ARF (1)
- PAR-CLIP (1)
- PD-L1 (1)
- PDE4d (1)
- PDGF (1)
- PDGFR (1)
- PDH (1)
- PER (1)
- PGE (1)
- PI3K/Akt/mTor pathway (1)
- PKA signaling (1)
- PROLOG <Programmiersprache> (1)
- PSMA (1)
- PTMs (1)
- PacBio sequencing (1)
- Paleopedology (1)
- Panorama Images (1)
- Parkinson disease (1)
- Peptide (1)
- Performance Evaluation (1)
- Performance analysis (1)
- Perylenbisimid (1)
- Perylenderivate (1)
- Perylene Bisimide (1)
- Phosphorylation (1)
- Phosphorylierung (1)
- Photorezeptor (1)
- Phyllosphere (1)
- Phyllosphäre (1)
- Physical activity (1)
- Physical fitness (1)
- Physik (1)
- Pilzkörper (1)
- Pipecolinsäurederivate (1)
- Pitfall (1)
- Plasmon (1)
- Plasmonik (1)
- Platelet granules (1)
- Platelet-derived Growth Factor (1)
- Platelets (1)
- Platingruppenmetalle (1)
- Platinmetalle (1)
- Pleckstrin homology containing family member 5 (Plekhg5) (1)
- PolSAR (1)
- Pollen (1)
- Polynomial matrices (1)
- Poorly water soluble drugs (1)
- Posttranslationale Änderung (1)
- Predictive toxicology (1)
- Preisbindung (1)
- Prevalence (1)
- Primary care (1)
- Process Mining (1)
- Produktivität (1)
- Proliferation (1)
- Prostata (1)
- Prostate Cancer (1)
- Protein chemistry (1)
- Proteininteraktion (1)
- Protons (1)
- Prozessanalyse (1)
- Präsenzerleben (1)
- Psychologie (1)
- Pulmonary function (1)
- Pycnogenol (1)
- Quadcopter (1)
- Quality of Experience (1)
- Quantenmechanik (1)
- Quantensensorik (1)
- Quantifizierung (1)
- Quantitation (1)
- Quantum chronodynamics (1)
- Quasi-eindimensionale Organische Metalle (1)
- Quecksilbertellurid (1)
- R-sneutrino (1)
- RADARSAT Constellation Mission (1)
- RADARSAT-2 (1)
- RECOLA (1)
- RIG-I (1)
- RIXS (1)
- RMnO3 (1)
- RNA (1)
- RNA binding potein CNBP (1)
- RNA binding protein (1)
- RNA chaperone Hfq (1)
- RNA export (1)
- RNA in situ hybridization (1)
- RNA interference (1)
- RNA sequencing (1)
- RNA-binding proteins (1)
- ROS (1)
- Radarsat-2 (1)
- Radikal <Chemie> (1)
- Radikalanionensalz (1)
- Radiotracer (1)
- Raman spectroscopy (1)
- Random Forests (1)
- Randomized controlled trial (1)
- RapidEye (1)
- Real-time Kinematics (RTK) (1)
- RecQ4 (1)
- Receptor internalization (1)
- Receptor signaling (1)
- Rechnungswesen (1)
- Rechtsvergleich (1)
- Recognition of depression (1)
- Reflexivität (1)
- Regelverstoß (1)
- Registrierung (1)
- RelB (1)
- Remote sensing (1)
- Resource Use (1)
- Retinoesäure (1)
- Retinoic acid (1)
- Rezension (1)
- Rhinitis (1)
- Ribosome profiling (1)
- Riesensynapsen (1)
- Ring Expansion Reaction (1)
- Risiko (1)
- Robotics (1)
- Rural Development (1)
- Ruvuma Development Association (1)
- Röntgenspektroskopie (1)
- Rückkopplung (1)
- SAH (1)
- SARPES (1)
- SH3 (1)
- SHERPA (1)
- SMN (1)
- SNI (1)
- SPA-LEED (1)
- SSTR (1)
- STAT1 (1)
- STEC (1)
- STM (1)
- Saccharomyces cerevisiae (1)
- Salmonella (1)
- Sammeldistanzen (1)
- Sap47 (1)
- Schlaganfall (1)
- Schnittstellengestaltung (1)
- Schwämme (1)
- Search window (1)
- Sekundärmetabolit (1)
- Selbst (1)
- Selbstassemblierung (1)
- Selbstorganisation (1)
- Self-Aware Computing (1)
- Self-Regulated Learning (1)
- Self-assembly (1)
- Semiconductor (1)
- Senescence (1)
- Septins (1)
- Sex determination (1)
- Shale (1)
- Shigella (1)
- Shigellosis (1)
- Shooting an Elephant (1)
- Signal Formation (1)
- Signaltransduktion (1)
- Silicium Fehlstelle (1)
- Siliciumcarbid (1)
- Siliciumvakanz (1)
- Simulation (1)
- Situation Awareness (1)
- Skin (1)
- SmB\(_{6}\) (1)
- Socio-Cultural (1)
- Sodium-myoinositol cotransporter-1 (SMIT1) (1)
- Software Architecture (1)
- Software Defined Networking (1)
- Software Engineering (1)
- Software Quality (1)
- Software-based Networks (1)
- Software-defined networking (1)
- Softwareergonomie (1)
- Solarzelle (1)
- South-western Burkina Faso (1)
- Soziale Norm (1)
- Soziale-Kulturelle (1)
- Spinal Muscular Atrophy (1)
- Spindiffusion (1)
- Spinpolarisation (1)
- Sponges (1)
- Springs and Parachutes (1)
- Sprödbruch (1)
- Ssl1 (1)
- Standardized Precipitation Evapotranspiration Index (SPEI) (1)
- Standardmodell <Elementarteilchenphysik> (1)
- Staphylococcus (1)
- Statisktik (1)
- Stem cell transplantation (1)
- Stiffness (1)
- Stoffwechsel (1)
- Strategies to Obtain Tumor-Reactive Cells (1)
- Streptomyces (1)
- Stroke (1)
- Structural Biology (1)
- Struktur (1)
- Strychnin (1)
- Sunfrail (1)
- Superconductor (1)
- Supersymmetry (1)
- Support vector machines (1)
- Supraleiter (1)
- Supramolekulare Chemie (1)
- Surface plasmons (1)
- Syap1 (1)
- Synapse-associated protein (1)
- Synapsen assoziiert (1)
- Synapses (1)
- Synaptic vesicles (1)
- System-on-Chip (1)
- Systematic review (1)
- Systematic reviews (1)
- Systole (1)
- T cell migration (1)
- T-Pattern (1)
- T-cadherin (1)
- T-cells (1)
- TAMs (1)
- TCF1 (1)
- TCF12 (1)
- TD Kohn-Sham equations (1)
- TDDFT (1)
- TFIIH (1)
- TGFβ1 (1)
- TIMESAT (1)
- TKI (1)
- TLO (1)
- TNFR2 (1)
- TP53 (1)
- Tagesrhythmus (1)
- Tansania (1)
- Targeted drug delivery (1)
- Technology-Enhanced Learning (1)
- Telekommunikationsnetz (1)
- Telepräsenz (1)
- Telomer (1)
- Temperatureinfluss (1)
- TerraSAR-X (1)
- Test system (1)
- Tetrafluorodiborane (1)
- Textverstehen (1)
- Tfb4 (1)
- Theme (1)
- Thermodynamik (1)
- Thermoelektrischer Effekt (1)
- Thermoelektrischer Generator (1)
- Thermotoleranz (1)
- Thrombosis (1)
- Thrombozyten (1)
- Thrombozytenaggregation (1)
- Thrombozytopathie (1)
- Thrombozytopoese (1)
- Time measurement (1)
- Tissue Engineering (1)
- Tonschiefer (1)
- Topological insulators (1)
- Topologie (1)
- Tourismus (1)
- Toxicity (1)
- Toxoplasma gondii (1)
- Tracer (1)
- Traffic Management (1)
- Transcription (1)
- Transcription profiling (1)
- Transcriptional control (1)
- Transcriptome analysis (1)
- Transition metals (1)
- Transkription (1)
- Translation efficiency (1)
- Transporteigenschaft (1)
- Transvaal Supergroup (1)
- Treatment guidelines (1)
- Trees (1)
- Triglyceride (1)
- Tropheryma whipplei (1)
- Tuberculosis (1)
- Tumor (1)
- Tumor Immunology (1)
- Tumorangiogenese (1)
- Tumorgefäßmorphologie (1)
- Tyrian purple (1)
- U snRNPs (1)
- UAV (1)
- USA (1)
- Ubiquitin (1)
- Ujamaa-Sozialismus (1)
- Ulcerative colitis (1)
- Ultimatum Game (1)
- Ultrafast spectroscopy (1)
- Ultrakurzzeitspektroskopie (1)
- Ultraschall (1)
- Ultraschallsensor (1)
- Unabhängigkeit (1)
- Untersuchungsinstrument (1)
- Ureaplasma (1)
- User interfaces (1)
- V. saphena magna (1)
- VASP (1)
- VHDL (1)
- Vaccinia virus (1)
- Vegetables (1)
- Verarbeitungsflüssigkeit (1)
- Verhaltensanalyse (1)
- Verhaltensmuster (1)
- Verhaltensplastizität (1)
- Verkehrsleitsystem (1)
- Verkehrsmanagement (1)
- Verkehrsregelung (1)
- Verteiltes Datenbanksystem (1)
- Vesicles (1)
- Videoübertragung (1)
- Virology (1)
- Virtual Reality (1)
- Virtual reality (1)
- Virtualisierung (1)
- Virtuelle Realität (1)
- Virus (1)
- Vorvermischung (1)
- Vulkanologie (1)
- WASp (1)
- Waste Heat Recovery (1)
- WebGL (1)
- Werbung (1)
- Werte (1)
- Wertschätzung (1)
- West Africa (1)
- Wettbewerbsverhalten (1)
- Weyl semimetals (1)
- Whipple's disease (1)
- Wiedemann Franz law (1)
- Wiedemann-Franz-Gesetz (1)
- Wilms tumour (1)
- Wirt-Gast-Beziehung (1)
- Wirt-Gast-Komplex-Chemie (1)
- Wirtschaftsprüfer (1)
- Wiskott-Aldrich syndrome (1)
- Witwatersrand Supergroup (1)
- Wohnungsbau (1)
- Work (1)
- Währungsunion (1)
- Wärmeleitung (1)
- Würde (1)
- Würzburg (1)
- X-Ray Chrystallography (1)
- XES (1)
- Yo‐Yo intermittent recovery (1)
- Zea mays (1)
- Zebrafish (1)
- Zellkultur (1)
- Zellskelett (1)
- Zirkulardichroismus Spektroskopie (1)
- ZnO (1)
- Zugangsnetz (1)
- Zytoskelett (1)
- [\(^{68}\)Ga] pentixafor (1)
- [\(^{68}\)Ga]Pentixafor (1)
- \(^{11}\)C-methionine (1)
- absorption (1)
- academic achievement (1)
- accelerometer (1)
- accuracy (1)
- action observation (1)
- active zone (1)
- acute (1)
- acute graft-versus-host disease (1)
- acute leukemia (AL) (1)
- acute myeloid leukaemia (1)
- acute slices (1)
- adaptation (1)
- adenocarcinoma of the lung (1)
- adenylyl cyclase signaling cascade (1)
- adhesion (1)
- adhesion GPCR (1)
- adhesion molecules (1)
- adipocytes (1)
- adrenal crisis (1)
- adrenal insufficiency (1)
- adrenal tumor (1)
- adrenocortical cancer (1)
- adsoption (1)
- adult-onset (1)
- aerobic fitness (1)
- aerobic glycolysis (1)
- agility (1)
- aging (1)
- agomelatine (1)
- agriculture (1)
- agroecology (1)
- airway remodeling (1)
- alcohol tolerance (1)
- altruism (1)
- alu elements (1)
- amenity migration (1)
- anaphylaxis (1)
- anaplasia (1)
- angle-resolved photoemission spectroscopy (1)
- anidulafungin (1)
- animal autobiography (1)
- animals (1)
- anorganic chemistry (1)
- anti-cancer-agent (1)
- anticipatory anxiety (1)
- antidepressant (1)
- antidepressants (1)
- antimicrobial resistance (1)
- antimicrobials (1)
- aorta (1)
- aortic valve replacement (1)
- aortic valve stenosis (AS) (1)
- apolipoprotein-E4 (1)
- arctic (1)
- arthritis (1)
- aryltricyanoborates (1)
- assistive technology (1)
- atherosclerosis (1)
- atomic and molecular spectroscopy, (1)
- atomic force microscopy (1)
- attitude determination (1)
- audit fees (1)
- auditor independence (1)
- auditory (1)
- auditory system (1)
- augmented reality (1)
- autism-like behavior (1)
- autoinflammation (1)
- autonomic nervous system (1)
- autotransporter (1)
- auxins (1)
- avoidance (1)
- awareness (1)
- bac-genomics-scripts (1)
- bacterial secretion (1)
- band structure (1)
- band structure methods (1)
- banksrevenue (1)
- bariatric surgery (1)
- bee (1)
- bees (1)
- behavior (1)
- behavioural ecology (1)
- benchmark (1)
- benzyl radical (1)
- beta oscillation (1)
- bi-temporal (1)
- bioactive (1)
- bioactive compound (1)
- biofeedback (1)
- biofilms (1)
- biogenic amines (1)
- biohybrid systems (1)
- bioinformatics (1)
- bioink (1)
- biological development (1)
- biological rapid deployment aortic valve (1)
- biomaterial tests (1)
- biomaterials (1)
- biomedical materials (1)
- bioprinting (1)
- blood platelets (1)
- blood-brain barrier (1)
- blood-brain barrier (BBB) model (1)
- body composition (1)
- bond activation (1)
- bone (1)
- bone ligament graft (1)
- bone marrow (1)
- bone marrow stromal cells (1)
- borderline personality disorder (1)
- boron-bound hydrogen (1)
- boron-centred nucleophile (1)
- brain computer interface (1)
- brain development (1)
- brain edema (1)
- brain-computer interface (1)
- branch point (1)
- brittle fragmentation (1)
- bronchopulmonary dysplasia (1)
- buildup phase (1)
- cAMP signaling (1)
- cadherin-13 (CDH13) (1)
- caffeine (1)
- calcification (1)
- calcium (1)
- calcium channel antagonists (1)
- calcium fluoride nanoparticles (1)
- caloric-restriction (1)
- cancer detection and diagnosis (1)
- capacity control (1)
- carben (1)
- carbene donor (1)
- cardiac (1)
- cardiac amyloidosis (1)
- cardiac dysfunction (1)
- cardiac rehabilitation (1)
- cardiogenic (1)
- cardiogenic shock (1)
- cardiomyocytes (1)
- cardiomyopathies (1)
- career choice (1)
- career construction (1)
- career development (1)
- cartilage (1)
- cartilage regeneration (1)
- cartographic requirements (1)
- cash crops (1)
- caspase-3 (1)
- caspofungin (1)
- catabolism (1)
- cavity device (1)
- cell binding (1)
- cell cultures (1)
- cell cycle (1)
- cell fusion (1)
- cell metabolism (1)
- cell phone conversation (1)
- cell proliferation (1)
- cell signalling (1)
- cell-autonomous defense (1)
- cells (1)
- cellular stress (1)
- central clocks (1)
- central complex (1)
- ceramic polymer composite (1)
- ceramide analogs (1)
- cerebral small vessel disease (1)
- change detection (1)
- change of direction (1)
- change‐of‐direction movement (1)
- characterization (1)
- charge carrier generation (1)
- charged hadron response (1)
- checkpoint inhibition (1)
- chemokine receptor (1)
- children (1)
- chinese tourists (1)
- cholera (1)
- cholesterol and oxy-cholesterol (1)
- cholinergic activity (1)
- cholinesterase (1)
- cholinesterase inhibitors (1)
- chondrogenesis (1)
- chorioamnionitis (1)
- chromatin remodeling (1)
- chromophore (1)
- chronic heart failure (1)
- chronic nonbacterial osteomyelitis (1)
- chronic pain (1)
- chronic recurrent multifocal osteomyelitis (1)
- chronobiology (1)
- circadian clock (1)
- circadian mechanisms (1)
- circadian rhythm (1)
- climate change (1)
- clinical applications (1)
- clinical genetics (1)
- clinical study (1)
- cloning (1)
- co-stimulation, (1)
- coaching (1)
- cognition (1)
- cognitive conflict (1)
- cognitive control (1)
- cognitive decline (1)
- cognitive impairment (1)
- cognitive processes (1)
- collagens (1)
- color psychology (1)
- colorectal cancer (CRC) (1)
- colorectal carcinoma (1)
- colour (1)
- comparison (1)
- complex disorders (1)
- compound conditioning (1)
- comprehensive management (1)
- conceptual metaphor theory (1)
- conflict adaptation (1)
- conflict experience (1)
- conflict strength (1)
- confocal laser scanning microscopy (1)
- confocal-microscopy based automated quantification (1)
- conservation laws (1)
- consistency (1)
- consumerism (1)
- consumption priming (1)
- contact lens (1)
- contextual anxiety (1)
- contextualist narratology (1)
- control (1)
- convolutional code (1)
- cooperative diversification (1)
- cord blood (1)
- coronary artery disease (1)
- correlates (1)
- costimulation (1)
- cotton (1)
- country-of-origin effect (1)
- coupled (1)
- coverage (1)
- cropping systems (1)
- cross-cultural study (1)
- cross-modal action (1)
- cross-priming (1)
- cross-sectional (1)
- crotonase (1)
- cryptic (1)
- cultural and literary animal studies (1)
- cuneiform (1)
- curative resection (1)
- cyclic (alkyl)(amino)carbene (1)
- cyclic dipeptide (1)
- cyclic nucleotides such as cyclic adenosine monophosphate (1)
- cysteine (1)
- cytokine secretion (1)
- cytokines (1)
- cytokinesis (1)
- cytosol (1)
- cytotoxic (1)
- cytotoxic effect (1)
- cytotoxicity (1)
- dCIRL (1)
- dRNA-seq (1)
- damped circadian clock (1)
- data fusion (1)
- decadal predictability (1)
- decay channels (1)
- decision-making (1)
- decomposition (1)
- deep brain stimulation (1)
- defensive system reactivity (1)
- deficiency (1)
- deformation quantization (1)
- deformed wing virus (1)
- dehydrogenase (1)
- deletion mutagenesis (1)
- delocalization (1)
- dementia (1)
- demographic change (1)
- dendritic spines (1)
- density functional theory (1)
- derivatives (1)
- desert ants (1)
- desk-based (1)
- detection (1)
- detector (1)
- deubiquitinase (1)
- developmental differentiation (1)
- diagnosis (1)
- diboraindanes (1)
- diborane (1)
- diboranes (1)
- dicalcium phosphate cement (1)
- diet (1)
- differential coverage binning (1)
- differential games (1)
- differential olfactory conditioning (1)
- differentiation (1)
- diffusion-weighted MRI (1)
- dimeric strychnine ligands (1)
- dimers (1)
- disfluency (1)
- dislocation (1)
- distinction (1)
- diurnal profile (1)
- division of labor (1)
- dobutamine stress echocardiography (1)
- domain knowledge (1)
- dorsal raphe (1)
- driving simulator (1)
- drug delivery (1)
- dual polarimetry (1)
- dual setting system (1)
- dual tasks (1)
- dual-response costs (1)
- dualsteric ligands (1)
- dunce (1)
- duodenal perforation (1)
- duodenal trauma (1)
- dynamical downscaling (1)
- dynamical mean field (1)
- eEF1A1 (1)
- echinocandin (1)
- echinocandins (1)
- eclosion (1)
- ecoli_VF_collection (1)
- ecosystem services (1)
- effective field theories (1)
- efficiency (1)
- effort (1)
- ejection fraction (1)
- electromagnon (1)
- electron donors (1)
- electronic coupling (1)
- electronic structure (1)
- electrostatics (1)
- elliptic problems (1)
- embryology (1)
- encephalitis (1)
- end-user evaluation (1)
- endocrinology (1)
- endophthalmitis (1)
- endophyte (1)
- endothelial cells (1)
- endurance (1)
- energy transfer (1)
- entero-aggregative-haemorrhagic Escherichia coli (EAHEC) (1)
- enzymes (1)
- epidermal growth factor (1)
- epigenetics in the nervous system (1)
- epigenomics (1)
- epithelial cells (1)
- epithelial-mesenchymal transition (1)
- equine autozoography (1)
- equivariant cohomology (1)
- eukaryota (1)
- euroaspire (1)
- event-related potential (ERP) (1)
- evolutionary optimization (1)
- evolutionary response (1)
- excitons (1)
- experimental archaeology (1)
- experimental models of disease (1)
- experimental physics (1)
- experimentelle autoimmune Enzephalomyelitis (1)
- explicit discontinuous Galerkin (1)
- extinction (1)
- extra corporeal membrane oxygenator (1)
- extracellular vesicles (EVs) (1)
- extracorporeal membrane oxygenation (1)
- eye movements (1)
- eye tracking (1)
- fMRI (1)
- face (1)
- facet joint degeneration (1)
- facet joint injection (1)
- factor H (1)
- factor XII (1)
- fat appetite (1)
- fatty degeneration (1)
- fear conditioning (1)
- fear of progression (1)
- feasibility (1)
- feedback (1)
- female (1)
- femtosecond pump-probe spectroscopy (1)
- femur (1)
- ferromagnetism (1)
- fetal cord blood (1)
- fetal programming (1)
- fibrinogen (1)
- fibroblast chemotaxis (1)
- fictional autobiography (1)
- fingolimod (1)
- finite differences (1)
- floral resource distribution (1)
- flotillin (1)
- flow cytometry (1)
- fluency (1)
- fluorescence resonance energy transfer (1)
- foamy virus (1)
- foamy viruses (1)
- focal brain lesion (1)
- follow-up (1)
- forager (1)
- foraging behaviour (1)
- foraging distances (1)
- foreign body reaction (1)
- fracture (1)
- fredholm operator (1)
- frequency combs (1)
- functional clustering (1)
- functional complementarity (1)
- functional magnetic resonance imaging (1)
- functional redundancy (1)
- functional training (1)
- fungal endophytes of grasses (1)
- fungal genetics (1)
- fungal physiology (1)
- fungal structure (1)
- future information (1)
- gambiense (1)
- gapless Andreev bound states (1)
- gastrointestinal tract (1)
- gauge-gravity correspondence (1)
- gaze (1)
- gaze patterns (1)
- gender differences (1)
- general transcription factor IIH (TFIIH) (1)
- generation effect (1)
- generative systems (1)
- genetic heterogeneity (1)
- genetic testing (1)
- genetically modified animals (1)
- genetically modified plants (1)
- genome collection (1)
- genome integrity (1)
- genome sequencing (1)
- genome-wide association study (GWAS) (1)
- genomic damage (1)
- genomic imprinting (1)
- genomic libraries (1)
- genomic sequence (1)
- genomics research (1)
- genotyping (1)
- gestational diabetes mellitus (1)
- glaucoma (1)
- glioblastoma multiforme (1)
- glucan synthase (1)
- glucocorticoids (1)
- glucose metabolism (1)
- glutaminase inhibition (1)
- glycine peptides (1)
- glycine receptor beta subunit (1)
- glycoprotein Ib (1)
- glycoprotein receptor Ib (1)
- glycosylation (1)
- gonococcal (1)
- gonococcal infection (1)
- gprotein (1)
- grass (1)
- growing season length (GSL) (1)
- growth cone (1)
- guideline implementation (1)
- gut microflora (1)
- habitat information (1)
- hadronic calorimeter (1)
- hadronic physics (1)
- halbnatürliche Habitate (1)
- half-metals (1)
- hangover (1)
- head and neck cancer (1)
- head and neck carcinoma (1)
- health monitoring (1)
- heart failure (1)
- heart valve prosthesis (1)
- heat currents (1)
- heavy fermion insulators (1)
- height-adjustable desk (1)
- helimagnets (1)
- hematopoietic stem cell transplantation (HSCT) (1)
- hematopoietic stem cells (1)
- hemodynamics (1)
- hepatic resection (1)
- herbivorous diet (1)
- herpes virus (1)
- heterogeneous compression (1)
- hexakisadducts (1)
- high energy neutrinos (1)
- high throughput (1)
- high-throughput screening (1)
- high-throughput sequencing (1)
- high-volume training (1)
- hippocampal formation (1)
- hippocampal volume (1)
- hippocampus (1)
- histones (1)
- homeostasis (1)
- honey bees (1)
- honeybees (1)
- hormone receptors (1)
- horse-science (1)
- hos tcells (1)
- hospital (1)
- human (1)
- human behaviour (1)
- human genetics (1)
- human induced pluripotent stem cells (hiPSCs)human induced pluripotent stem cells (hiPSCs) (1)
- human leukocyte antigen-E (HLA-E) (1)
- human-machine interaction (1)
- humanized mice (1)
- humanized tumor (1)
- hyaline cartilage (1)
- hybrid assembly (1)
- hydroarylation (1)
- hydrocortisone (1)
- hydrogen bonding (1)
- hymenoptera (1)
- hypercholesterolemia (1)
- hyperglycemia (1)
- hypoplasia of fatty tissue (1)
- identification (1)
- identified particle response (1)
- image analysis (1)
- imaging (1)
- imaging the immune system (1)
- immune cells (1)
- immune regulation (1)
- immune response (1)
- immunity (1)
- immunoblotting (1)
- immunoglobin-A (1)
- immunohistochemistry (1)
- immunology and microbiology section (1)
- impella 5.0 (1)
- implant (1)
- implantable neurostimulators (1)
- implants (1)
- indigo (1)
- indoor navigation (1)
- inducible deletion (1)
- inelastic neutron scattering (1)
- infectious diseases (1)
- infectious-disease diagnostics (1)
- influence of temperature (1)
- infrared radiation (1)
- infrared spectroscopy (1)
- ingestible sensor (1)
- inguinal lymph node dissection (1)
- inhibitors (1)
- innate immune response (1)
- innate immunity (1)
- insect (1)
- insect visual learning (1)
- insertion (1)
- insula (1)
- insulin (1)
- insulin treatment (1)
- integer linear programming (1)
- intelligence (1)
- intercellular adhesion (1)
- interface energetics (1)
- interleukin 1 receptor antagonist (1)
- intermediate phenotype approach (1)
- intermuscular bone (1)
- interval training (1)
- intrauterine growth (1)
- intravenous ceftriaxone (1)
- intravitreal vancomycin and amikacin (1)
- intrinsic reflexivity (1)
- invasion (1)
- inverse seesaw (1)
- ion channels in the nervous system (1)
- ion-specific effects (1)
- ionenspezifische Effekte (1)
- ionic liquids (1)
- iron (1)
- irrigation (1)
- isoproterenol (1)
- judgments (1)
- jump-diffusion processes (1)
- just noticeable difference (JND) (1)
- juvenile idiopathic arthritis (1)
- kinases (1)
- kinesin (1)
- l-type calcium channel antagonist (1)
- laboratory techniques and procedures (1)
- lactase persistence (1)
- lactoferricin B (1)
- lactose (1)
- land surface phenology (1)
- landscape ecology (1)
- landscape structure (1)
- laser physics (1)
- laser spectroscopy (1)
- latent change (1)
- lead structure (1)
- learning outcome (1)
- learning with expository texts (1)
- leaves (1)
- leukemia (1)
- levodopa-induced dyskinesia (1)
- life writing (1)
- light pulses (1)
- linalool (1)
- linalyl acetate (1)
- linear system (1)
- lipid remodeling (1)
- lipids (1)
- listeriolysin O (1)
- literature (1)
- liver metastasis (1)
- liver resection (1)
- livin (1)
- long-term memory formation (1)
- long-term monitoring (1)
- long-term patency (1)
- look-back behavior (1)
- lovastatin (1)
- low-gradient AS (1)
- low-temperature magnetotransport (1)
- lower body (1)
- lumbar degenerative disease (1)
- lumbar spinal stenosis (1)
- lung resection (1)
- luxury market (1)
- lymph nodes (1)
- lymphocyte activation (1)
- mIBG (1)
- mTOR-inhibitor RAD-001 (1)
- magnetic properties and materials (1)
- magnetic resonance imaging (1)
- magnetic resonance imaging (MRI) (1)
- magnetometer (1)
- malignant melanoma (1)
- map labeling (1)
- marine natural products (1)
- maritime pine bark extract (1)
- markers (1)
- mass spectrometry (1)
- mastitis-associated Escherichia coli (MAEC) (1)
- materials for optics (1)
- mating success (1)
- mature cell-cell contacts (1)
- mayo stem (1)
- measles (1)
- measurement invariance (1)
- mechanical reinforcement (1)
- mechanical shock (1)
- mechanobiology (1)
- mechanosensing (1)
- media design (1)
- medical dialysis (1)
- megakaryocyte (1)
- melatonin (1)
- membrane receptor signaling (1)
- memory bias (1)
- meningitis (1)
- mental health (1)
- meristems (1)
- mesenchymal stem cell (1)
- meta-autobiography (1)
- metabotropic signalling (1)
- metacognition (1)
- metacomprehension (1)
- metaproteomics (1)
- metatranscriptomics (1)
- miRNAs (1)
- micafungin (1)
- microRNA–target interaction (1)
- microalga-bacteria interaction (1)
- microbial rhodopsin (1)
- microbiome (1)
- microenvironment (1)
- microglia (1)
- microresonators (1)
- microsoft band 2 (1)
- microswimmer (1)
- migration (1)
- mineralocorticoid antagonist (1)
- minimal invasive surgery (1)
- minimal supersymmetric standard model (MSSM) (1)
- minimally invasive surgery (1)
- mitochondria (1)
- mitotic gene expression (1)
- mode matching (1)
- modelling (1)
- modulation spectroscopy (1)
- molecular imaging (1)
- molecular modelling (1)
- molecular neuroscience (1)
- molting (1)
- monocyte (1)
- monocyte differentiation (1)
- monsoon rainfall (1)
- mood states (1)
- morphometry (1)
- motoneuron disease (1)
- motor axon (1)
- motor cortex (1)
- motor simulation (1)
- motorcycle simulator (1)
- mouse brain microvascular endothelial cell cultur (1)
- multi-leaf collimator (1)
- multi-sensor (1)
- multiferroics (1)
- multifunctional nanoparticles (1)
- multigrid schemes (1)
- multimedia learning (1)
- multimodal imaging (1)
- multiple-level replantation (1)
- multipotent fetal neural stem cells (fNSCs) (1)
- murine model (1)
- muscarinic acetylcholine receptor (1)
- muscle oxygen saturation (1)
- mushroom body (1)
- mushroom body calyx microglomeruli (1)
- musical syntax (1)
- myeloid (1)
- myocarditis (1)
- nano optics (1)
- nanocavities (1)
- nanoparticles (1)
- nanoscience and technology (1)
- naphthylisoquinoline alkaloid (1)
- national parks (1)
- natural approach (1)
- natural history (1)
- natural killer cells (1)
- near-gap spectra (1)
- necrotic cell death (1)
- neisseria meningitidis (1)
- neonatal morbidity (1)
- nephroblastoma (1)
- nesting habit (1)
- networks (1)
- neural fear network activation (1)
- neuroanatomy (1)
- neurodegeneration (1)
- neurodevelopment (1)
- neuroendocrine tumor (1)
- neurological disorders (1)
- neuronal activation (1)
- neuronal development (1)
- neuropeptide pathway (1)
- neurophysiology (1)
- neuroprotection (1)
- neuropsychiatric disorders (1)
- neurotrophic factors (1)
- neurovascular unit in vitro (1)
- neutral sphingomyelinase (1)
- neutrino (1)
- neutrino emission (1)
- neutrino flux (1)
- neutrino telescope (1)
- next-generation sequencing (1)
- next-to-leading-order electroweak corrections (1)
- nickel (1)
- none (1)
- novelty processing (1)
- nucleophilic addition (1)
- nucleophilic substitution (1)
- numerical analysis (1)
- numerical methods (1)
- nurse bee (1)
- nutrition (1)
- nutritional ecology (1)
- observation inflation (1)
- occlusion (1)
- occupational sitting and physical activity questionnaire (1)
- octopamine (1)
- ocular infection (1)
- oculomotor control (1)
- office-workers (1)
- older poor readers (1)
- oligopeptides (1)
- oncostatin M (1)
- open-shell molecules (1)
- opioid peptides (1)
- opioid receptors (1)
- optical antennas (1)
- optical spectroscopy (1)
- optics (1)
- optics and photonics (1)
- optimal control problems (1)
- optogenetics (1)
- oral anticancer drugs (1)
- oral cefpodoxime (1)
- oral doxycycline (1)
- organic interfaces (1)
- organic solar cell (1)
- organische Grenzflächen (1)
- orientation (1)
- origin of life (1)
- oscillator strengths (1)
- osteocytes (1)
- osteopontin (1)
- outdoor recreation (1)
- ovarian cancer (1)
- overconfidence (1)
- oxaliplatin (1)
- oxidation (1)
- oxidative stress (1)
- oxygen tension (1)
- oxygenation (1)
- oxytocin (1)
- pH-regulated antigen 1 (Pra1) (1)
- pICln (1)
- paediatric research (1)
- pain (1)
- pain behavior (1)
- paradoxical effect (1)
- paradoxical growth (1)
- parasitic cell cycles (1)
- parasitic diseases (1)
- parasomn (1)
- particle physics (1)
- patch-clamp (1)
- patella (1)
- pathogenic bacteria (1)
- pathogens (1)
- pathotypes (1)
- patient education (1)
- patients’ awareness (1)
- pattern recognition receptors (1)
- patterning (1)
- pedestrian motion (1)
- pellet culture (1)
- people with dementia (1)
- peptide receptor radionuclide therapy (1)
- peptide sensors (1)
- perceived external financial reporting quality (1)
- perception (1)
- performance (1)
- performance monitoring (1)
- peri-implant disease (1)
- periodization (1)
- perioperative changes (1)
- peripheral clocks (1)
- permease (1)
- pharmacotherapy (1)
- phase contrast (1)
- phasic threat responding (1)
- phenomenological models (1)
- phosphorylation (1)
- photoluminescence (1)
- photoluminescence excitation (1)
- photonic devices (1)
- photoreceptors (1)
- phycosphere biofilm (1)
- phylogeny (1)
- physicians’ awareness (1)
- physiological (1)
- phytic acid (1)
- pine bark extract (1)
- planar heterojunction (1)
- planning study (1)
- plant defense (1)
- plant extract (1)
- plant growth and development (1)
- plant-insect interactions (1)
- plantation (1)
- plant–insect interactions (1)
- plasma oxysterols (1)
- plasmonics (1)
- plasmons (1)
- plasticity (1)
- platelet aggregation (1)
- platelets (1)
- pleural mesothelioma (1)
- poetics of knowledge (1)
- point mutation (1)
- point-feature label placement (1)
- point-of-care echocardiography (1)
- polaritons (1)
- polarization (1)
- pollination (1)
- pollinator decline (1)
- polycyclic aromatic hydrocarbons (1)
- polyglandular autoimmune syndrome (1)
- polymerase chain reaction (1)
- polymers (1)
- polyphenols (1)
- population (1)
- population structure (1)
- population-based study (1)
- porous materials (1)
- positron emission tomography imaging (1)
- postoperativ (1)
- posttranscriptional gene regulation (1)
- power training (1)
- practical electrodes (1)
- prediction (1)
- prefrontal cortex (1)
- pregnancy anxiety (1)
- premix (1)
- prenatal stress (1)
- presence (1)
- preserved ejection fraction (1)
- prevalence (1)
- primary care (1)
- primary prevention (1)
- primary school (1)
- proGenomes (1)
- proboscis extension reflex (1)
- product qualitymodulation (1)
- profitability (1)
- prognosis (1)
- prokaryotic clade (1)
- prokaryotic subspecies (1)
- proliferation (1)
- proskynesis (1)
- prosocial behavior (1)
- prosocial tendency measure (1)
- protein design (1)
- protein immobilization (1)
- protein structure (1)
- proteininteraction (1)
- protein–protein interaction (1)
- proteomes (1)
- proton pump (1)
- pseudo-severe AS (1)
- psychiatric disorders (1)
- psychophysics (1)
- psychosocial workplace risk assessment (1)
- pulley rupture (1)
- pulse wave velocity (1)
- pulsed ODMR (1)
- purine-rich element (1)
- qPCR (1)
- quad polarimetry (1)
- quality indicators (1)
- quality of health care (1)
- quality of life (1)
- quanititative characterization (1)
- quantum dot (1)
- quantum dots (1)
- quantum information (1)
- quantum mechanical coupling (1)
- quantum metrology (1)
- quantum sensing (1)
- quantum well (1)
- quartic gauge couplings (QGCs) (1)
- quasi-one-dimensional organic metals (1)
- queueing (1)
- radial glia (1)
- radii (1)
- radionuclide therapy (1)
- radiotherapy (1)
- random forest (1)
- randomized controlled study (1)
- re-irradiation (1)
- re-planning (1)
- reach-to-grasp movement (1)
- reactivating p53 and inducing tumor apoptosis (RITA) (1)
- reading comprehension (1)
- receptor (1)
- receptor pharmacology (1)
- receptors (1)
- reconstruction (1)
- recovery (1)
- recruitment (1)
- refeeding syndrome (1)
- reflexive component (1)
- regeneration (1)
- regional development (1)
- regional recurrence (1)
- regulatory T cell (1)
- regulatory circuit downstream (1)
- relA (1)
- remyelination (1)
- renal dysfunction (1)
- repeated sprint ability (1)
- replication (1)
- reproductive asynchrony (1)
- rescue behavior (1)
- resin (1)
- resistance mechanism (1)
- resolvin (1)
- resveratrol (1)
- retinal development (1)
- retrospective study (1)
- rheology (1)
- rhythm perception (1)
- ribosome profiling (1)
- ring expansion (1)
- risk (1)
- risk factor (1)
- risk factor control (1)
- robotic table motion (1)
- root growth (1)
- rotator cuff (1)
- rule violations (1)
- sacbrood virus (1)
- samarium hexaboride (1)
- scaffold protein (1)
- scanning electron microscopy (1)
- screening for distress (1)
- season (1)
- secondary brain damage (1)
- sedentary behavior (1)
- self (1)
- self-management (1)
- semi-natural habitat (1)
- semiconductor quantum dot (1)
- sensor assessment (1)
- sensory chewing gums (1)
- sensory physiology (1)
- sept3 (1)
- sept5a (1)
- sept5b (1)
- septic (1)
- septin (1)
- sequence alignment (1)
- sequence assembly tools (1)
- serum (1)
- sesame (1)
- sex-specific mortality (1)
- sexual dimorphism in timing (1)
- shape (1)
- shock (1)
- shorelines (1)
- short hip stem (1)
- short-term memory (1)
- shoulder surgery (1)
- signal transduction (1)
- silicon photo multiplier (1)
- silicon vacancy (1)
- silylenes (1)
- single nucleotide polymorphisms (1)
- single-cell genomics (1)
- single-electron transistor (1)
- single-electron tunneling (1)
- site-specific immobilization (1)
- sitting time (1)
- skin conductance response (SCR) (1)
- sky-compass pathway (1)
- slash-and-burn (1)
- sleep-related eating (1)
- sleeping sickness (1)
- small HOMO-LUMO gap (1)
- smell (1)
- smells (1)
- social cognition (1)
- social immunity (1)
- social stimuli (1)
- sodium/glucose cotransporters (SGLT) (1)
- solar cell (1)
- solitons (1)
- spatial behaviour (1)
- specimen storage (1)
- spectroscopic analysis (1)
- spectroscopy (1)
- speed (1)
- speed perception (1)
- sperm (1)
- sphingolipids (1)
- spider (1)
- spidroin (1)
- spin (1)
- spin waves (1)
- spin-orbit-coupling (1)
- spin-phonon coupling (1)
- spindiffusion (1)
- spintronics (1)
- splice regulation (1)
- sponge microbiome (1)
- sponges (1)
- sports (1)
- standard seesaw (1)
- staphilococci (1)
- stem cells (1)
- stereochemistry (1)
- stereotactic irradiation (1)
- stereotypes (1)
- streptomyces (1)
- stress (1)
- stringent response (1)
- stroke register (1)
- stroke unit (1)
- stroke unit care (1)
- strong coupling (1)
- structural analysis (1)
- structural biology (1)
- structure-activity (1)
- strychnine (1)
- subcutaneous human tumors (1)
- substrate channeling (1)
- subthalamic nucleus (1)
- sucrose (1)
- sulfates (1)
- sulfides (1)
- sulfites (1)
- sulfur (1)
- super-resolution microscopy (1)
- supersymmetric model (1)
- supersymmetry (SUSY) (1)
- surface collisions (1)
- surface stress (1)
- surfactants (1)
- surgery (1)
- surgical oncology (1)
- surgical resection (1)
- surgical site infection (1)
- surveillance (1)
- survival (1)
- survival analysis (1)
- sustained attention (1)
- sustained threat responding (1)
- swimming (1)
- syllable-based intervention (1)
- sympathetic nerve (1)
- symplectic geometry (1)
- synaptic transmission (1)
- synaptic vesicle tethering (1)
- synaptic vesicles (1)
- synovial fluid (1)
- synovitis (1)
- synthesis (1)
- synthetic methods (1)
- synthetic peptides (1)
- systems biology (1)
- systolic dysfunction (1)
- task rules (1)
- taxonomic description (1)
- technology (1)
- telomere-binding protein (1)
- temperate Europe (1)
- tetracyclines (1)
- tetraparesis (1)
- therapeutic gases (1)
- therapeutic strategy (1)
- thermal devices (1)
- thermodynamics (1)
- thermoelectric generator (1)
- thermotolerance (1)
- thiosulfates (1)
- throat (1)
- thrombo-inflammation (1)
- thrombopoiesis (1)
- time perception (1)
- time-resolved photoelectron spectroscopy (1)
- time-resolved photoluminescence (1)
- time-resolved spectroscopy (1)
- tinnitus (1)
- tissue regeneration (1)
- tissue remodeling (1)
- tongue (1)
- topic ofloxacin (1)
- topological insulators (1)
- topological magnetoelectric effect (1)
- topological materials (1)
- topological matter (1)
- total hip arthroplasty (1)
- toxicity (1)
- toxicology (1)
- toxins (1)
- training evaluation (1)
- training intensity distribution (1)
- training optimization (1)
- trans-Golgi network (1)
- transcriptional control (1)
- transient middle cerebral artery (1)
- transient middle cerebral artery occlusion (1)
- transient receptor potential channels (1)
- transition metal complex (1)
- transition metals (1)
- translational regulation (1)
- transstomal endoluminal vacuum therapy (1)
- travel experience (1)
- treg cells (1)
- trend analysis (1)
- triboson production (1)
- triple gauge couplings (TGCs) (1)
- trkB (1)
- tsetse fly (1)
- tumor angiogenesis (1)
- tumor immunology (1)
- tumor vaccination (1)
- tumor vascular morphologie (1)
- tumour heterogeneity (1)
- tundra (1)
- twin study (1)
- type VII secretion system (1)
- ultrasound (1)
- user experience (1)
- user interface design (1)
- user interfaces (1)
- vaccination (1)
- vaccinia virus (1)
- vagus nerve stimulation (1)
- valence (1)
- valleytronics (1)
- vandetanib (1)
- variability (1)
- varicella (1)
- variocosities (1)
- vascular surgery (1)
- vector navigation (1)
- vector-boson scattering (1)
- vegetarians (1)
- verbal fluency task (1)
- very high energy gamma rays (1)
- vespula (1)
- vibration testing (1)
- vicinal surfaces (1)
- video recording (1)
- vigilance (1)
- virtual isocentre (1)
- virtual reality (1)
- virulence factors (1)
- virulenceregulatory evolution (1)
- virus vectors (1)
- visual (1)
- visual attention (1)
- visual orientation (1)
- visual saliency (1)
- visuelles Langzeitgedächtnis (1)
- vitamin D (1)
- vitrectomy (1)
- vocational interests (1)
- wall shear stress (1)
- water microbiology (1)
- waveguides (1)
- wearable (1)
- wearable sensors (1)
- weight loss (1)
- whole genome (1)
- word reading fluency (1)
- work-related stress (1)
- worker mobility (1)
- working memory (1)
- worship (1)
- wässrige Lösung (1)
- x-ray crystallography (1)
- zinc oxide (1)
- zinc oxide nanoparticles (1)
- zinc-finger (1)
- zoology (1)
- α-synuclein (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (74)
- Physikalisches Institut (41)
- Graduate School of Life Sciences (31)
- Institut für Psychologie (24)
- Institut für Theoretische Physik und Astrophysik (24)
- Fakultät für Physik und Astronomie (20)
- Medizinische Klinik und Poliklinik I (19)
- Rudolf-Virchow-Zentrum (19)
- Neurologische Klinik und Poliklinik (18)
- Institut für Molekulare Infektionsbiologie (17)
Schriftenreihe
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine, Baltimore, MD, U.S. (4)
- Institut für Optik und Atomare Physik, Technische Universität Berlin, 10623 Berlin, Germany (2)
- Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan (2)
- CERN (Geneva, Switzerland) (1)
- Fraunhofer-Institut für Silicatforschung ISC (1)
- GEOMAR Helmholtz-Zentrum für Ozeanforschung Kiel (1)
- Hospital Augsburg, Augsburg, Germany (1)
- Institute for Sustainable Chemistry & Catalysis with Boron (1)
- Johns Hopkins University School of Medicine, Baltimore, MD, U.S. (1)
- Johns Hopkis School of Medicine (1)
ResearcherID
- M-1240-2017 (1)
The mechanism of excimer formation: an experimental and theoretical study on the pyrene dimer
(2017)
The understanding of excimer formation in organic materials is of fundamental importance, since excimers profoundly influence their functional performance in applications such as light-harvesting, photovoltaics or organic electronics. We present a joint experimental and theoretical study of the ultrafast dynamics of excimer formation in the pyrene dimer in a supersonic jet, which is the archetype of an excimer forming system. We perform simulations of the nonadiabatic photodynamics in the frame of TDDFT that reveal two distinct excimer formation pathways in the gas-phase dimer. The first pathway involves local excited state relaxation close to the initial Franck–Condon geometry that is characterized by a strong excitation of the stacking coordinate exhibiting damped oscillations with a period of 350 fs that persist for several picoseconds. The second excimer forming pathway involves large amplitude oscillations along the parallel shift coordinate with a period of ≈900 fs that after intramolecular vibrational energy redistribution leads to the formation of a perfectly stacked dimer. The electronic relaxation within the excitonic manifold is mediated by the presence of intermolecular conical intersections formed between fully delocalized excitonic states. Such conical intersections may generally arise in stacked π-conjugated aggregates due to the interplay between the long-range and short-range electronic coupling. The simulations are supported by picosecond photoionization experiments in a supersonic jet that provide a time-constant for the excimer formation of around 6–7 ps, in good agreement with theory. Finally, in order to explore how the crystal environment influences the excimer formation dynamics we perform large scale QM/MM nonadiabatic dynamics simulations on a pyrene crystal in the framework of the long-range corrected tight-binding TDDFT. In contrast to the isolated dimer, the excimer formation in the crystal follows a single reaction pathway in which the initially excited parallel slip motion is strongly damped by the interaction with the surrounding molecules leading to the slow excimer stabilization on a picosecond time scale.
Background:
To prevent bone loss in hip arthroplasty, several short stem systems have been developed, including the Mayo conservative hip system. While there is a plethora of data confirming inherent advantages of these systems, only little is known about potential complications, especially when surgeons start to use these systems.
Methods:
In this study, we present a retrospective analysis of the patients’ outcome, complications and the complication management of the first 41 Mayo conservative hips performed in 37 patients. For this reason, functional scores, radiographic analyses, peri- and postoperative complications were assessed at an average follow-up of 35 months.
Results:
The overall HHS improved from 61.2 pre-operatively to 85.6 post-operatively. The German Extra Short Musculoskeletal Function Assessment Questionnaire (XSFMA-D) improved from 30.3 pre-operatively to 12.2 post-operatively. The most common complication was an intraoperative non-displaced fracture of the proximal femur observed in 5 cases (12.1%). Diabetes, higher BMI and older ages were shown to be risk factors for these intra-operative periprosthetic fractures (p < 0.01). Radiographic analysis revealed a good offset reconstruction in all cases.
Conclusion:
In our series, a high complication rate with 12.1% of non-displaced proximal femoral fractures was observed using the Mayo conservative hip. This may be attributed to the flat learning curve of the system or the inherent patient characteristics of the presented cohort."
The issue of quantum mechanical coupling between a semiconductor quantum dot and a quantum well is studied in two families of GaAs- and InP- based structures at cryogenic temperatures. It is shown that by tuning the quantum well parameters one can strongly disturb the 0D-character of the coupled system ground state, initially located in a dot. The out-coupling of either an electron or a hole state from the quantum dot confining potential is viewed by a significant elongation of the photoluminescence decay time constant. Band structure calculations show that in the GaAs-based coupled system at its ground state a hole remains isolated in the dot, whereas an electron gets delocalized towards the quantum well. The opposite picture is built for the ground state of a coupled system based on InP.
The general transcription factor IIH (TFIIH) is a multi-protein complex and its 10 subunits are engaged in an intricate protein–protein interaction network critical for the regulation of its transcription and DNA repair activities that are so far little understood on a molecular level. In this study, we focused on the p44 and the p34 subunits, which are central for the structural integrity of core-TFIIH. We solved crystal structures of a complex formed by the p34 N-terminal vWA and p44 C-terminal zinc binding domains from Chaetomium thermophilum and from Homo sapiens. Intriguingly, our functional analyses clearly revealed the presence of a second interface located in the C-terminal zinc binding region of p34, which can rescue a disrupted interaction between the p34 vWA and the p44 RING domain. In addition, we demonstrate that the C-terminal zinc binding domain of p34 assumes a central role with respect to the stability and function of TFIIH. Our data reveal a redundant interaction network within core-TFIIH, which may serve to minimize the susceptibility to mutational impairment. This provides first insights why so far no mutations in the p34 or p44 TFIIH-core subunits have been identified that would lead to the hallmark nucleotide excision repair syndromes xeroderma pigmentosum or trichothiodystrophy.
Background:
According to only a handful of historical sources, Osmunda regalis, the royal fern, has been used already in the middle age as an anti-cancer remedy. To examine this ancient cancer cure, an ethanolic extract of the roots was prepared and analysed in vitro on its effectiveness against head and neck cancer cell lines.
Methods:
Proliferation inhibition was measured with the MTT assay. Invasion inhibition was tested in a spheroid-based 3-D migration assay on different extracellular matrix surfaces. Corresponding changes in gene expression were analysed by qRT-PCR array. Induction of apoptosis was measured by fluorescence activated cell sorting (FACS) with the Annexin V binding method. The plant extract was analysed by preliminary phytochemical tests, liquid chromatography/mass spectroscopy (LC-MS) and thin layer chromatography (TLC). Anti-angiogenetic activity was determined by the tube formation assay.
Results:
O. regalis extract revealed a growth inhibiting effect on the head and neck carcinoma cell lines HLaC78 and FaDu. The toxic effect seems to be partially modulated by p-glycoprotein, as the MDR-1 expressing HLaC79-Tax cells were less sensitive. O. regalis extract inhibited the invasion of cell lines on diverse extracellular matrix substrates significantly. Especially the dispersion of the highly motile cell line HlaC78 on laminin was almost completely abrogated. Motility inhibition on laminin was accompanied by differential gene regulation of a variety of genes involved in cell adhesion and metastasis. Furthermore, O. regalis extract triggered apoptosis in HNSCC cell lines and inhibited tube formation of endothelial cells. Preliminary phytochemical analysis proved the presence of tannins, glycosides, steroids and saponins. Liquid chromatography/mass spectroscopy (LC-MS) revealed a major peak of an unknown substance with a molecular mass of 864.15 Da, comprising about 50% of the total extract. Thin layer chromatography identified ferulic acid to be present in the extract.
Conclusion:
The presented results justify the use of royal fern extracts as an anti-cancer remedy in history and imply a further analysis of ingredients.
Background
40–50% of patients with colorectal cancer (CRC) will develop liver metastases (CRLM) during the course of the disease. One third of these patients will additionally develop pulmonary metastases.
Methods
137 consecutive patients with CRLM, were analyzed regarding survival data, clinical, histological data and treatment. Results were stratified according to the occurrence of pulmonary metastases and metastases resection.
Results
39% of all patients with liver resection due to CRLM developed additional lung metastases. 44% of these patients underwent subsequent pulmonary resection. Patients undergoing pulmonary metastasectomy showed a significantly better five-year survival compared to patients not qualified for curative resection (5-year survival 71.2% vs. 28.0%; p = 0.001). Interestingly, the 5-year survival of these patients was even superior to all patients with CRLM, who did not develop pulmonary metastases (77.5% vs. 63.5%; p = 0.015). Patients, whose pulmonary metastases were not resected, were more likely to redevelop liver metastases (50.0% vs 78.6%; p = 0.034). However, the rate of distant metastases did not differ between both groups (54.5 vs.53.6; p = 0.945).
Conclusion
The occurrence of colorectal lung metastases after curative liver resection does not impact patient survival if pulmonary metastasectomy is feasible. Those patients clearly benefit from repeated resections of the liver and the lung metastases.
The CCHC-type zinc finger nucleic acid-binding protein (CNBP/ZNF9) is conserved in eukaryotes and is essential for embryonic development in mammals. It has been implicated in transcriptional, as well as post-transcriptional, gene regulation; however, its nucleic acid ligands and molecular function remain elusive. Here, we use multiple systems-wide approaches to identify CNBP targets and function. We used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) to identify 8,420 CNBP binding sites on 4,178 mRNAs. CNBP preferentially bound G-rich elements in the target mRNA coding sequences, most of which were previously found to form G-quadruplex and other stable structures in vitro. Functional analyses, including RNA sequencing, ribosome profiling, and quantitative mass spectrometry, revealed that CNBP binding did not influence target mRNA abundance but rather increased their translational efficiency. Considering that CNBP binding prevented G-quadruplex structure formation in vitro, we hypothesize that CNBP is supporting translation by resolving stable structures on mRNAs.
The genetic information encoded with in the genes are transcribed and translated to give rise to
the functional proteins, which are building block of a cell. At first, it was thought that the
regulation of gene expression particularly occurs at the level of transcription by various
transcription factors. Recent discoveries have shown the vital role of gene regulation at the level
of RNA also known as post-transcriptional gene regulation (PTGR). Apart from non-coding RNAs
e.g. micro RNAs, various RNA binding proteins (RBPs) play essential role in PTGR. RBPs have
been implicated in different stages of mRNA life cycle ranging from splicing, processing,
transport, localization and decay. In last 20 years studies have shown the presence of hundreds
of RBPs across eukaryotic systems many of which are widely conserved. Given the rising number
of RBPs and their link to human diseases it is quite evident that RBPs have major role in cellular
processes and their regulation. The current study is aimed to describe the so far unknown
molecular mechanism of CCHC-type Zinc Finger Nucleic Acid Binding Protein (CNBP/ZNF9)
function in vivo.
CNBP is ubiquitously expressed across various human tissues and is a highly conserved RBP in
eukaryotes. It is required for embryonic development in mammals and has been implicated in
transcriptional as well as post-transcriptional gene regulation; however, its molecular function
and direct target genes remain elusive. Here, we use multiple systems-wide approaches to
identify CNBP targets and document the consequences of CNBP binding. We established CNBP as
a cytoplasmic RNA-binding-protein and used Photoactivatable Ribonucleoside Enhanced
Crosslinking and Immunoprecipitation (PAR-CLIP) to identify direct interactions of CNBP with
4178 mRNAs. CNBP preferentially bound a G-rich motif in the target mRNA coding sequences.
Functional analyses, including ribosome profiling, RNA sequencing, and luciferase assays
revealed the CNBP mode of action on target transcripts. CNBP binding was found to increase the
translational efficiency of its target genes. We hypothesize that this is consistent with an RNA
chaperone function of CNBP helping to resolve secondary structures, thus promoting
translation. Altogether this study provides a novel mechanism of CNBP function in vivo and acts
as a step-stone to study the individual CNBP targets that will bring us closer to understand the
disease onset.
A successful therapy for colorectal cancer (CRC), one of the most common malignancies worldwide, requires the greatest possible research effort. Of critical importance is an understanding of the relevant intracellular networks of signaling cascades, their activation, and the resulting cellular changes that are a prerequisite for a more successful CRC therapy. Vascular endothelial growth factor (VEGF) and the appropriate VEGF receptors represent molecular targets that have already been successfully implemented in the clinic (i.e. using monoclonal antibodies, tyrosine kinase inhibitors). However, for platelet derived growth factor (PDGF) and the relevant PDGF receptors, there are currently no clinically approved molecular therapeutics available. However, there are preliminary data to show that PDGF and its associated signaling pathways play an important role in CRC progression. In particular, the PI3K/Akt/mTOR pathway is emerging as an important intracellular partner of PDGF with which to control proliferation, migration, and angiogenesis in tumor cells.
Therefore it was the objective of this work to investigate the multifactorial influence of PDGF on proliferation and metabolism, depending on CRC mutation status. The intention was to identify new therapeutic targets for future cancer therapy through analyses of PDGF-induced intracellular changes.
For this purpose two human colorectal cancer cell lines were analyzed at gene and/or protein level for components of the PI3K/Akt/mTOR and MAPK signaling pathway, c-Myc, p53, and HIF1α (hypoxia-inducible-factor 1α). Changes in proliferation and metabolism, either during stimulation with PDGF and/or PI3K/Akt/mTOR inhibition, were also investigated. Experiments conducted at protein level during PDGF stimulation and/or PI3K/Akt/mTOR inhibition revealed changes in signaling pathways and crosstalk. The influence of the tumor suppressors (retinoblastoma, Rb), oncogenes (c-Myc, p53mut), and HIF1α during stimulation with PDGF, and their interactions in the tumor cell with respect to proliferation and glycolysis warrant further examination in terms of clinical treatment options. Investigations at the gene level of ex vivo samples (UICC I-IV) complete the study with regards to the clinical relevance of PDGF.
PDGF stimulation increases tumor cell proliferation in HT29 cells via the PI3K/Akt/mTOR pathway rather than the MAPK pathway. However, if the PI3K/Akt/mTOR pathway is pharmacologically blocked, PDGF stimulation is mediated by inhibitory crosstalk through the MAPK pathway. Further analyses revealed that specific Akt inhibition impedes tumor cell growth, while PI3K inhibition had little effect on proliferation. Inhibitory crosstalk was found to be responsible for these different effects. Careful intervention strategies are therefore required if future therapies intend to make use of these specific signaling pathways. One aim of future research should be to gain a better understanding of the crosstalk between these signaling pathways. In this fashion, “over-inhibition” of the signal pathways, which would result in additional clinical side effects for patients, could be prevented.
In late stage UICC, more mutation events occur, with tumorigenicity promoted by an increased mutation rate. Given that PDGF is increasingly expressed in the late UICC stages, our data would indicate that PDGF's effects are amplified with increasing malignancy. The activating effect of PDGF on the PI3K/Akt/mTOR pathway and subsequent changes in the activity of p53mut, Rb, c-Myc, and HIF1α, lead to an unfavorable prognosis for colon cancer patients. PDGF acts on colon cancer cells in an Akt-activating, glycolysis-dependent manner. PDGF increases glycolysis and the ability of CRC cells to adjust their energy metabolism. These activities should be taken as possible starting points with which to design therapeutic interventions for CRC therapy.
PDGF, as another representative of the growth factor family, seems to play a similar role to VEGF in CRC. The data from this study underline the importance of the PDGF - PI3K/Akt/mTOR pathway-axis and its potential as a possible target in colorectal cancer. Thus PDGF represents an attractive therapeutic target, besides the VEGF/EGFR-based therapies already used in CRC.
Describing the light-to-energy conversion in OSCs requires a multiscale understanding of the involved optoelectronic processes, i.e., an understanding from the molecular, intermolecular, and aggregate perspective. This thesis presents such a multiscale description to provide insight into the processes in the vicinity of the organic::organic interface, which are crucial for the overall performance of OSCs. Light absorption, exciton diffusion, photoinduced charge transfer at the donor-acceptor interface, and charge separation are included. In order to establish structure-property relationships, a variety of different molecular p-type semiconductors are combined at the organic donor-acceptor heterojunction with fullerene C60, one of the most common acceptors in OSCs. Starting with a comprehensive analysis of the accuracy of diverse ab initio, DFT, and semiempiric methods for the properties of the individual molecules, the intermolecular, and aggregate/device stage are subsequently addressed. At all stages, both methodological concepts and physical aspects in OSCs are discussed to extend the microscopic understanding of the charge generation processes.
Background
Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4–6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen.
Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual.
Methods/design
The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient’s antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depressionmeasured using the Quick Inventory of Depressive Symptoms – Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed.
Discussion
This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients.
Trial registration
ClinicalTrials.gov, ID: NCT02790970. Registered on 30 March 2016.
Division of labor is a hallmark of social insects. In the honeybee (Apis mellifera) each sterile female worker performs a series of social tasks. The most drastic changes in behavior occur when a nurse bee, who takes care of the brood and the queen in the hive, transitions to foraging behavior. Foragers provision the colony with pollen, nectar or water. Nurse bees and foragers differ in numerous behaviors, including responsiveness to gustatory stimuli. Differences in gustatory responsiveness, in turn, might be involved in regulating division of labor through differential sensory response thresholds. Biogenic amines are important modulators of behavior. Tyramine and octopamine have been shown to increase gustatory responsiveness in honeybees when injected into the thorax, thereby possibly triggering social organization. So far, most of the experiments investigating the role of amines on gustatory responsiveness have focused on the brain. The potential role of the fat body in regulating sensory responsiveness and division of labor has large been neglected. We here investigated the role of the fat body in modulating gustatory responsiveness through tyramine signaling in different social roles of honeybees. We quantified levels of tyramine, tyramine receptor gene expression and the effect of elevating fat body tyramine titers on gustatory responsiveness in both nurse bees and foragers. Our data suggest that elevating the tyramine titer in the fat body pharmacologically increases gustatory responsiveness in foragers, but not in nurse bees. This differential effect of tyramine on gustatory responsiveness correlates with a higher natural gustatory responsiveness of foragers, with a higher tyramine receptor (Amtar1) mRNA expression in fat bodies of foragers and with lower baseline tyramine titers in fat bodies of foragers compared to those of nurse bees. We suggest that differential tyramine signaling in the fat body has an important role in the plasticity of division of labor through changing gustatory responsiveness.
Background:
Sleep-related eating may occur in the context of mental illness, sleep disorders, or psychopharmacological treatment. Frequently, sleep-related eating leads to severe weight gain and, so far, there are no treatment options for the condition.
Case presentation:
We report the case of a 54-year-old white woman with depression, panic disorder, and sleep apnea under treatment with various antidepressants who developed severe sleep-related eating. Her sleep-related eating completely vanished after addition of agomelatine, it reoccurred after cessation of agomelatine, and vanished again after her re-exposure to another melatonergic drug, extended melatonin.
Conclusions:
This case suggests that melatonergic drugs lead to relief from sleep-related eating, even when the condition occurs in the context of physical and mental disorders as well as psychopharmacological treatment.
The blunt snout bream Megalobrama amblycephala is the economically most important cyprinid fish species. As an herbivore, it can be grown by eco-friendly and resource-conserving aquaculture. However, the large number of intermuscular bones in the trunk musculature is adverse to fish meat processing and consumption. As a first towards optimizing this aquatic livestock, we present a 1.116-Gb draft genome of M. amblycephala, with 779.54 Mb anchored on 24 linkage groups. Integrating spatiotemporal transcriptome analyses, we show that intermuscular bone is formed in the more basal teleosts by intramembranous ossification and may be involved in muscle contractibility and coordinating cellular events. Comparative analysis revealed that olfactory receptor genes, especially of the beta type, underwent an extensive expansion in herbivorous cyprinids, whereas the gene for the umami receptor T1R1 was specifically lost in M. amblycephala. The composition of gut microflora, which contributes to the herbivorous adaptation of M. amblycephala, was found to be similar to that of other herbivores. As a valuable resource for the improvement of M. amblycephala livestock, the draft genome sequence offers new insights into the development of intermuscular bone and herbivorous adaptation.
This thesis investigates the impact of the country-of-origin effect on Chinese luxury brands which intend to enter the German luxury goods market. By means of a questionnaire and a quantitative analysis, possible threats to Chinese newcomers that derive from an unfavorable country image are illustrated. In fact, the Chinese origin of luxury goods has an impact on German consumers' perception.
Nest ventilation in the leaf-cutting ant Atta vollenweideri is driven via a wind-induced mechanism. On their nests, workers construct small turrets that are expected to facilitate nest ventilation. We hypothesized that the construction and structural features of the turrets would depend on the colony’s current demands for ventilation and thus might be influenced by the prevailing environmental conditions inside the nest. Therefore, we tested whether climate-related parameters, namely airflow, air humidity and CO\(_{2}\) levels in the outflowing nest air influenced turret construction in Atta vollenweideri. In the laboratory, we simulated a semi-natural nest arrangement with fungus chambers, a central ventilation tunnel providing outflow of air and an aboveground building arena for turret construction. In independent series, different climatic conditions inside the ventilation tunnel were experimentally generated, and after 24 hours, several features of the built turret were quantified, i.e., mass, height, number and surface area (aperture) of turret openings. Turret mass and height were similar in all experiments even when no airflow was provided in the ventilation tunnel. However, elevated CO\(_{2}\) levels led to the construction of a turret with several minor openings and a larger total aperture. This effect was statistically significant at higher CO\(_{2}\) levels of 5% and 10% but not at 1% CO\(_{2}\). The construction of a turret with several minor openings did not depend on the strong differences in CO\(_{2}\) levels between the outflowing and the outside air, since workers also built permeated turrets even when the CO\(_{2}\) levels inside and outside were both similarly high. We propose that the construction of turrets with several openings and larger opening surface area might facilitate the removal of CO\(_{2}\) from the underground nest structure and could therefore be involved in the control of nest climate in leaf-cutting ants.
The aim of the present study was to examine whether fostering positive activating affect during multimedia learning enhances learning outcome. University students were randomly assigned to either a multimedia learning environment designed to induce positive activating affect through the use of “warm” colours and rounded shapes () or an affectively neutral environment that used achromatic colours and sharp edges (). Participants learned about the topic of functional neuroanatomy for 20 minutes and had to answer several questions for comprehension and transfer afterwards. Affective states as well as achievement goal orientations were investigated before and after the learning phase using questionnaires. The results show that participants in the affectively positive environment were superior in comprehension as well as transfer when initial affect was strong. Preexperimental positive affect was therefore a predictor of comprehension and a moderator for transfer. Goal orientations did not influence these effects. The findings support the idea that positive affect, induced through the design of the particular multimedia learning environment, can facilitate performance if initial affective states are taken into account.
Plants have to tightly control their energy homeostasis to ensure survival and fitness under constantly changing environmental conditions. Thus, it is stringently required that energy-consuming stress-adaptation and growth-related processes are dynamically tuned according to the prevailing energy availability. The evolutionary conserved SUCROSE NON-FERMENTING1 RELATED KINASES1 (SnRK1) and the downstream group C/S\(_{1}\) basic leucine zipper (bZIP) transcription factors (TFs) are well-characterised central players in plants’ low-energy management. Nevertheless, mechanistic insights into plant growth control under energy deprived conditions remains largely elusive. In this work, we disclose the novel function of the low-energy activated group S\(_{1}\) bZIP11-related TFs as regulators of auxin-mediated primary root growth. Whereas transgenic gain-of-function approaches of these bZIPs interfere with the activity of the root apical meristem and result in root growth repression, root growth of loss-of-function plants show a pronounced insensitivity to low-energy conditions. Based on ensuing molecular and biochemical analyses, we propose a mechanistic model, in which bZIP11-related TFs gain control over the root meristem by directly activating IAA3/SHY2 transcription. IAA3/SHY2 is a pivotal negative regulator of root growth, which has been demonstrated to efficiently repress transcription of major auxin transport facilitators of the PIN-FORMED (PIN) gene family, thereby restricting polar auxin transport to the root tip and in consequence auxin-driven primary root growth. Taken together, our results disclose the central low-energy activated SnRK1-C/S\(_{1}\)-bZIP signalling module as gateway to integrate information on the plant’s energy status into root meristem control, thereby balancing plant growth and cellular energy resources.
5’-3’ decay is the major mRNA decay pathway in many eukaryotes, including trypanosomes. After deadenylation, mRNAs are decapped by the nudix hydrolase DCP2 of the decapping complex and finally degraded by the 5’-3’ exoribonuclease. Uniquely, trypanosomes lack homologues to all subunits of the decapping complex, while deadenylation and 5’-3’ degradation are conserved. Here, I show that the parasites use an ApaH-like phosphatase (ALPH1) as their major mRNA decapping enzyme. The protein was recently identified as a novel trypanosome stress granule protein and as involved in mRNA binding. A fraction of ALPH1 co-localises exclusively with the trypanosome 5’-3’ exoribonuclease XRNA to a special granule at the posterior pole of the cell, indicating a connection between the two enzymes. RNAi depletion of ALPH1 is lethal and causes a massive increase in total mRNAs that are deadenylated, but have not yet started 5’-3’ decay. These data suggest that ALPH1 acts downstream of deadenylation and upstream of mRNA degradation, consistent with a function in mRNA decapping. In vitro experiments show that recombinant, N-terminally truncated ALHP1 protein, but not a catalytically inactive mutant, sensitises the capped trypanosome spliced leader RNA to yeast Xrn1, but only if an RNA 5’ polyphosphatase is included. This indicates that the decapping mechanism of ALPH1 differs from the decapping mechanism of Dcp2 by leaving more than one phosphate group at the mRNA’s 5’ end. This is the first reported function of a eukaryotic ApaH-like phosphatase, a bacterial-derived class of enzymes present in all phylogenetic super-groups of the eukaryotic kingdom. The substrates of eukaryotic ApaH-like phosphatases are unknown. However, the substrate of the related bacterial enzyme ApaH, diadenosine tetraphosphate, is highly reminiscent of a eukaryotic mRNA cap.
Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48–72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.
Background:
Colorectal cancer (CRC) is the second leading cause of cancer-related death in men and women. Systemic disease with metastatic spread to distant sites such as the liver reduces the survival rate considerably. The aim of this study was to investigate the changes in gene expression that occur on invasion and expansion of CRC cells when forming metastases in the liver.
Methods:
The livers of syngeneic C57BL/6NCrl mice were inoculated with 1 million CRC cells (CMT-93) via the portal vein, leading to the stable formation of metastases within 4 weeks. RNA sequencing performed on the Illumina platform was employed to evaluate the expression profiles of more than 14,000 genes, utilizing the RNA of the cell line cells and liver metastases as well as from corresponding tumour-free liver.
Results:
A total of 3329 differentially expressed genes (DEGs) were identified when cultured CMT-93 cells propagated as metastases in the liver. Hierarchical clustering on heat maps demonstrated the clear changes in gene expression of CMT-93 cells on propagation in the liver. Gene ontology analysis determined inflammation, angiogenesis, and signal transduction as the top three relevant biological processes involved. Using a selection list, matrix metallopeptidases 2, 7, and 9, wnt inhibitory factor, and chemokine receptor 4 were the top five significantly dysregulated genes.
Conclusion:
Bioinformatics assists in elucidating the factors and processes involved in CRC liver metastasis. Our results support the notion of an invasion-metastasis cascade involving CRC cells forming metastases on successful invasion and expansion within the liver. Furthermore, we identified a gene expression signature correlating strongly with invasiveness and migration. Our findings may guide future research on novel therapeutic targets in the treatment of CRC liver metastasis.
Breakdown of sphingomyelin as catalyzed by the activity of sphingomyelinases profoundly affects biophysical properties of cellular membranes which is particularly important with regard to compartmentalization of surface receptors and their signaling relay. As it is activated both upon TCR ligation and co-stimulation in a spatiotemporally controlled manner, the neutral sphingomyelinase (NSM) has proven to be important in T cell activation, where it appears to play a particularly important role in cytoskeletal reorganization and cell polarization. Because these are important parameters in directional T cell migration and motility in tissues, we analyzed the role of the NSM in these processes. Pharmacological inhibition of NSM interfered with early lymph node homing of T cells in vivo indicating that the enzyme impacts on endothelial adhesion, transendothelial migration, sensing of chemokine gradients or, at a cellular level, acquisition of a polarized phenotype. NSM inhibition reduced adhesion of T cells to TNF-α/IFN-γ activated, but not resting endothelial cells, most likely via inhibiting high-affinity LFA-1 clustering. NSM activity proved to be highly important in directional T cell motility in response to SDF1-α, indicating that their ability to sense and translate chemokine gradients might be NSM dependent. In fact, pharmacological or genetic NSM ablation interfered with T cell polarization both at an overall morphological level and redistribution of CXCR4 and pERM proteins on endothelial cells or fibronectin, as well as with F-actin polymerization in response to SDF1-α stimulation, indicating that efficient directional perception and signaling relay depend on NSM activity. Altogether, these data support a central role of the NSM in T cell recruitment and migration both under homeostatic and inflamed conditions by regulating polarized redistribution of receptors and their coupling to the cytoskeleton.
C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma.
Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up.
Whereas [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed.
In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.
Nowadays, more than half of the biotherapeutics are produced in mammalian cell lines as a result of correct protein folding and assembly as well as their faculty to bring about a variety of post-translational modifications. The widespread progression of biosimilars has moved the focus in mammalian cell-culture process development. Thereby, the modulation of quality attributes of recombinant therapeutic proteins has increasingly gained importance from early process development stages. Protein quality directly shapes the clinical efficacy and safety in vivo, and therefore, the control of the complex post-translational modifications, such as glycosylation (e.g. high mannose, fucosylation, galactosylation and sialylation), charge variants, aggregates and low-molecular-weight species formation, is pivotal for efficient receptor binding and for triggering the desired immune responses in patients. In the frame of biosimilar development, product quality modulation methods using the potential of the host cell line are particularly sought after to match the quality profile of the targeted reference medicinal product (RMP) as closely as possible. The environment the cell is dwelling in directly influences its metabolism and the resulting quality profile of the expressed protein. Thereby the cell culture medium plays a central role in upstream manufacturing. In this work, concentration adjustment of selected media components and supplementation with a variety of compounds was performed to alter various metabolic pathways, enzyme activities and in some cases the gene expression levels of Chinese Hamster Ovary (CHO) cells in culture. The supplementation of cell culture medium with the trisaccharide raffinose in fed-batch cultures entailed an increase of the abundance of high mannose glycans in two different CHO cell lines. Raffinose especially favored mannose 5 glycans. At the same time, it impaired cell culture performance, induced changes on the intracellular nucleotide levels and even varied the expression levels of glycosylation-related genes. Supplementation with a number of galactosyltransferase inhibiting compounds, in particular fluorinated galactose analogs (alpha- and beta-2F-peracetyl-galactose), consistently decreased the production of galactosylated monoclonal antibodies (mAb). By means of targeted addition during the culture rather than at the beginning, the inhibition was further increased, while limiting detrimental effects on both growth and productivity. High-throughput screening in 96-deepwell plates showed that spermine and L-ornithine also reduced the level of galactosylation. On the other hand, exploratory screening of a variety of potentially disulfide-bridge-reducing agents highlighted that the inherent low-molecular-species level of the proprietary platform cell culture process was likely due to favored reduction. This hypothesis was reinforced by the observation that supplementation of cysteine and N-acetylcysteine promoted fragmentation. Additionally, fragmentation decreased with higher protein expression.
At that point, aiming to improve the efficiency in process development, a rational experimental design method was developed to identify and to define the optimal concentration range of quality modulating compounds by calling on a combination of high throughput fed-batch testing and multivariate data analysis. Seventeen medium supplements were tested in five parallel 96-deepwell plate experiments. The selection process of promising modulators for the follow-up experiment in shake tubes consisted in a three-step procedure, including principal component analysis, quantitative evaluation of their performance with respect to the specifications for biosimilarity and selection following a hierarchical order of decisions using a decision tree. The method resulted in a substantial improvement of the targeted glycosylation profile in only two experimental rounds. Subsequent development stages, namely validation and transfer to industrial-scale facilities require tight control of product quality. Accordingly, further mechanistic understanding of the underlying processes was acquired by non-targeted metabolomic profiling of a CHO cell line expressing a mAb cultured in four distinct process formats. Univariate analysis of intra- and extracellular metabolite and temporal glycosylation profiles provided insights in various pathways. The numerous of parameters were the main driver to carry out principal component analysis, and then, using the methodology of partial-least-square (PLS) projection on latent structures, a multivariate model was built to correlate the extracellular data with the distinct glycosylation profiles. The PLS observation model proved to be reliable and showed its great benefit for glycan pattern control in routine manufacturing, especially at large scale. Rather than relying on post-production interpretation of glycosylation results, glycosylation can be predicted in real-time based on the extracellular metabolite levels in the bioreactor.
Finally, for the bioactivity assessment of the glycan differences between the biosimilar and the reference medicinal product (RMP), the health agencies may ask for in the drug registration process, extended ranges of glycan variants need to be generated so that the in vitro assays pick up the changes. The developed glycosylation modulator library enabled the generation of extreme glycosylation variants, including high mannose, afucosylated, galactosylated as well as sialic acid species of both a mAb and an antibody fusion molecule with three N-glycosylation sites. Moreover, to create increased variety, enzymatic glycoengineering was explored for galactosylation and sialylation. The glyco variants induced significant responses in the respective in vitro biological activity assays. The data of this work highlight the immense potential of cell culture medium optimization to adjust product quality. Medium and feed supplementation of a variety of compounds resulted in reproducible and important changes of the product quality profile of both mAbs and a fusion antibody. In addition to the intermediate modulation ranges that largely met the requirements for new-biological-entity and biosimilar development, medium supplementation even enabled quick and straightforward generation of extreme glycan variants suitable for biological activity testing.
In the present report, well-defined WO3 nanorods (NRs) and a rGO–WO\(_3\) composite were successfully synthesized using a one-pot hydrothermal method. The crystal phase, structural morphology, shape, and size of the as-synthesized samples were studied using X-ray diffraction (XRD) and transmission electron microscopy (TEM) measurements. The optical properties of the synthesized samples were investigated by Raman, ultraviolet-visible (UV-Vis) and photoluminescence (PL) spectroscopy. Raman spectroscopy and TEM results validate the formation of WO\(_3\) (NRs) on the rGO sheet. The value of the dielectric constant (ε′) of WO3 NRs and rGO–WO\(_3\) composite is decreased with an increase in frequency. At low frequency (2.5 to 3.5 Hz), the value of ε′ for the rGO–WO3 composite is greater than that of pure WO\(_3\) NRs. This could be due to the fact that the induced charges follow the ac signal. However, at higher frequency (3.4 to 6.0), the value of ε′ for the rGO–WO\(_3\) composite is less compared to that of the pure WO3 NRs. The overall decrease in the value of ε′ could be due to the occurrence of a polarization process at the interface of the rGO sheet and WO3 NRs. Enhanced interfacial polarization in the rGO–WO\(_3\) composite is observed, which may be attributed to the presence of polar functional groups on the rGO sheet. These functional groups trap charge carriers at the interface, resulting in an enhancement of the interfacial polarization. The value of the dielectric modulus is also calculated to further confirm this enhancement. The values of the ac conductivity of the WO\(_3\) NRs and rGO–WO\(_3\) composite were calculated as a function of the frequency. The greater value of the ac conductivity in the rGO–WO\(_3\) composite compared to that of the WO\(_3\) NRs confirms the restoration of the sp:\(^{++}\) network during the in situ synthesis of the rGO–WO\(_3\) composite, which is well supported by the results obtained by Raman spectroscopy.
Synthesis of Dualsteric Ligands for Muscarinic Acetylcholine Receptors and Cholinesterase Inhibitors
(2017)
The study is dealing with the synthesis and pharmacological investigation of newly designed dualsteric ligands of muscarinic acetylcholine receptors belonging to the superfamily of G protein-coupled receptors. Such bipharmacophoric ligands combine the advantages of the orthosteric binding site (high-affinity) and of the topographically distinct allosteric binding site (subtype-selectivity) resulting in compounds with reduced side effects. This opens the way to a new therapeutic approach in the treatment of e.g. chronic pain, drug withdrawal, Parkinson`s and Alzheimer`s disease. Furthermore, the newly synthesized dualsteric compounds were pharmacologically investigated in order to get a better understanding of the activation and signaling processes in muscarinic acetylcholine receptors, especially with regard to partial agonism.
The development of the “dynamic ligand binding” concept offers new perspectives for ligand binding and signaling at G protein-coupled receptors. GPCRs are no longer considered as simple on/off switches. Dualsteric ligands can bind in a dualsteric pose, reflecting an active receptor state as well as in a purely allosteric binding pose, characterized by an inactive receptor state resulting in partial agonism. The degree of partial agonism depends on the ratio of active versus inactive receptor populations. On this basis, orthosteric/orthosteric hybrid ligands consisting of the antagonist atropine and scopolamine, respectively, as well as of the agonist iperoxo and isoxazole, respectively, linked via different alkyl chain length were synthesized in order to investigate partial agonism (Figure 1).
Figure 1: Structures of the synthesized iperoxo/isoxazole-atropine/scopolamine-hybrids.
Furthermore, different sets of quaternary and tertiary homodimers consisting either of two iperoxo or two acetylcholine units were synthesized in order to study their extent on partial agonism (Figure 2). The two agonists were connected by varying alkyl chain length. Binding studies on CHO-hM2 cells of the quaternary compounds revealed that dimerization of the agonist results in a loss of potency. The iperoxo-dimers reached higher maximum effects on the Gi- as well as on the Gs pathway in comparison to the acetylcholine-dimers. Besides the choice of the orthosteric building block (potency of the agonist), the alkyl chain length is also crucial for the degree of partial agonism.
Figure 2: Structures of the synthesized quat./tert. iperoxo/acetylcholine-homodimers.
Quinolone-based hybrids connected to the superagonist iperoxo and to the endogenous ligand acetylcholine, respectively, linked through an alkyl chain of different length were synthesized in order to develop further partial agonists (Figure 3). FRET studies confirmed M1 subtype-selectivity as well as linker dependent receptor response. The greatest positive FRET signal was observed with quinolone-C6-iper resulting from a positive cooperativity between the two separated moieties, alloster and orthoster. However, the corresponding hybrids with a longer linker led to an inverse FRET signal indicating a different binding mode, e.g. purely allosteric, in contrast to the shorter linked hybrids. Furthermore, the flexible alkyl spacer was replaced by a rigidified linker resulting in the hybrid quinolone-rigid-iperoxo (Figure 3). FRET studies on the M1 receptor showed reduced FRET kinetics, resulting from interactions between the bulky linker and the aromatic lid, located between the orthosteric and allosteric binding site. A bitopic binding mode of the rigidified hybrid is presumed. For further clarity, mutational studies are necessary.
Figure 3: M1-selective hybrid compounds.
Another aim of this work was the design and synthesis of new hybrid compounds, acting as agonists at the M1 and M2 receptor and as inhibitors for AChE and BChE in the context of M. Alzheimer. Several sets of hybrid compounds consisting of different pharmacophoric units (catalytic active site: phthalimide, naphthalimide, tacrine; peripheric anionic site: iperoxo, isoxazole) linked through a polymethylene chain of varying length were synthesized. Tac-C10-iper (Figure 4), consisting of tacrine and the superagonist iperoxo linked by a C10 polymethylene spacer, was found to have excellent anticholinesterase activity for both AChE (pIC50 = 9.81) and BChE (pIC50 = 8.75). Docking experiments provided a structural model to rationalize the inhibitory power towards AChE. Additionally, the tacrine related hybrids showed affinity to the M1 and M2 receptor. Such compounds, addressing more than one molecular target are favorable for multifactorial diseases such as Alzheimer.
Figure 4: Structure of the most active compound regarding anticholinesterase activity.
In summary, the choice of the pharmacophoric units, their connecting point as well as the nature, length, and flexibility of the linker play an important role for the activity of designed bivalent ligands. A shorter linker length cannot bridge both binding sites simultaneously in contrast to longer linker chains. On the other hand, too long linker chains can result in unwanted steric interactions. Further investigations with respect to structural variations of hybrid compounds, with or without quaternary ammonium groups, are necessary in the light of drug development.
Background
The role of hospital water systems in the development of Pseudomonas aeruginosa (P. aeruginosa) surgical site infections (SSIs) in low-income countries is barely studied. This study characterized P. aeruginosa isolates from patients and water in order to establish possible epidemiological links.
Methods:
Between December 2014 and September 2015, rectal and wound swabs, and water samples were collected in the frame of active surveillance for SSIs in the two Tanzanian hospitals. Typing of P. aeruginosa was done by multi-locus sequence typing.
Results:
Of 930 enrolled patients, 536 were followed up, of whom 78 (14.6%, 95% CI; 11.6–17.5) developed SSIs. P. aeruginosa was found in eight (14%) of 57 investigated wounds. Of the 43 water sampling points, 29 were positive for P. aeruginosa. However, epidemiological links to wound infections were not confirmed. The P. aeruginosa carriage rate on admission was 0.9% (8/930). Of the 363 patients re-screened upon discharge, four (1.1%) possibly acquired P. aeruginosa during hospitalization. Wound infections of the three of the eight P. aeruginosa SSIs were caused by a strain of the same sequence type (ST) as the one from intestinal carriage. Isolates from patients were more resistant to antibiotics than water isolates.
Conclusions:
The P. aeruginosa SSI rate was low. There was no evidence for transmission from tap water. Not all P. aeruginosa SSI were proven to be endogenous, pointing to other routes of transmission.
Background:
Fatty Degeneration (FD) of the rotator cuff muscles influences functional and anatomical outcome after rotator cuff repair. The MRI based estimation of fatty degeneration is the gold standard. There is some evidence that Ultrasound elastography (EUS) can detect local differences of tissue stiffness in muscles and tendons. Shear-wave elastography (SWE) was evaluated to determine the extent to which shear wave velocity was associated with measures of fatty degeneration. MRI-spectroscopic fat measurement was used as a reference to quantify the amount of fat in the muscle belly.
Methods:
Forty-two patients underwent SWE of the supraspinatus muscles at its thickest diameter. After ultrasound evaluation an MRI-spectroscopic fat measurement of the supraspinatus muscle was performed using the SPLASH-technique. A gel filled capsule was used to locate the measured area in the MRI. The values of shear wave velocity (SWV) measured with SWE and spectroscopic fat measurement were correlated statistically using Pearson’s correlation test.
Results:
Correlation of the fat amount measured with MRI-spectroscopy and the SWV measured with SWE was ρ =0.82. Spectroscopic measured fat ratio of the supraspinatus muscle ranged from 0% to 77.41% and SWV from 1.59 m/s to 5.32 m/s. In 4 patients no sufficient SWE could be performed, these individuals showed a larger diameter of the overlying soft tissue. SWV measured with SWE showed a good correlation with MRI spectroscopic fat amount of the supraspinatus muscle.
Conclusion:
These preliminary data suggest that SWE may be a sufficient tool in detecting and estimating the amount of fatty degeneration in the supraspinatus muscle in real time. Large overlying soft tissue may be a limitation in performing sufficient EUS.
[60]Fullerene hexakisadducts possessing 12 carboxylic acid side chains form crystalline hydrogen-bonding frameworks in the solid state. Depending on the length of the linker between the reactive sites and the malonate units, the distance of the [60]fullerene nodes and thereby the spacing of the frameworks can be controlled and for the most elongated derivative, continuous channels are obtained within the structure. Stability, structural integrity and porosity of the material were investigated by powder X-ray diffraction, thermogravimetry and sorption measurements.
Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [\(^{11}\)C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [\(^{11}\)C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.
In early spring, red wood ants Formica polyctena are often observed clustering on the nest surface in large numbers basking in the sun. It has been hypothesized that sun-basking behaviour may contribute to nest heating because of both heat carriage into the nest by sunbasking workers, and catabolic heat production from the mobilization of the workers’ lipid reserves. We investigated sun-basking behaviour in laboratory colonies of F. polyctena exposed to an artificial heat source. Observations on identified individuals revealed that not all ants bask in the sun. Sun-basking and non-sun-basking workers did not differ in body size nor in respiration rates. The number of sun-basking ants and the number of their visits to the hot spot depended on the temperature of both the air and the hot spot. To investigate whether sun basking leads to a physiological activation linked with increased lipolysis, we measured respiration rates of individual workers as a function of temperature, and compared respiration rates of sun-basking workers before and two days after they were allowed to expose themselves to a heat source over 10 days, at self-determined intervals. As expected for ectothermic animals, respiration rates increased with increasing temperatures in the range 5 to 35˚C. However, the respiration rates of sun-basking workers measured two days after a long-term exposure to the heat source were similar to those before sun basking, providing no evidence for a sustained increase of the basal metabolic rates after prolonged sun basking. Based on our measurements, we argue that self-heating of the nest mound in early spring has therefore to rely on alternative heat sources, and speculate that physical transport of heat in the ant bodies may have a significant effect.
Population genomics of prokaryotes has been studied in depth in only a small number of primarily pathogenic bacteria, as genome sequences of isolates of diverse origin are lacking for most species. Here, we conducted a large‐scale survey of population structure in prevalent human gut microbial species, sampled from their natural environment, with a culture‐independent metagenomic approach. We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72% of the total assigned microbial abundance, single‐nucleotide variation clearly indicates the existence of sub‐populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identified genes that consistently distinguish them in a manner that is independent of reference genomes. We further associated these subspecies‐specific genes with properties of the microbial community and the host. For example, two of the three Eubacterium rectale subspecies consistently harbor an accessory pro‐inflammatory flagellum operon that is associated with lower gut community diversity, higher host BMI, and higher blood fasting insulin levels. Using an additional 676 human oral samples, we further demonstrate the existence of niche specialized subspecies in the different parts of the oral cavity. Taken together, we provide evidence for subspecies in the majority of abundant gut prokaryotes, leading to a better functional and ecological understanding of the human gut microbiome in conjunction with its host.
Summary
Platelet activation and aggregation at sites of vascular injury is critical to prevent excessive blood loss, but may also lead to life-threatening ischemic disease states, such as myocardial infarction and stroke. Glycoprotein (GP) VI and C type lectin-like receptor 2 (CLEC-2) are essential platelet activating receptors in hemostasis and thrombo-inflammatory disease which signal through a (hem)immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway. The adapter molecules Src-like adapter protein (SLAP) and SLAP2 are involved in the regulation of immune cell receptor surface expression and signaling, but their function in platelets is unknown. As revealed in this thesis, single deficiency of SLAP or SLAP2 in mice had only moderate effects on platelet function, while SLAP/SLAP2 double deficiency resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity and thrombin generation following (hem)ITAM-coupled, but not G protein-coupled receptor activation. Slap-/-/Slap2-/- mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. These results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke.
GPVI has emerged as a promising novel pharmacological target for treatment of thrombotic and inflammatory disease states, but the exact mechanisms of its immunodepletion in vivo are incompletely understood. It was hypothesized that SLAP and SLAP2 may be involved in the control of GPVI down-regulation because of their role in the internalization of immune cell receptors. As demonstrated in the second part of the thesis, SLAP and SLAP2 were dispensable for antibody-induced GPVI down-regulation, but anti-GPVI treatment resulted in prolonged strong thrombocytopenia in Slap-/-/Slap2-/- mice. The profound thrombocytopenia likely resulted from the powerful platelet activation which the anti-GPVI antibody induced in Slap-/-/Slap2-/- platelets, but importantly, not in wild-type platelets. These data indicate that the expression and activation state of key modulators of the GPVI signaling cascade may have important implications for the safety profile and efficacy of anti-GPVI agents.
Small GTPases of the Rho family, such as RhoA and Cdc42, are critically involved in the regulation of cytoskeletal rearrangements during platelet activation, but little is known about the specific roles and functional redundancy of both proteins in platelet biogenesis. As shown in the final part of the thesis, combined deficiency of RhoA and Cdc42 led to marked alterations in megakaryocyte morphology and the generation of platelets of heterogeneous size and granule content. Despite severe hemostatic defects and profound thrombo¬cytopenia, circulating RhoA-/-/Cdc42-/- platelets were still capable of granule secretion and the formation of occlusive thrombi. These results implicate the existence of both distinct and overlapping roles of RhoA and Cdc42 in platelet production and function.
The production of a \(Z\) boson and a photon in association with a high-mass dijet system is studied using 20.2 fb\(^{−1}\) of proton-proton collision data at a centre-of-mass energy of \(\sqrt{s}\) = 8 TeV recorded with the ATLAS detector in 2012 at the Large Hadron Collider. Final states with a photon and a Z boson decaying into a pair of either electrons, muons, or neutrinos are analysed. Electroweak and total \(pp\) → \(Zγjj\) cross-sections are extracted in two fiducial regions with different sensitivities to electroweak production processes. Quartic couplings of vector bosons are studied in regions of phase space with an enhanced contribution from pure electroweak production, sensitive to vector-boson scattering processes \(V V → Zγ\). No deviations from Standard Model predictions are observed and constraints are placed on anomalous couplings parameterized by higher-dimensional operators using effective field theory.
The present thesis demonstrates the importance of the solid state packing of dipolar merocyanine dyes with regard to charge transport and exciton coupling.
Due to the charge transport theory for disordered materials, it is expected that high ground state dipole moments in amorphous thin films lead to low mobility values due to a broadening of the density of states. However, due to their inherent dipolarity, merocyanine dyes usually align in antiparallel dimers in an ordered fashion. The examination of twenty different molecules with ground state dipole moments up to 15.0 D shows that by a high dipolarity and well-defined sterics, the molecules pack in a highly regular two-dimensional brickwork-type structure, which is beneficial for hole transport. Utilization of these molecules for organic thin-film transistors (OTFTs) leads to hole mobility values up to 0.21 cm²/Vs. By fabrication of single crystal field-effect transistors (SCFETs) for the derivative showing the highest mobility values in OTFTs, even hole mobilities up to 2.34 cm²/Vs are achieved. Hence, merocyanine based transistors show hole mobility values comparable to those of conventional p-type organic semiconductors and therefore high ground state dipole moments are not necessarily disadvantageous regarding high mobility applications.
By examination of a different series of ten merocyanine dyes with the same chromophore backbone but different donor substituents, it is demonstrated that the size of the donor has a significant influence on the optical properties of thin films. For small and rigid donor substituents, a hypsochromic shift of the absorption compared to the monomer absorption in solution is observed due to the card stack like packing of the molecules in the solid state. By utilization of sterical demanding or flexible donor substituents, a zig-zag type packing is observed, leading to a bathochromical shift of the absorption. These packing motifs and spectral shifts with an offset of 0.93 eV of the H- and J-bands comply with the archetype examples of H- and J-aggregates from Kasha’s exciton theory.
The inhibitory glycine receptors are one of the major mediators of rapid synaptic inhibition in the mammalian brainstem, spinal cord and higher brain centres. They are ligand-gated ion channels that are mainly involved in the regulation of motor functions. Dysfunction of the receptor is associated with motor disorders such as hypereklepxia or some forms of spasticity. GlyR is composed of two glycosylated integral membrane proteins α and β and a peripheral membrane protein of gephyrin. Moreover, there are four known isoforms of the α-subunit (α1-4) of GlyR while there is a single β-subunit. Glycine receptors can be homomeric including α subunits only or heteromeric containing both α and β subunits. To date, strychnine is the ligand that has the highest affinity as glycine receptor ligand. It acts as a competitive antagonist of glycine that results in the inhibition of Cl- ions permeation and consequently reducing GlyR-mediated inhibition.
For a long time, the details of the molecular mechanism of GlyRs inactivation by strychnine were insufficient due to the lack of high-resolution structures of the receptor. Only homology models based on structures of other cys-loop receptors have been available. Recently, 3.0 Å X-ray structure of the human glycine receptor- α3 homopentamer in complex with strychnine, as well as electro cryo-microscopy structures of the zebra fish α1 GlyR in complex with strychnine and glycine were published. Such information provided detailed insight into the molecular recognition of agonists and antagonists and mechanisms of GlyR activation and inactivation.
Very recently, a series of dimeric strychnine analogs obtained by diamide formation of two molecules of 2-aminostrychnine with diacids of different chain length was pharmacologically evaluated at human α1 and α1β glycine receptors. None of the dimeric analogs was superior to strychnine.
The present work focused on the extension of the structure-activity relationships of strychnine derivatives at glycine receptors
All the synthesized compounds were pharmacologically evaluated at human α1 and α1β glycine receptors in a functional FLIPRTM assay and the most potent analogs were pharmacologically evaluated in a whole cell patch-clamp assay and in [3H]strychnine binding studies.
It was reported that 11-(E)-isonitrosostrychnine displayed a 2-times increased binding to both α1 and α1β glycine receptors which prompted us to choose the hydroxyl group as a suitable attachment point to connect two 11-(E)-isonitrosostrychnine molecules using a spacer. In order to explore the GlyR pocket tolerance for oxime extension, a series of oxime ethers with different spacer lengths and sterical/lipophilic properties were synthesized biologically evaluated. Among all the oxime ethers, methyl, allyl and propagyl oxime ethers were the most potent antagonists displaying IC50 values similar to that of strychnine. These findings indicated that strychnine binding site at GlyRs comprises an additional small lipophilic pocket located in close proximity to C11 of strychnine and the groups best accommodated in this pocket are (E)-allyl and (E)-propagyl oxime ethers.
Moreover, 11-aminostrychnine, and the corresponding propionamide were prepared and pharmacologically evaluated to examine the amide function at C11 as potential linker.
A series of dimeric strychnine analogs designed by linking two strychnine molecules through amino groups in position 11 with diacids were synthesized and tested in binding studies and functional assays at human α1 and α1β glycine receptors. The synthesized bivalent ligands were designed to bind simultaneously to two α-subunits of the pentameric glycine receptors causing a possibly stronger inhibition than the monomeric strychnine. However, all the bivalent derivatives showed no significant difference in potency compared to strychnine. When comparing the reference monomeric propionamide containing ethylene spacer to the dimeric ligand containing butylene spacer, a 3-fold increase in potency was observed. Since the dimer containing (CH2)10 spacer length was found to be equipotent to strychnine, it is assumed that one molecule of strychnine binds to the receptor and the ‘additional’ strychnine molecule in the dimer probably protrudes from the orthosteric binding sites of the receptor.
Multifunctional enzyme, type-1 (MFE1) is a monomeric enzyme with a 2E-enoyl-CoA hydratase and a 3S-hydroxyacyl-CoA dehydrogenase (HAD) active site. Enzyme kinetic data of rat peroxisomal MFE1 show that the catalytic efficiencies for converting the short-chain substrate 2E-butenoyl-CoA into acetoacetyl-CoA are much lower when compared with those of the homologous monofunctional enzymes. The mode of binding of acetoacetyl-CoA (to the hydratase active site) and the very similar mode of binding of NAD\(^+\) and NADH (to the HAD part) are described and compared with those of their monofunctional counterparts. Structural comparisons suggest that the conformational flexibility of the HAD and hydratase parts of MFE1 are correlated. The possible importance of the conformational flexibility of MFE1 for its biocatalytic properties is discussed.
Several important cellular processes, including transcription, nucleotide excision repair and cell cycle control are mediated by the multifaceted interplay of subunits within the general transcription factor II H (TFIIH).
A better understanding of the molecular structure of TFIIH is the key to unravel the mechanism of action of this versatile protein complex within these pathways. This becomes especially important in the context of severe diseases like xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, that arise from single point mutations in some of the TFIIH subunits.
In an attempt to structurally characterize the TFIIH complex, we harnessed the qualities of the eukaryotic thermophile Chaetomium thermophilum, a remarkable fungus, which has only recently been recognized as a novel model organism. Homologues of TFIIH from C. thermophilum were expressed in E. coli, purified to homogeneity and subsequently utilized for crystallization trials and biochemical studies.
The results of the present work include the first crystal structure of the p34 subunit of TFIIH, comprising the N-terminal domain of the protein. The structure revealed a von Willebrand Factor A (vWA) like fold, which is generally known to be involved in a multitude of protein-protein interactions. Structural comparison allowed to delineate similarities as well as differences to already known vWA domains, providing insight into the role of p34 within TFIIH. These results indicate that p34 assumes the role of a structural scaffold for other TFIIH subunits via its vWA domain, while likely serving additional functions, which are mediated through its
C-terminal zinc binding domain and are so far unknown.
Within TFIIH p34 interacts strongly with the p44 subunit, a positive regulator of the XPD helicase, which is required for regulation of RNA Polymerase II mediated transcription and essential for eukaryotic nucleotide excision repair. Based on the p34 vWA structure putative protein-protein interfaces were analyzed and binding sites for the p34 p44 interaction suggested. Continuous crystallization efforts then led to the first structure of a p34 p44 minimal complex, comprising the N-terminal vWA domain of p34 and the C-terminal C4C4 RING domain of p44. The structure of the p34 p44 minimal complex verified the previous hypothesis regarding the involved binding sites. In addition, careful analysis of the complex interface allowed to identify critical residues, which were subsequently mutated and analyzed with respect to their significance in mediating the p34 p44 interaction, by analytical size exclusion chromatography, electrophoretic mobility shift assays and isothermal titration calorimetry. The structure of the p34 p44 complex also revealed a binding mode of the p44 C4C4 RING domain, which differed from that of other known RING domains in several aspects, supporting the hypothesis that p44 contains a novel variation of this domain.
Background:
Factors influencing access to stroke unit (SU) care and data on quality of SU care in Germany are scarce. We investigated characteristics of patients directly admitted to a SU as well as patient-related and structural factors influencing adherence to predefined indicators of quality of acute stroke care across hospitals providing SU care.
Methods:
Data were derived from the German Stroke Registers Study Group (ADSR), a voluntary network of 9 regional registers for monitoring quality of acute stroke care in Germany. Multivariable logistic regression analyses were performed to investigate characteristics influencing direct admission to SU. Generalized Linear Mixed Models (GLMM) were used to estimate the influence of structural hospital characteristics (percentage of patients admitted to SU, year of SU-certification, and number of stroke and TIA patients treated per year) on adherence to predefined quality indicators.
Results:
In 2012 180,887 patients were treated in 255 hospitals providing certified SU care participating within the ADSR were included in the analysis; of those 82.4% were directly admitted to a SU. Ischemic stroke patients without disturbances of consciousness (p < .0001), an interval onset to admission time ≤3 h (p < .0001), and weekend admission (p < .0001) were more likely to be directly admitted to a SU. A higher proportion of quality indicators within predefined target ranges were achieved in hospitals with a higher proportion of SU admission (p = 0.0002). Quality of stroke care could be maintained even if certification was several years ago.
Conclusions:
Differences in demographical and clinical characteristics regarding the probability of SU admission were observed. The influence of structural characteristics on adherence to evidence-based quality indicators was low.
Recent advances in the field of cancer immunotherapy have enabled this therapeutic approach to enter the mainstream of modern cancer treatment. In particular, adoptive T cell therapy (ACT) is a potentially powerful immunotherapy approach that relies on the administration of tumor-specific T cells into the patient. There are several strategies to obtain tumor-reactive cytotoxic T lymphocytes (CTLs), which have already been shown to induce remarkable responses in the clinical setting. However, there are concerns and limitations regarding the conventional approaches to obtain tumor-reactive T cells, such as accuracy of the procedure and reproducibility. Therefore, we aimed to develop two approaches to improve the precision and efficacy of tumor-reactive T cells therapy. These two techniques could constitute effective, safe and broadly applicable alternatives to the conventional methods for obtaining tumor-specific CTLs.
The first approach of this study is the so called “Doublet Technology”. Here, we demonstrate that peptide-human leukocyte antigen-T cell receptor (pHLA-TCR) interactions that involve immune reactive peptides are stable and strong. Therefore, the CTLs that are bound by their TCR to tumor cells can be selected and isolated through FACS-based cell sorting taking advantage of this stable interaction between the CTLs and the target cells. The CTLs from acute myeloid leukemia (AML) patients obtained with this technique show cytolytic activity against blast cells suggesting a potential clinical use of these CTLs. “Doublet Technology” offers a personalized therapy in which there is no need for a priori knowledge of the exact tumor antigen.
The second approach of this study is the Chimeric Antigen Receptor (CAR) Technology. We design several CARs targeting the B-Cell Maturation Antigen (BCMA). BCMA CAR T cells show antigen-specific cytolytic activity, production of cytokines including IFN-γ and IL-2, as well as productive proliferation. Although we confirm the presence of soluble BCMA in serum of multiple myeloma (MM) patients, we demonstrate that the presence of soluble protein does not abrogate the efficacy of BCMA CAR T cells suggesting that BCMA CAR T cells can be used in the clinical setting to treat MM patients. The high antigen specificity of CAR T cells allows efficient tumor cell eradication and makes CAR Technology attractive for broadly applicable therapies.
The subject of this thesis is the control of strain in HgTe thin-film crystals. Such systems are members of the new class of topological insulator materials and therefore of special research interest. A major task was the experimental control of the strain in the HgTe films. This was achieved by a new epitaxial approach and confirmed by cristallographic analysis and magneto-transport measurements.
In this work, strain was induced in thin films by means of coherent epitaxy on substrate crystals. This means that the film adopts the lattice constant of the substrate in the plane of the substrate-epilayer interface. The level of strain is determined by the difference between the strain-free lattice constants of the substrate and epilayer material (the so-called lattice mismatch). The film responds to an in-plane strain with a change of its lattice constant perpendicular to the interface. This relationship is crucial for both the correct interpretation of high resolution X-ray diffraction (HRXRD) measurements, and the precise determination of the band dispersion. The lattice constant of HgTe is smaller than the lattice constant of CdTe. Therefore, strain in HgTe is tensile if it is grown on a CdTe substrate. In principle, compressive strain can be achieved by using an appropriate \(\text{Cd}_{1-x}\text{Zn}_{x}\text{Te}\) substrate. This concept was modified and applied in this work.
Epilayers have been fabricated by molecular-beam epitaxy (MBE). The growth of thick buffer layers of CdTe on GaAs:Si was established as an alternative to commercial CdTe and \(text{Cd}_{0.96}\text{Zn}_{0.04}\text{Te}\) substrates. The growth conditions have been optimized by an analysis of atomic force microscopy and HRXRD studies. HRXRD measurements reveal a power-law increase of the crystal quality with increasing thickness. Residual strain was found in the buffer layers, and was attributed to a combination of finite layer thickness and mismatch of the thermal expansion coefficients of CdTe and GaAs. In order to control the strain in HgTe epilayers, we have developed a new type of substrate with freely adjustable lattice constant.
CdTe-\(\text{Cd}_{0.5}\text{Zn}_{0.5}\text{Te}\) strained-layer-superlattices have been grown by a combination of MBE and atomic-layer epitaxy (ALE), and have been analyzed by HRXRD. ALE of the \(\text{Cd}_{0.5}\text{Zn}_{0.5}\text{Te}\) layer is self-limiting to one monolayer, and the effective lattice constant can be controlled reproducibly and straightforward by adjusting the CdTe layer thickness. The crystal quality has been found to degrade with increasing Zn-fraction. However, the effect is less drastic compared to single layer \(\text{Cd}_{1-x}\text{Zn}_{x}\text{Te}\) solid solutions. HgTe quantum wells (QWs) sandwiched in between CdHgTe barriers have been fabricated in a similar fashion on superlattices and conventional CdTe and \(\text{Cd}_{0.96}\text{Zn}_{0.04}\text{Te}\) substrates. The lower critical thickness of the CdHgTe barrier material grown on superlattice substrates had to be considered regarding the sample design. The electronic properties of the QWs depend on the strain and thickness of the QW. We have determined the QW thickness with an accuracy of \(\pm\)0.5 nm by an analysis of the beating patterns in the thickness fringes of HRXRD measurements and X-ray reflectometry measurements. We have, for the first time, induced compressive strain in HgTe QWs by an epitaxial technique (i.e. the effective lattice constant of the superlattice is lower compared to the lattice constant of HgTe). The problem of the lattice mismatch between superlattice and barriers has been circumvented by using CdHgTe-ZnHgTe superlattices instead of CdHgTe as a barrier material. Furthermore, the growth of compressively strained HgTe bulk layers (with a thickness of at least 50 nm) was demonstrated as well.
The control of the state of strain adds a new degree of freedom to the design of HgTe epilayers, which has a major influence on the band structure of QWs and bulk layers. Strain in bulk layers lifts the degeneracy of the \(\Gamma_8\) bands at \(\mathbf{k}=0\). Tensile strain opens an energy gap, compressive strain shifts the touching points of the valence- and conduction band to positions in the Brillouin zone with finite \(\mathbf{k}\). Such a situation has been realized for the first time in the course of this work. For QWs in the inverted regime, it is demonstrated that compressive strain can be used to significantly enhance the thermal energy gap of the two-dimensional electron gas (2DEG). In addition, semi-metallic and semiconducting behavior is expected in wide QWs, depending on the state of strain. An examination of the temperature dependence of the subband ordering in QWs revealed that the band gap is only temperature-stable for appropriate sample parameters and temperature regimes. The band inversion is always lifted for sufficiently high temperatures.
A large number of models investigate the influence of the band gap on the stability of the quantum-spin-Hall (QSH) effect. An enhancement of the stability of QSH edge state conductance is expected for enlarged band gaps. Furthermore, experimental studies on the temperature dependence of the QSH conductance are in contradiction to theoretical predictions. Systematic studies of these aspects have become feasible based on the new flexibility of the sample design.
Detailed low-temperature magnetotransport studies have been carried out on QWs and bulk layers. For this purpose, devices have been fabricated lithographically, which consist of two Hall-bar geometries with different dimensions. This allows to discriminate between conductance at the plane of the 2DEG and the edge of the sample. The Fermi energy in the 2DEG has been adjusted by means of a top gate electrode. The strain-induced transition from semi-metallic to semiconducting characteristics in wide QWs was shown. The magnitude of the semi-metallic overlap of valence- and conduction band was determined by an analysis of the two-carrier conductance and is in agreement with band structure calculations. The band gap of the semiconducting sample was determined by measurements of the temperature dependence of the conductance at the charge-neutrality point. Agreement with the value expected from theory has been achieved for the first time in this work. The influence of the band gap on the stability of QSH edge state conductance has been investigated on a set of six samples. The band gap of the set spans a range of 10 to 55 meV. The latter value has been achieved in a highly compressively strained QW, has been confirmed by temperature-dependent conductance measurements, and is the highest ever reported in the inverted regime. Studies of the carrier mobility reveal a degradation of the sample quality with increasing Zn-fraction in the superlattice, in agreement with HRXRD observations. The enhanced band gap does not suppress scattering mechanisms in QSH edge channels, but lowers the conductance in the plane of the 2DEG. Hence, edge state conductance is the dominant conducting process even at elevated temperatures. An increase in conductance with increasing temperature has been found, in agreement with reports from other groups. The increase follows a power-law dependency, the underlying physical mechanism remains open. A cause for the lack of an increase of the QSH edge state conductance with increasing energy gap has been discussed. Possibly, the sample remains insulating even at finite carrier densities, due to localization effects. The measurement does not probe the QSH edge state conductance at the situation where the Fermi energy is located in the center of the energy gap, but in the regime of maximized puddle-driven scattering. In a first set of measurements, it has been shown that the QSH edge state conductance can be influenced by hysteretic charging effects of trapped states in the insulating dielectric. A maximized conductance of \(1.6\ \text{e}^2/\text{h}\) was obtained in a \(58\ \mu\text{m}\) edge channel. Finally, measurements on three dimensional samples have been discussed. Recent theoretical works assign compressively strained HgTe bulk layers to the Weyl semi-metal class of materials. Such layers have been synthesized and studied in magnetotransport experiments for the first time. Pronounced quantum-Hall- and Shubnikov-de-Haas features in the Hall- and longitudinal resistance indicate two-dimensional conductance on the sample surface. However, this conductance cannot be assigned definitely to Weyl surface states, due to the inversion of \(\Gamma_6\) and \(\Gamma_8\) bands. If a magnetic field is aligned parallel to the current in the device, a decrease in the longitudinal resistance is observed with increasing magnetic field. This is a signature of the chiral anomaly, which is expected in Weyl semi-metals.
Within this thesis, synthetic strategies for self-assembled organic cage compounds have been developed that allow for both stimuli-responsive control over assembly/disassembly processes and spatial control over functionalization. To purposefully operate the reversible assembly of organic cages, boron-nitrogen dative bonds have been exploited for the formation of a well-defined, discrete bipyramidal organic assembly in solution. Thermodynamic association equilibria for cage formation have been investigated by Isothermal Titration Calorimetry (ITC). Temperature-dependent NMR studies revealed a reversible cage opening upon heating and quantitative reassembly upon cooling. For the spatial functionalization of organic cages, two divergent molecular building units have been designed and synthesized, namely tribenzotriquinacene derivatives possessing a terminal alkyne moiety at the apical position and a meta-diboronic acid having a pyridyl group at the 2-position. Facile access to a variety of apically functionalized tribenzotriquinacenes has been illustrated by post-synthetic modifications at the terminal alkyne group by Sonogashira cross-coupling and azide-alkyne click reactions. Finally, these apically functionalized tribenzotriquinacene building blocks have been implemented into boronate ester-based organic cage compounds showing modular exohedral functionalities.
A search for high-energy neutrino emission correlated with gamma-ray bursts outside the electromagnetic prompt-emission time window is presented. Using a stacking approach of the time delays between reported gamma-ray burst alerts and spatially coincident muon-neutrino signatures, data from the Antares neutrino telescope recorded between 2007 and 2012 are analysed. One year of public data from the IceCube detector between 2008 and 2009 have been also investigated. The respective timing profiles are scanned for statistically significant accumulations within 40 days of the Gamma Ray Burst, as expected from Lorentz Invariance Violation effects and some astrophysical models. No significant excess over the expected accidental coincidence rate could be found in either of the two data sets. The average strength of the neutrino signal is found to be fainter than one detectable neutrino signal per hundred gamma-ray bursts in the Antares data at 90% confidence level.
Successful formulation development of novel, particularly organic APIs of low molecular weight as candidates for ground-breaking pharmaceutical products is a major challenge for the pharmaceutical industry because of the poor aqueous solubility of most of these compounds.
The hit identification strategies of drug development in use today apply high throughput screening techniques for the investigation of thousands of substances. This approach led to a systematical increase in molecular weight and lipophilicity and a decrease of water solubility of lead compounds reaching market access.
The high lipophilicity causes an excellent permeability of the compounds which favours the absorption process from the small intestine, but it causes a decrease of water-solubility. It becomes evident that an adequate aqueous solubility is necessary for absorption of the API from the gastrointestinal fluids into the systemic circulation and hence for efficacy of the pharmaceutical product. Only an dissolved API is getting absorbed and becomes efficacious. The precipitated proportion is resigned directly. Therefore, the development of an individual formulation aligning the physicochemical characteristics is necessary for every API to produce supersaturated solutions in the small intestine and to reach an adequate bioavailability after absorption into the systemic circulation.
In this thesis a specific formulation development was investigated for two exemplary poorly water-soluble APIs to replace the empirical approach often used today. The basic tyrosine-kinase inhibitor imatinib and six different acetylated amino acids were transferred into ILs. As compared to the free base and the mesylate salt, which is marketed by Novartis AG as Gleevec®, the dissolution rate as well as the supersaturation time was increased significantly. By changing the mesylate anion with its potential genotoxic risks, the total toxicity of the drug product could be decreased. The amorphous ILs proved adequate stability under forcing conditions and there was no recrystallization of the free base observed. The amorphous character of the ILs caused an increased amount of water vapour sorption which can be compensated by special packaging materials. Taken together, the presentation of imatinib as an IL is intended for oral administration as a tablet and can cause a reduction of dose because of the increased solubility. Therefore, the occurrence of side effects can be reduced as compared to Gleevec®. If there is actually an increased bioavailability to observe, has to be proved by the execution of animal trials.
The novel NOX inhibitor VAS3947 is intended for the treatment of endothelial dysfunctions causing diseases like heart failure and stroke. The compounds poor aqueous solubility hindered further clinical development so far and make the drug candidate to remain in a very early stage of the drug development process. Therefore, different formulation concepts were evaluated in this study:
An amorphous solid dispersion prepared from VAS3947 and Eudragit® L100 by means of spray drying was able to increase the dissolution rate and solubility of the compound significantly, but with the accomplished kinetic solubility being in the low µM range it is not possible to reach therapeutic plasma concentrations.
In contrast, the incorporation into cyclodextrins resulted in an 760-fold increased solubility. Different cyclodextrins were evaluated. Especially the lipophilic derivatives of the β-cyclodextrin showed to be the most adequate excipients. The incorporation of the API into the cyclodextrin cavity was proved by means of NMR spectroscopy. Additionally, a formulation of VAS3947 and hydroxypropyl-β-cyclodextrin was prepared. This formulation is intended for the intravenous application during animal trials, which have to be conducted to get to know the pharmacokinetics of VAS3947. This formulation reached a concentration of 1 mg/mL spending striking protection of VAS3947 against degradation.
Presentation of VAS3947 as a microemulsion system led also to increase the aqueous solubility of the compound, but not in the same extent as the cyclodextrin formulation. Beside the formulation development a physicochemical characterization was performed to get to know important parameters such as log P and pKa values of VAS3947. An HPLC method was developed and validated to analyse the extent of solubility improvement.
A major issue of the compound VAS3947 and all related triazolopyrimidine derivatives, developed by Vasopharm GmbH, is the insufficient chemical stability because of presence of a hemiaminal moiety in the chemical structure. Stability investigations and an extensive biopharmaceutical characterization confirm the hindering of further clinical development by insufficient drug stability and high cytotoxicity. Poor aqueous solubility is an additional disadvantage which can be handled by a concerted formulation development.
Macrophages predominate the inflammatory landscape within multiple sclerosis (MS) lesions, not only regarding cellularity but also with respect to the diverse functions this cell fraction provides during disease progression and remission. Researchers have been well aware of the fact that the macrophage pool during central nervous system (CNS) autoimmunity consists of a mixture of myeloid cells. Yet, separating these populations to define their unique contribution to disease pathology has long been challenging due to their similar marker expression. Sophisticated lineage tracing approaches as well as comprehensive transcriptome analysis have elevated our insight into macrophage biology to a new level enabling scientists to dissect the roles of resident (microglia and non-parenchymal macrophages) and infiltrating macrophages with unprecedented precision. To do so in an accurate way, researchers have to know their toolbox, which has been filled with diverse, discriminating approaches from decades of studying neuroinflammation in animal models. Every method has its own strengths and weaknesses, which will be addressed in this review. The focus will be on tools to manipulate and/or identify different macrophage subgroups within the injured murine CNS.
Spin- and angle-resolved photoelectron spectroscopy is the prime method to investigate
spin polarized electronic states at solid state surfaces. In how far the spin polarization
of an emitted photoelectron reflects the intrinsic spin character of an electronic state is
the main question in the work at hand. It turns out that the measured spin polarization
is strongly influenced by experimental conditions, namely by the polarization of the
incoming radiation and the excitation energy. The photoemission process thus plays a
non-negligible role in a spin-sensitive measurement. This work is dedicated to unravel
the relation between the result of a spin-resolved measurement and the spin character
in the ground state and, therefore, to gain a deep understanding of the spin-dependent
photoemission process.
Materials that exhibit significant spin-splittings in their electronic structure,
owing to a strong spin-orbit coupling, serve as model systems for the investigations in
this work. Therefore, systems with large Rashba-type spin-splittings as BiTeI(0001)
and the surface alloys BiAg2/Ag(111) and PbAg2/Ag(111) are investigated. Likewise,
the surface electronic structure of the topological insulators Bi2Te2Se(0001) and
Bi2Te3(0001) are analyzed.
Light polarization dependent photoemission experiments serve as a probe of the
orbital composition of electronic states. The knowledge of the orbital structure helps
to disentangle the spin-orbital texture inherent to the different surface states, when
in addition the spin-polarization is probed. It turns out that the topological surface
state of Bi2Te2Se(0001) as well as the Rashba-type surface state of BiTeI(0001) exhibit
chiral spin-textures associated with the p-like in-plane orbitals. In particular, opposite
chiralities are coupled to either tangentially or radially aligned p-like orbitals,
respectively. The results presented here are thus evidence that a coupling between
spin- and orbital part of the wave function occurs under the influence of spin-orbit
coupling, independent of the materials topology.
Systematic photon energy dependent measurements of the out-of-plane spin polarization
of the topological surface state of Bi2Te3(0001) reveal a strong dependence and
even a reversal of the sign of the photoelectron spin polarization with photon energy.
Similarly, the measured spin component perpendicular to the wave vector of the surface
state of BiAg2/Ag(111) shows strong modulations and sign reversals when the photon energy is changed. In BiAg2/Ag(111) the variations in the photoelectron spin
polarization are accompanied by significant changes and even a complete suppression
of the photoemission intensity from the surface state, indicating that the variations of
the spin polarization are strongly related to the photoemission cross section.
This relation is finally analyzed in detail by employing a simple model, which is
based on an evaluation of the transition matrix elements that describe the presented
experiments. The model shows that the underlying cause for the observed photoelectron
spin reversals can be found in the coupling of the spin structure to the spatial part
of the initial state wave function, revealing the crucial role of spin-orbit interaction
in the initial state wave function. The model is supported by ab initio photoemission
calculations, which show strong agreement with the experimental results.
Neisseria gonorrhoeae, the causative agent of the sexually transmitted disease gonorrhea, has the potential to spread in the human host and cause a severe complication called disseminated gonococcal infection (DGI). The expression of the major outer membrane porin PorBIA is a characteristic of most gonococci associated with DGI. PorBIA binds to the scavenger receptor expressed on endothelial cells (SREC-I), which mediates the so-called low phosphate-dependent invasion (LPDI). This uptake mechanism enables N. gonorrhoeae to rapidly invade epithelial and endothelial cells in a phosphate-sensitive manner.
We recently demonstrated that the neutral sphingomyelinase, which catalyses the hydrolysis of sphingomyelin to ceramide and phosphorylcholine, is required for the LPDI of gonococci in non-phagocytic cells. Neutral sphingomyelinase 2 (NSM2) plays a key role in the early PorBIA signaling by recruiting the PI3 kinase to caveolin. The following activation of the PI3 kinase-dependent downstream signaling leads to the engulfment of the bacteria. As a part of this work, I could confirm the involvement of the NSM2. The role of the enzyme was further elucidated by the generation of antibodies directed against NSM2 and the construction of an epithelium-based NSM2 knockout cell line using CRISPR/Cas9. The knockout of the NSM2 strongly inhibits the LPDI. The invasion could be, however, restored by the complementation of the knockout using an NSM2-GFP construct. However, the results could not be reproduced.
In this work, I could show the involvement of further members of the sphingolipid pathway in the PorBIA-mediated invasion. Lipidome analysis revealed an increase of the bioactive molecules ceramide and sphingosine due to gonococcal infection. Both molecules do not only affect the host cell, but seem to influence the bacteria as well: while ceramide seems to be incorporated by the gonococci, sphingosine is toxic for the bacteria. Furthermore, the sphingosine kinase 2 (SPHK2) plays an important role in invasion, since the inhibition and knockdown of the enzyme revealed a negative effect on gonococcal invasion. To elucidate the role of the sphingosine kinases in invasion in more detail, an activity assay was established in this study. Additionally, the impact of the sphingosine-1-phosphate lyase (S1PL) on invasion was investigated. Inhibitor studies and infection experiments conducted with a CRISPR/Cas9 HeLa S1PL knockout cell line revealed a role of the enzyme not only in the PorBIA-mediated invasion, but also in the Opa50/HSPG-mediated gonococcal invasion. The signaling experiments allowed the categorization of the SPHK and S1PL activation in the context of infection. Like the NSM2, both enzymes play a role in the early PorBIA signaling events leading to the uptake of the bacteria. All those findings indicate an important role of sphingolipids in the invasion and survival of N. gonorrhoeae.
In the last part of this work, the role of the NSM2 in the inhibition of apoptosis in neutrophils due to gonococcal infection was investigated. It could be demonstrated that the delayed onset of apoptosis is independent of neisserial porin and Opa proteins. Furthermore, the influence of neisserial peptidoglycan on PMN apoptosis was analysed using mutant strains, but no connection could be determined. Since the NSM2 is the most prominent sphingomyelinase in PMNs, fulfils manifold cell physiological functions and has already been connected to apoptosis, the impact of the enzyme on apoptosis inhibition due to gonococcal infection was investigated using inhibitors, with no positive results.
Soft x-ray spectroscopic study of methanol and glycine peptides in different physical environments
(2017)
Ion-specific effects occur in a huge variety of aqueous solutions of electrolytes and larger molecules like peptides, altering properties such as viscosity, enzyme activity, protein stability, and salting-in and salting-out behavior of proteins. Typically, these type of effects are rationalized in terms of the Hofmeister series, which originally orders cations and anions according to their ability to enhance or suppress the solubility of proteins in water. This empirical order, however, is still not understood yet. Quite some effort was made to gain a molecular level understanding of this phenomenon, yet no consensus has been found about the underlying mechanisms and the determination and localization of the interaction sites.
Resonant inelastic soft x-ray scattering (RIXS) combines x-ray emission (XES) and absorption spectroscopies (XAS), probing the partial local density of states of both occupied and unoccupied electronic states and is thus a promising candidate to shed more light onto the issue. The studies presented in this work are directed towards an improved understanding of the interaction between salts and peptides. In order to address this topic, the impact of different physical environments on the electronic structure of small molecules (i.e., methanol and glycine derived peptides) is investigated systematically using soft x-ray spectroscopic methods, corroborated with density functional theory (DFT) calculations.
In a first step, molecules without any interactions to the surrounding are investigated, using gas-phase methanol as a model system. Thereby, the local and element specific character of RIXS is demonstrated and used to separately probe the local electronic structure of methanol’s hydroxyl and methyl group, respectively. The attribution of the observed emission features to distinct molecular orbitals is confirmed by DFT calculations, which also quantitatively explain the different relative intensities of the emission features. For resonant excitation of the O K pre-edge absorption resonance, strong isotope effects are found that are explained by dynamical processes at the hydroxyl group. This serves as an excellent example for possible consequences of a local change in the geometric structure or symmetry of a molecule on its electronic structure.
In the following, the sample system is expanded to the amino acid glycine and its smallest derived peptides diglycine and triglycine. As a first step, they are studied in their crystalline form in solid state. Again, a comprehensive picture of the electronic structure is developed by measuring RIXS maps at the oxygen and nitrogen K absorption edge, corroborated by DFT calculations. Similar to the case of methanol, dynamic processes at the protonated amino group of the molecules after exciting the nitrogen atom have a strong influence on the emission spectra. Furthermore, it is shown that RIXS can be used to selectively excite the peptide nitrogen to probe the electronic structure around it. A simple building block approach for XES spectra is applied to separate the contribution of the emission attributed to transitions into core holes at the peptide and the amino nitrogen, respectively.
In the aqueous solution, the surrounding water molecules slightly change the electronic structure, probably via interactions with the charged functional groups. The effects on the x-ray emission spectra, however, are rather small. Much bigger changes are observed when manipulating the protonation state of the functional groups by adjusting the pH value of the solution. A protonation of the carboxyl group at low pH values, as well as a deprotonation of the amino group at high pH values lead to striking changes in the shape of the RIXS maps. In a comprehensive study of glycine’s XES spectra at varying pH values, changes in the local electronic structure are not only observed in the immediate surrounding of the manipulated functional groups but also in more distant moieties of the molecule.
Finally, the study is extended to mixed aqueous solutions of diglycine and a variety of different salts as examples for systems where Hofmeister effects are observed. To investigate the influence of different cations and anions on the electronic structure of diglycine, two series of chlorine and potassium salts are used. Ion-specific effects are identified for both cases. Some of the changes in the x-ray emission spectra of diglycine in the mixed solutions qualitatively follow the Hofmeister series as a function of the used salt. The observed trends thereby indicate an increased interaction between the electron density around the peptide oxygen with the cations, whereas anions seem to interact with the amino group of the peptide.
Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to HG. In contrast, myo-inositol (transported through SMIT1) reproduced the toxic effects of HG. SMIT1 overexpression exacerbated glucotoxicity and sensitized cardiomyocytes to HG, whereas its deletion prevented HG-induced NOX2 activation. In conclusion, our results show that heart SMIT1 senses HG and triggers NOX2 activation. This could participate in the redox signaling in hyperglycemic heart and contribute to the pathophysiology of diabetic cardiomyopathy.
Site Directed Immobilization of BMP-2: Two Approaches for the Production of Osteoinductive Scaffolds
(2017)
Bone fractures typically heal without surgical intervention. However, pathological situations exist which impede the healing process resulting in so-called non-union fractures. Such fractures are nowadays treated with scaffold material being introduced into the defect area. These scaffolds can be doped with osteogenic factors, such as bone morphogenetic protein (BMP)2. BMP2 belongs to the most osteogenic growth factors known to date. Its medical use, efficiency and safety have been approved by FDA for certain applications. Currently, BMP2 is distributed with a stabilizing scaffold, which is simply soaked with the growth factor. Due to fast release kinetics supraphysiological high doses of BMP2 are required which are causally associated with severe side effects observed in certain applications being most harmful in the area of the cervical spine. These side-effects include inflammation, swelling and breathing problems, leading to disastrous consequences or secondary surgical interventions. Since it could be shown that a retardation of BMP2 release from the scaffold resulted in superior bone forming properties in vivo, it seems obvious to further reduce this release to a minimum. This can be achieved by covalent coupling which in the past was already elaborated using mainly classical EDC/NHS chemistry. Using this technique coupling of the protein occurs non-site-directedly leading mainly to an unpredictable product outcome with variable osteogenic activities. In order to improve the reproducibility of scaffold functionalization by BMP2 we created variants one of which contains a unique unnatural amino acid substitution within the mature polypeptide sequence (BMP2-K3Plk) and another, BMP2-A2C, in which an N-terminal alanine has been substituted by cysteine. These modifications enable site-specific and covalent immobilization of BMP2 e.g. onto polymeric beads. Both proteins were expressed in E. coli, renatured and purified by cation-exchange chromatography. Both variants were extensively analyzed in terms of purity and biological activity which was tested by in vitro interaction analyses as well as in cell based assays. Both proteins could be successfully coupled to polymeric beads. The different BMP2 functionalized beads were shown to interact with the ectodomain of the type I receptor BMPR-IA in vitro indicating that the biological activity of both BMP2 variants retained upon coupling. Both functionalized beads induced osteogenic differentiation C2C12 cells but only of those cells which have been in close contact to the particular beads. This strongly indicates that the BMP2 variant are indeed covalently coupled and not just adsorbed.
We claim that we have developed a system for a site-specific and covalent immobilization of BMP-2 onto solid scaffolds, potentially eliminating the necessity of high-dose scaffold loading. Since immobilized proteins are protected from removal by extracellular fluids, their activities now rely mainly on the half-life of the used scaffold and the rate of proteolytic degradation. Assuming that due to prolonged times much lower loading capacities might be required we propose that the immobilization strategy employed in this work may be further refined and optimized to replace the currently used BMP2-containing medical products.