Refine
Is part of the Bibliography
- yes (163)
Year of publication
- 2019 (163) (remove)
Document Type
- Doctoral Thesis (163) (remove)
Language
- English (163) (remove)
Keywords
- Tissue Engineering (6)
- Drosophila melanogaster (4)
- Hydrogel (4)
- Maschinelles Lernen (4)
- Taufliege (4)
- Übergangsmetalloxide (4)
- 3D-Druck (3)
- Ancistrocladaceae (3)
- Chronobiologie (3)
- Elektrophysiologie (3)
- Fluoreszenzmikroskopie (3)
- Genexpression (3)
- Leistungsbewertung (3)
- Maus (3)
- Megakaryozyt (3)
- Raman-Spektroskopie (3)
- Schlaganfall (3)
- Soziale Wahrnehmung (3)
- AdS/CFT (2)
- Aggregation (2)
- Angst (2)
- Aufmerksamkeit (2)
- Bilanzpolitik (2)
- Bildverarbeitung (2)
- Bioinformatik (2)
- Biomaterial (2)
- Blutgerinnung (2)
- Channelrhodopsin (2)
- Deutschland (2)
- Gedächtnis (2)
- Halbleiter (2)
- Implantat (2)
- In vitro (2)
- Inhibitor (2)
- Kernspintomografie (2)
- Knochenzement (2)
- Kognition (2)
- Lungenkrebs (2)
- Machine Learning (2)
- Merocyanine (2)
- Mitose (2)
- Molekulargenetik (2)
- Muscarinrezeptor (2)
- Naphthylisochinolinalkaloide (2)
- Optimierung (2)
- Optogenetik (2)
- Perylenderivate (2)
- Quanten-Vielteilchensysteme (2)
- Quantum Information (2)
- Quantum many-body systems (2)
- Regenerative Medizin (2)
- Röntgen-Photoelektronenspektroskopie (2)
- Selbstorganisation (2)
- Serotonin (2)
- Signaltransduktion (2)
- Spektroskopie (2)
- Staphylococcus aureus (2)
- Supramolekulare Chemie (2)
- Telekommunikationsnetz (2)
- Thrombozyt (2)
- Vaskularisierung (2)
- Verhalten (2)
- Zellteilung (2)
- antibiotics (2)
- biofabrication (2)
- dSTORM (2)
- hydrogel (2)
- in vitro (2)
- megakaryopoiesis (2)
- (hem)ITAM signaling (1)
- 2D material (1)
- 3D (1)
- 3D Bioprinting (1)
- 3D Modell (1)
- 3D Point Cloud Processing (1)
- 3D Tumormodell (1)
- 3D model (1)
- 3D printing (1)
- 3D tissue model (1)
- 3D tumour model (1)
- 3D-Modell (1)
- 4-HNE (1)
- A-D-A dyes (1)
- A-priori-Wissen (1)
- A. abbreviatus (1)
- A. likoko (1)
- ADHD (1)
- AMP‐activated protein kinase (1)
- APOBEC3G (1)
- Abfallbehandlung (1)
- Abfallwirtschaft (1)
- Absorbed Doses (1)
- Abszision (1)
- Ackerschmalwand (1)
- Actin (1)
- Actin-bindende Proteine (1)
- Active Galactic Nuclei (1)
- AdS-CFT-Korrespondenz (1)
- AdS/CFT correspondence (1)
- Adaptation (1)
- Adhesion GPCR (1)
- Adipositas (1)
- Administered Activities (1)
- Advanced Analytics (1)
- Affekt (1)
- African Trypanosomiasis (1)
- Akt (1)
- Aktionsforschung (1)
- Alkaloid (1)
- Aminerge Nervenzelle (1)
- Amygdala (1)
- Angiogenese (1)
- Angstverarbeitung (1)
- Animales Nervensystem (1)
- Anisotropic Magnetoresistance (1)
- Annotation (1)
- Anreize (1)
- Anti-infective (1)
- Antibiotikum (1)
- Antigen CD19 (1)
- Antigen CD28 (1)
- Antigenrezeptor (1)
- Antikörper (1)
- Antimalariamittel (1)
- Antizipation (1)
- Anxiety (1)
- Arabidopsis thaliana (1)
- Arbeitsmobilität (1)
- Aromatically annulated triquinacenes (1)
- Aromatisch anellierte Triquinacene (1)
- Arzneimittel (1)
- Assistenzbedarf (1)
- Astronomie (1)
- Astroteilchenphysik (1)
- Attitude Determination and Control (1)
- Attitude Dynamics (1)
- Audit Quality (1)
- Audit sampling (1)
- Aufsichtsrat (1)
- Autoaggressionskrankheit (1)
- Autoproteolysis (1)
- Auxine (1)
- Außenhandel (1)
- B-MYB (1)
- BRAF-mutant (1)
- BRAF-mutiert (1)
- BaBiO3 (1)
- Bank (1)
- Banking (1)
- Behaviour (1)
- Benchmarking (1)
- Benutzeroberfläche (1)
- Berechnung (1)
- Berufsbildung (1)
- Big Data (1)
- Bildbearbeitung (1)
- Bildgebung intakten Knochens (1)
- Bildungswesen (1)
- Biofabrication (1)
- Biofabrikation (1)
- Biofilm (1)
- Biofilmarchitektur (1)
- Bioink (1)
- Biokinetics (1)
- Biologika (1)
- Biomedicine (1)
- Bioreaktor (1)
- Biotinten (1)
- Bioverfügbarkeit (1)
- Biradikal (1)
- Black holes (1)
- Blazar (1)
- Brustkrebs (1)
- C/EBP (1)
- CDC42 (1)
- Cadherine (1)
- Caenorhabditis elegans (1)
- Calcium (1)
- Calciumphosphat (1)
- Calciumphosphate (1)
- Calciumphosphatzemente (1)
- Candida albicans (1)
- Capillary Electrophoresis (1)
- Carotisstenose (1)
- Cataglyphis (1)
- Cdh13 (1)
- Cell migration (1)
- Ceramic polymer composite (1)
- Channelrhodopsin-2 (1)
- Charge carrier recombination (1)
- Charge-transfer-Komplexe (1)
- Chelatbildner (1)
- Chemical stability (1)
- Chemische Synthese (1)
- Chimeric Antigen Receptor (1)
- Chimärer Antigenrezeptor (1)
- China (1)
- Chiral spin liquids (1)
- Chirale Spinflússigkeiten (1)
- Chlamydia trachomatis (1)
- Chondrogenesis (1)
- Chromatographie (1)
- Chronische Nierenerkrankung (1)
- Chronobiology (1)
- Click Chemie (1)
- Clinical Data Warehouse (1)
- CoQ10 (1)
- Codon (1)
- Coherent Multidimensional Spectroscopy (1)
- Commuting (1)
- Complexity (1)
- Computersimulation (1)
- Confidence intervals (1)
- Conformal Metrics (1)
- Congolese Ancistrocladus plants (1)
- Conical Intersections (1)
- Construct Modeling (1)
- Controlling (1)
- Corporate Governance (1)
- Corporate Social Responsibility (1)
- Correlated Electron Materials (1)
- Correlated Fermions (1)
- Curvature Equation (1)
- Cushing-Syndrom (1)
- Cysteinproteasen (1)
- Cytokine (1)
- Cytologie (1)
- DCAF17 (1)
- DNA damage (1)
- DNA-Schäden (1)
- DPP IV (1)
- DRG (1)
- DROSHA (1)
- Data Analytics (1)
- Data Warehouse (1)
- Data-Warehouse-Konzept (1)
- Decision Support (1)
- Declarative Performance Engineering (1)
- Demokratische Republik Kongo (1)
- Dendritic cell (1)
- Dendritische Zelle (1)
- Dental Phobia (1)
- Depression (1)
- Development (1)
- Dezellularisierung (1)
- Diabetes mellitus (1)
- Diagnostic Imaging Exams (1)
- Dickdarmtumor (1)
- Dopamin (1)
- Dosimetry (1)
- Dosis (1)
- Dotierung (1)
- Drosophila (1)
- Drug delivery platforms (1)
- Drug testing (1)
- Dual setting system (1)
- Dynamical Systems (1)
- Dynamical system (1)
- Dünne Schicht (1)
- Dünnschichten (1)
- E-Learning (1)
- Earnings Management (1)
- Earnings Quality (1)
- Earnings management (1)
- Ecology (1)
- Efficiency (1)
- Efficiency Gains (1)
- Effizienzsteigerung (1)
- Eierstockkrebs (1)
- Einkommensverteilung (1)
- Einwandige Kohlenstoff-Nanoröhre (1)
- Einzelmolekülmikroskopie (1)
- Electromagnon (1)
- Electrophysiology (1)
- Electrospinning (1)
- Elektrizitätsverbrauch (1)
- Elektromagnon (1)
- Elektron-Phonon-Wechselwirkung (1)
- Elektronentransfer (1)
- Elektrospinnen (1)
- Emotionales Verhalten (1)
- Enantiomerentrennung (1)
- Endogene Rhythmik (1)
- Endothel (1)
- Energieeffizienz (1)
- Energy Efficiency (1)
- Entscheidungsunterstützung (1)
- Entscheidungsunterstützungssystem (1)
- Entwicklung (1)
- Entzündung (1)
- Epitaxy (1)
- Erfolgsplanung (1)
- European Organization for Nuclear Research. ATLAS Collaboration (1)
- Exciton coupling (1)
- Experimental Studies (1)
- Experimentelle Psychologie (1)
- Expiry date (1)
- Explosives (1)
- Explosivstoff (1)
- Extrazelluläre Matrix (1)
- Exziton (1)
- Exziton-Polariton (1)
- Exzitonenkopplung (1)
- Face Voice Matching (1)
- Fahrerassistenzsystem (1)
- Farbstoff (1)
- Fear Generalization (1)
- Fear Learning (1)
- Fertigarzneimittel (1)
- Festkörperphysik (1)
- Fibroblastenwachstumsfaktor (1)
- Finite support distributions (1)
- Fliegenkippen (1)
- Fluoreszenzspektroskopie (1)
- Fluorine (1)
- Fluorverbindungen (1)
- Flüssigkristall (1)
- Fotochemie (1)
- Fotophysik (1)
- Fourier-Spektroskopie (1)
- Fractional quantum Hall effect (1)
- Fraktionaler Quanten-Hall-Effekt (1)
- Functional Connectivity (1)
- Funktionalisierung <Chemie> (1)
- Funktionalisierung von elektrogesponnenen Fasern (1)
- Funktionelle Konnektivität (1)
- Furchkonditionierung (1)
- Furcht (1)
- Furchtgeneralisierung (1)
- G Protein-coupled receptor (1)
- G-Protein gekoppelte Rezeptor (1)
- G-quadruplex (1)
- Ga-68-labelled Peptides (1)
- Gallensalze (1)
- Gas chromatography (1)
- Gauge/Gravity Duality (1)
- Gelatine (1)
- Gen-Umwelt Interaktion (1)
- Gene by Environment (1)
- Generalisierung (1)
- Generalisierung <Kartografie> (1)
- Genetik (1)
- Genmutation (1)
- Genom (1)
- Genome Annotation (1)
- Gesicht (1)
- Gestational diabetes (1)
- Gestationsdiabetes (1)
- Gitterdynamik (1)
- Gliazelle (1)
- Glycidol (1)
- Glycoengineering (1)
- Glykane (1)
- Glykosylierung (1)
- Governance (1)
- Graft versus host disease (1)
- Graph (1)
- Grenzfläche (1)
- Grenzflächenleitfähigkeit (1)
- Grundlagenforschung (1)
- GvHD (1)
- Gyrasehemmer (1)
- HARPES (1)
- HNE (1)
- HPLC (1)
- Hard X-ray Angle Resolved Photoemission (1)
- Haut (1)
- Helicasen (1)
- Herzmuskelzelle (1)
- Heterosolarzelle (1)
- Heterostruktur (1)
- High-Z Oxides (1)
- High-energy astrophysics (1)
- Hippo pathway (1)
- Hippocampus (1)
- Hochauflösende Fluoreszenzmikroskopie (1)
- Holstein model (1)
- Holstein-Modell (1)
- Hormontransport (1)
- Host Genome Integrity (1)
- Human Body Weight (1)
- Human Herpesvirus 6 (1)
- Human-Computer Interaction (1)
- Humanes Herpesvirus 6 (1)
- Humangenetik (1)
- Hyaluronic Acid (1)
- Hyaluronsäure (1)
- Hybrid Dynamical Systems (1)
- Hybridsystem (1)
- Hypoxia (1)
- Hypoxie (1)
- Ideomotor Theory (1)
- Ideomotorik (1)
- Image Processing (1)
- Imatinib (1)
- Immunologe (1)
- Immuntherapie (1)
- Imo Bundesstaat (1)
- Imo State - Nigeria (1)
- Individualität (1)
- Induzierte pluripotente Stammzelle (1)
- Inflammatory Pain (1)
- Inflammatory pain (1)
- Information (1)
- Information Extraction (1)
- Information seeking and sharing (1)
- Informationsverarbeitung (1)
- Inhibition (1)
- Innovation (1)
- Input-Output-Tabelle (1)
- Insulin (1)
- Insulin-like Growth Factor I (1)
- Insulin-like growth factor-I (1)
- Integrine (1)
- Intention (1)
- Intentional Nonaction (1)
- Intentionale Nichthandlung (1)
- Interaction Design (1)
- Interactions (1)
- Interconnection (1)
- Interface Conductivity (1)
- Interfaces (1)
- Intergenerational income mobility (1)
- Intergenerationenmobilität (1)
- Intergenerative Einkommensmobilität (1)
- Invasion (1)
- Inverse Gaschromatographie (1)
- Invertebrate herbivory (1)
- Ionenkanal (1)
- Ionenleitfähigkeit (1)
- Ionic Liquid (1)
- Ionische Flüssigkeit (1)
- Iridate (1)
- Isocyanate (1)
- Isolation (1)
- J-Aggregate (1)
- K-RAS (1)
- KDELR2 (1)
- KTaO3 (1)
- Kapillarelektrophorese (1)
- Kinect (1)
- Kinetic Self-assembly (1)
- Kleinsatellit (1)
- Klinisches Experiment (1)
- Knochenimplantat (1)
- Knochenkleber (1)
- Knochenregeneration (1)
- Knochenwachs (1)
- Knorpelbildung (1)
- Kohärente Multidimensionale Spektroskopie (1)
- Kokristallisation (1)
- Kollektive Invasion (1)
- Komplexität (1)
- Komponentenanalyse (1)
- Konditionierung (1)
- Konfidenzintervall (1)
- Konfokale Mikroskopie (1)
- Konforme Metrik (1)
- Kongo (1)
- Konische Durchschneidung (1)
- Korrelierte Fermionen (1)
- Krebs (1)
- Krebs <Medizin> (1)
- Kreditgenossenschaft (1)
- Kristallfeld (1)
- Körpergewicht (1)
- L1 reading comprehension (1)
- L2 reading comprehension (1)
- L2 reading motivation (1)
- LC3-associated phagocytosis (1)
- LCD Pulse Shaper (1)
- LCD Pulsformer (1)
- LMICS (1)
- La gestion des déchets (1)
- LaAlO3/SrTiO3 (1)
- Ladungstrennung (1)
- Ladungsträger (1)
- Ladungsträgerlokalisation (1)
- Lageregelung (1)
- Landnutzungskartierung (1)
- Lanthantitanate (1)
- Laser Pulse Shaping (1)
- Laserpulsformung (1)
- Latrophilin (1)
- Leaf traits (1)
- Learning walk (1)
- Lebende Polymerisation (1)
- Lernen (1)
- Lernverhalten (1)
- Leseverstehen (1)
- Library Screening (1)
- Lichtabsorption (1)
- Lichtblattmikroskopie (1)
- Lichtscheibenmikroskopie (1)
- Lichtstreuung (1)
- Lidschlag (1)
- Ligand <Biochemie> (1)
- Light sheet microscopy (1)
- Liquid Crystal (1)
- Liquid Crystals (1)
- Living Polymerisation (1)
- Lokalisation (1)
- Low-income Countries (1)
- Lung (1)
- Lunge (1)
- Lyapunov Stability (1)
- Löslichkeit (1)
- MMB (1)
- MMB complex (1)
- MOF (1)
- MRI (1)
- MRSA (1)
- Magnesiumphosphate (1)
- Magnetic Resonance Imaging (1)
- Magnetische Eigenschaft (1)
- Magnetismus (1)
- Magnetit (1)
- Magnetometry (1)
- Magnetoresistance (1)
- Magnetowiderstand (1)
- Magnon (1)
- Makrokolonie (1)
- Mamma carcinoma (1)
- Mammakarzinom (1)
- Management (1)
- Managementinformationssystem (1)
- Mangansilicide (1)
- Manöverintention (1)
- Masern-Virus (1)
- Mathematik (1)
- Measles virus (1)
- Measurement-based Analysis (1)
- Mechanisms of Social Attention (1)
- Mechanismus (1)
- Mechanosensation (1)
- Media Psychology (1)
- Medienkonsum (1)
- Megakaryopoese (1)
- Megakaryozytopoese (1)
- Melanom (1)
- Melanoma (1)
- Melt Electrowriting (1)
- Meniskus (1)
- Meniskusimplantat (1)
- Mensch-Maschine-Kommunikation (1)
- Merger-specific Efficiency Gains (1)
- Mergers (1)
- Mergers and Acquisitions (1)
- Merocyanine dyes (1)
- Messung (1)
- Metadynamics (1)
- Metadynamik (1)
- Metall-Isolator-Phasenumwandlung (1)
- Metallorganisches Netzwerk (1)
- Methodology (1)
- Metrics (1)
- Metrologie (1)
- Mikroskopie (1)
- Mikrotubulus (1)
- MnSi (1)
- Model-based Performance Prediction (1)
- Modell (1)
- Modifikation von Biokeramiken (1)
- Modular Hamiltonian (1)
- Modularer Hamiltonoperator (1)
- Molekulardynamik (1)
- Molekularstrahlepitaxie (1)
- Molekülsystem (1)
- Monoschicht (1)
- Monte-Carlo-Simulation (1)
- Moral Hazard (1)
- Motivation (1)
- Mott Transistion (1)
- Mott-Isolator (1)
- Mott-Übergang (1)
- Multi-Messenger (1)
- Multiferroics (1)
- Multiferroika (1)
- Multiphotonenmikroskopie (1)
- Multiwavelength Astronomy (1)
- Muster (1)
- Mutation (1)
- Myrmecology (1)
- NCO-sP(EO-stat-PO) (1)
- NIQs (1)
- NMR-Spektroskopie (1)
- Nachhaltigkeit (1)
- Nahfeldoptik (1)
- Nahrungserwerb (1)
- Nanostruktur (1)
- Naphthylisoquinoline (1)
- Naphthylisoquinoline alkaloids (1)
- Neisseria meningitidis (1)
- Nephroblastom (1)
- Nephrogenese (1)
- Netzwerk (1)
- Neuroanatomie (1)
- Neurodevelopmental Disorder (1)
- Neuroimaging (1)
- Neutrinos (1)
- Nicht-kleinzelliges Bronchialkarzinom (1)
- Nigeria (1)
- Nociceptor (1)
- Non-coding RNA (1)
- Non-smooth optimal control (1)
- Nuclear Medicine (1)
- Nucleus subthalamicus (1)
- Numerical Cognition (1)
- Oberflächenfunktionalisierung (1)
- Oberflächenphonon (1)
- Oberflächenphysik (1)
- Oberflächenplasmon (1)
- Operations Management (1)
- Optik (1)
- Optimal foraging (1)
- Optimale Kontrolle (1)
- Optogenetics (1)
- Ordered metal adsorbates on semiconductor surfaces (1)
- Ordinal Categorical Indictators (1)
- Organic and hybrid semiconductors (1)
- Organische Chemie (1)
- Overstatement models (1)
- OxPL (1)
- Oxide Heterostructure (1)
- Oxidized Phospholipids (1)
- Oxidized phospholipids (1)
- PDF neurons (1)
- PKD1 (1)
- PRKACA (1)
- Parametric inference (1)
- Partial Least Squares Path Modeling (1)
- Paternal age and BMI effects (1)
- Patterns and drivers of invertebrate herbivory (1)
- Patterns and drivers of species diversity of phytophagous beetles (1)
- Patterns and drivers of species richness and community biomass of large mammals (1)
- Pediatric Nuclear Medicine (1)
- Pediatric Patients (1)
- Peierls-Übergang (1)
- Pendeln (1)
- Perception (1)
- Perowskit (1)
- Perturbative/Functional Renormalization Group (1)
- Perturbative/Funktionale Renormierungsgruppe (1)
- Perylenbisdicarboximide <Perylen-3,4:9,10-bis(dicarboximide)> (1)
- Perylenbisimide (1)
- Perylenbisimides (1)
- Perylene Bisimide (1)
- Perylene Bisimides (1)
- Pfadintegral (1)
- Pflanzenhormone (1)
- Phagozytose (1)
- Pharmakokinetik (1)
- Pharmakotherapie (1)
- Phobie (1)
- Phosphatasen (1)
- Phosphoglykolat-Phosphatase (1)
- Phosphoglykolatphosphatase (1)
- Phospholipide (1)
- Photoelectron Spectroscopy (1)
- Photoelektronenspektroskopie (1)
- Photoluminescence (1)
- Photolumineszenz (1)
- Photoreceptor (1)
- Physiologie (1)
- Phytochemical investigations of a Congolese Ancistrocladus Liana (1)
- Phytochemie (1)
- Pigmentdispergierender Faktor (1)
- Plasmaantrieb (1)
- Plasmamembranorganisation (1)
- Plasmon (1)
- Platzierungsalgorithmen (1)
- Poly(2-oxazolin)e (1)
- Polyethylenglykole (1)
- Polymere (1)
- Polynomial Factor Models (1)
- Polyphenole (1)
- Polysaccharide (1)
- Pontryagin maximum principle (1)
- Preconcentration (1)
- Predictive Analytics (1)
- Prefrontal cortex (1)
- Prescriptive Analytics (1)
- Prior information (1)
- Privatsphäre (1)
- Probability theory (1)
- Prospektives Gedächtnis (1)
- Protease-sensitive release (1)
- Protein Kinase D (1)
- Protein Kinase D 1 (1)
- Proteinkinase A (1)
- Proteinkinase D (1)
- Proteomics Analysis of Complexes (1)
- Proteotype (1)
- Präsenz (1)
- Präzisionsmessung (1)
- Psychiatrie (1)
- Psychologie (1)
- Psychometrie (1)
- Pulsed laser deposition (1)
- Punktwolke (1)
- Quality assessment of antimalarial medicines from the Congo (1)
- Quality ccontrol (1)
- Qualität der Abschlussprüfung (1)
- Qualität der Rechnungslegung (1)
- Qualitätskontrolle (1)
- Quanten-Hall-Effekt (1)
- Quanten-Monte-Carlo (1)
- Quanteninformation (1)
- Quantenpunkt (1)
- Quantifizierung (1)
- Quantitative Mikroskopie (1)
- Quantum Hall effect (1)
- Quinolone amides (1)
- RAS Evaluation (1)
- REDD1 (1)
- RFID (1)
- RNA Sequencing (1)
- RNA protein interactions (1)
- RNA secondary structures (1)
- RNA-Seq (1)
- RNA-seq (1)
- RNS (1)
- ROS (1)
- Radiation Protection (1)
- Radiation-associated Cancer Risk (1)
- Raphe (1)
- Raumwahrnehmung (1)
- Regelbasiertes Modell (1)
- Regional trade (1)
- Regionaler Arbeitsmarkt (1)
- Regionaler Handel (1)
- Regionalpolitik (1)
- Regionalwirtschaft (1)
- Regulierung (1)
- Reiz (1)
- Reporter Cells (1)
- Reporterzellen (1)
- Rescue behaviour (1)
- RhoA (1)
- Rhodopsin (1)
- Ringöffnungspolymerisation (1)
- Risk (1)
- Risk Assessment (1)
- Roboter (1)
- Runge-type Theorems (1)
- Röntgenastronomie (1)
- Röntgendiffraktometrie (1)
- SIX1 (1)
- SREBP (1)
- SSR42 (1)
- Satellit (1)
- Scheme for solving optimal control problems (1)
- Schlichte Funktion (1)
- Schmerzforschung (1)
- Schmerztherapie (1)
- Screening (1)
- Segmentation (1)
- Sekundärprävention (1)
- Selbstassemblierung (1)
- Self-assembly (1)
- Semantics (1)
- Semantik (1)
- Sense of Agency (1)
- Sensor Fusion (1)
- Septine (1)
- Sequential quadratic Hamiltonian scheme (1)
- Server (1)
- Shelf-life (1)
- Simulation (1)
- Situationsbewusstsein (1)
- Small RNA (1)
- Small-Gain Theorem (1)
- Social Cognition (1)
- Social Cueing (1)
- Social Web (1)
- Software (1)
- Software Defined Networking (1)
- Software Performance Engineering (1)
- Software-defined Networking (1)
- Softwarisierte Netze (1)
- Soziale Aufmerksamkeit (1)
- Soziale Mobilität (1)
- Soziale Software (1)
- Spatial Cognition (1)
- Species richness (1)
- Specific Phobia (1)
- Speckle tracking (1)
- Spezifische Phobien (1)
- Spezifische Wärme (1)
- Sphingosine-1-phosphate (1)
- Sphingosine-1-phosphats (1)
- Spin flip (1)
- Spin-Bahn-Kopplung (1)
- Spin-Orbit interaction (1)
- Spin-Phonon Kopplung (1)
- Spin-chemistry (1)
- Spin-phonon coupling (1)
- Spinflüssigkeit (1)
- Stability (1)
- Stabilität (1)
- Stammzelle (1)
- Standardmodell <Elementarteilchenphysik> (1)
- Starke Kopplung (1)
- Stechameisen (1)
- Stenosis degree (1)
- Stenosis length (1)
- Sternpolymere (1)
- Stigmatisierung (1)
- Stimme (1)
- Stimmverarbeitung (1)
- Stoffwechsel (1)
- Strategisches Management (1)
- Stroke (1)
- Strontiumtitanat (1)
- Strontiumvanadate (1)
- Structural Equation Modeling (1)
- Structural elucidation (1)
- Struktur-Aktivitäts-Beziehung (1)
- Strukturgleichungsmodell (1)
- Sub-Saharan Africa (1)
- Supramolecular Block Copolymers (1)
- Supramolecular aggregates (1)
- Supramolekulare Aggregate (1)
- Supramolekulare Struktur (1)
- Surface Plasmon (1)
- Surface Raman spectroscopy (1)
- Suspensionskultur (1)
- TFP (1)
- TLR3 (1)
- TMEM16F (1)
- TRPA1 channel (1)
- TWEAK (1)
- Tagesrhythmus (1)
- Tamoxifen (1)
- Tc-99m-MAG3 Scans (1)
- Telemedizin (1)
- Theoretische Chemie (1)
- Therapeutisches System (1)
- Therapie (1)
- Therapiesimulation (1)
- Thermodynamik (1)
- Thin Films (1)
- Thin intermetallic films (1)
- Thrombo-inflammation (1)
- Thrombosis (1)
- Thrombozytopenie (1)
- Thrust Vector Control (1)
- Tiermodell (1)
- Time-resolved photoluminescence (1)
- Tissue engineering (1)
- Topological insulators (1)
- Topologische Isolatoren (1)
- Topologischer Isolator (1)
- Total Factor Productivity (1)
- Tourenplanung (1)
- Transplantat-Wirt-Reaktion (1)
- Triquinacenderivate (1)
- Trypanosomiase (1)
- Tryptophan hydroxylase (1)
- Tumor (1)
- Tumorzelle (1)
- Twin Domains (1)
- Twin Suppression (1)
- USA (1)
- UV-VIS-Spektroskopie (1)
- Ultrakurzzeitspektroskopie (1)
- Ultrashort echo time - UTE (1)
- Umwelt (1)
- Unconventional/Topological superconductivity (1)
- Universal Functions (1)
- Unkonventionelle/Topologische Supraleitung (1)
- Unnötige Warnung (1)
- Unternehmensverfassung (1)
- User Behavior (1)
- User-Guidelines (1)
- Vakuole (1)
- Vascularized (1)
- Vaskularisation (1)
- Verarbeitende Industrie (1)
- Verbundwerkstoff (1)
- Verkehrspsychologie (1)
- Virtuelle Realität (1)
- Visuelle Aufmerksamkeit (1)
- Voice Processing (1)
- W-Boson (1)
- Wahrscheinlichkeitstheorie (1)
- Warnung (1)
- Waste management (1)
- Wechselwirkungen (1)
- White matter lesions (1)
- Wide-gap-Halbleiter (1)
- Wilms tumor (1)
- Wilms-Tumor (1)
- Winkelaufgelöste Photoemission mit harten Röntgenstrahlen (1)
- Wirkstoff (1)
- Wirkstofftestung (1)
- Wirtschaftliche Integration (1)
- Wirtschaftsinformatik (1)
- Woodhouse-Sakati Syndrom (1)
- Woodhouse-Sakati sydrome (1)
- Wundheilung (1)
- XRD (1)
- ZF1 degradation assay (1)
- ZFAND1 (1)
- Zahnbehandlungsphobie (1)
- Zell Migration (1)
- Zelloberfläche (1)
- Zinkselenid (1)
- Zusammenstoß (1)
- Zwillingsbildung (1)
- accessory medulla (1)
- actin cytoskeleton (1)
- actin-binding proteins (1)
- adalimumab (1)
- adipocyte (1)
- adipose (1)
- administrative boundary (1)
- alkaloids-Quinoid (1)
- aminergic neurons (1)
- amodiaquine (1)
- amorphous solid dispersion (1)
- anakinra (1)
- anticipation (1)
- artemether - lumefantrine (1)
- artifacts (1)
- autoimmune disease (1)
- autosomal recessive (1)
- back reaction (1)
- beige adipocytes (1)
- bioavailability (1)
- bioceramics (1)
- biofilm architecture (1)
- bioinks (1)
- biological scaffolds (1)
- biomaterials (1)
- bioreactor (1)
- blood brain barrier (1)
- blood cerebrospinal fluid barrier (1)
- bohrbar (1)
- bone (1)
- bone adhesive (1)
- bone wax (1)
- building (1)
- cancer (1)
- capillary zone electrophoresis (1)
- cardiac tissue (1)
- cardiomyocytes (1)
- cell therapy (1)
- cellular model (1)
- charge carrier localization (1)
- charge recombination (1)
- charge separation (1)
- chemical crosslinking (1)
- chronic kidney disease (1)
- circadian clock (1)
- circadian rhythms (1)
- click chemistry (1)
- clinical pharmacy (1)
- closed-loop systems (1)
- cocrystal (1)
- collective invasion (1)
- colorectal cancer (1)
- commission error (1)
- coronary heart disease (1)
- correspondence (1)
- curved hydrocarbons (1)
- cyclase-associated protein (1)
- cyclase-associated protein 2 (1)
- cytokinesis (1)
- data structure (1)
- decellularization (1)
- designer cell (1)
- diluted magnetic Semiconductor (1)
- disease modelling (1)
- dopamine (1)
- dose individualization (1)
- drillable (1)
- drivers and patterns of diversity and herbivory (1)
- drug delivery (1)
- dual abbindend (1)
- dual setting (1)
- dualsteric (1)
- dyads (1)
- e-learning (1)
- echocardiography (1)
- education system (1)
- eindimensionale Systeme (1)
- electrospun fibers (1)
- emotion (1)
- enbrel (1)
- endothelial cells (1)
- endothelium (1)
- environmental sustainability (1)
- etanercept (1)
- evolution (1)
- exciton dynamics (1)
- exciton-polariton (1)
- external stimuli (1)
- eye-tracking (1)
- fMRI (1)
- fMRT (1)
- fliegende Toilette (1)
- fluorescence microscopy (1)
- fluxosome (1)
- fly-tipping (1)
- flying toilet (1)
- folda-dimer (1)
- functional connectivity (1)
- funktionale Präpolymere (1)
- gauge/gravity duality (1)
- gekrümmte Kohlenwasserstoffe (1)
- gene network (1)
- genetic codon expansion (1)
- genetics (1)
- glia cells (1)
- guanylyl cyclase (GC) (1)
- hadronic Recoil (1)
- hadronischer Rückstoß (1)
- hard x-ray photoemission (1)
- hiPSC aggregation (1)
- hydrogels (1)
- iGC (1)
- iPSC (1)
- immunocompetent skin (1)
- implant (1)
- impurity profiling (1)
- in situ microscopy (1)
- individualization (1)
- induced pluripotent stem cells (1)
- information extraction (1)
- information retrieval (1)
- information sharing (1)
- inherited macrothrombocytopenia (1)
- intact bone imaging (1)
- integrins (1)
- interactions (1)
- interface conductivity (1)
- intervention point analyzing (1)
- ischemic stroke (1)
- isotropic hyper fine coupling (1)
- kidney development (1)
- kolorektales Karzinom (1)
- koronare Herzerkrankung (1)
- la durabilité environnementale (1)
- labour market (1)
- land-cover area (1)
- lattice forces (1)
- learner characteristics (1)
- learning (1)
- les toilettes volantes (1)
- light-matter interaction (1)
- lightsheet microscopy (1)
- localization microscopy (1)
- lung cancer (1)
- macrocolony (1)
- macrophages (1)
- magnetic field effect (1)
- manoeuvre intention (1)
- measles virus (1)
- measurement (1)
- megakaryocyte (1)
- memory (1)
- meniscus implant (1)
- merocyanines (1)
- metabolite profiling (1)
- metacognition (1)
- micro processor complex (1)
- microRNA (1)
- midbody remnant (1)
- mitosis (1)
- mitotic gene expression (1)
- morphing (1)
- multi-photon microscopy (1)
- multiphoton microscopy (1)
- murine (1)
- muscarinic receptors (1)
- n-Halbleiter (1)
- n-type semiconductors (1)
- naphthylisoquinoline alkaloids (1)
- natural language processing (1)
- need for assistance (1)
- negation detection (1)
- next generation sequencing (1)
- null-aggregate (1)
- object segmentation (1)
- one-dimensional systems (1)
- open waste burning (1)
- optical antenna (1)
- optimal drug combination (1)
- optogenetics (1)
- organic solar cells (1)
- oscillations (1)
- oxide heterostructure (1)
- oxidische Heterostruktur (1)
- oxygen vacancies (1)
- p53 (1)
- permeability (1)
- personality development (1)
- perylene bisimide dimers (1)
- pharmacokinetics (1)
- photoluminescence spectroscopy (1)
- pkd (1)
- plasma membrane organization (1)
- platelets (1)
- podosome formation (1)
- polarization (1)
- poly(2-oxazoline)s (1)
- poly(glycidol) (1)
- premixed (1)
- presence (1)
- prospective memory (1)
- protein kinase D1 (1)
- präfabriziert (1)
- quantum Monte Carlo (1)
- quantum dot (1)
- quantum gravity (1)
- quantum optics (1)
- radical ion pair (1)
- reactive oxygen species (1)
- restriction factors (1)
- rheumatoid arthritis (1)
- ring-opening polymerization (1)
- risk society (1)
- rulebased analysis (1)
- sPEG (1)
- screening (1)
- seco-NIQs-Naphthylisoindolinone (1)
- secondary prevention (1)
- self-determination theory (1)
- short neuropeptide F (1)
- short-range JCT-coupling (1)
- simple (1)
- single cell anatomy (1)
- site-specific protein modification (1)
- situation awareness (1)
- skin model (1)
- sleep (1)
- small RNA (1)
- social attention (1)
- soft x-ray photoemission (1)
- solubility (1)
- spacer-controlled self-assembly (1)
- specific heat (1)
- spin relaxation (1)
- starPEG (1)
- stigma (1)
- strain rate (1)
- strong coupling (1)
- strong light matter coupling (1)
- structural restriction (1)
- structure-activity relationship (1)
- substandard and falsified medicines from the Congo (1)
- subthalamic nucleus (1)
- super-resolution fluorescence microscopy (1)
- suppressor cells (1)
- surface functionalization (1)
- surface plasmon (1)
- synapses (1)
- synthetic biology (1)
- systematic drug targeting (1)
- targeted therapy (1)
- telemedicine (1)
- therapy simulation (1)
- thiol-ene (1)
- time-resolved spectroscopy (1)
- tissue engineering (1)
- transcriptome (1)
- transient absorption (1)
- transition metall dichalcogenide monolayer (1)
- triquinacene derivatives (1)
- tumour (1)
- two-component (1)
- ubiquitin (1)
- unnecessary alarm (1)
- vascularization (1)
- verdünnt magnetische Halbleiter (1)
- vessel wall resident stem cells (1)
- viability (1)
- virus (1)
- vocational education (1)
- waste sorting (1)
- wound healing (1)
- zeitaufgelöste Spektroskopie (1)
- zielgerichtete Behandlung (1)
- zooming (1)
- État d'Imo (1)
- β3 adrenergic receptor (1)
Institute
- Graduate School of Life Sciences (51)
- Theodor-Boveri-Institut für Biowissenschaften (15)
- Institut für Pharmazie und Lebensmittelchemie (12)
- Physikalisches Institut (12)
- Institut für Informatik (9)
- Institut für Organische Chemie (9)
- Institut für Psychologie (8)
- Institut für Theoretische Physik und Astrophysik (8)
- Abteilung für Funktionswerkstoffe der Medizin und der Zahnheilkunde (7)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin (5)
Sonstige beteiligte Institutionen
- Bio-Imaging Center Würzburg (1)
- CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - the development agency of the Brazilian Federal Government (1)
- DAAD - Deutscher Akademischer Austauschdienst (1)
- Fraunhofer-Institut für Chemische Technologie (ICT) (1)
- Institute for Biochemistry I, University of Cologne (1)
- Lehrkrankenhaus II. Medizinische Klinik Klinikum Coburg (1)
- Medizinische Klinik und Poliklinik 1, Abteilung Kardiologie (1)
- Medizinische Klinik und Poliklinik 1, Abteilung Nephrologie (1)
- Medizinische Universität Innsbruck (1)
- Queensland University of Technology (1)
ResearcherID
- B-4606-2017 (1)
Abscission marks the last step of cytokinesis and gives rise to two physically separated daughter cells and a midbody remnant. This work studies abscission by examining the extent of the abscission failure in C. elegans septin and ESCRT mutants with the help of the ZF1-degradation technique. The ZF1 technique is also applied to discern a possible role for PI3K during abscission. Lastly, we test the role of proteins required for macroautophagy but not for LC3-associated phagocytosis (LAP) and show that after release into the extracellular space, the midbody is resolved via LAP.
Surface systems attract great scientific attention due to novel and exotic properties. The atomically structured surfaces lead to a reduced dimensionality which alters electronic correlations, vibrational properties, and their impact on each other. The emerging physical phenomena are not observed for related bulk materials. In this thesis, ordered (sub)monolayers of metal atoms (Au and Sn) on semiconductor substrates (Si(111) and Ge(111)) and ultrathin intermetallic films (CePt5 and LaPt5) on metal substrate (Pt(111)) are investigated by polarized in situ surface Raman spectroscopy. The surface Raman spectra exhibit features of specific elementary excitations like surface phonons and electronic excitations, which are suitable to gain fundamental insights into the surface systems.
The Au-induced surface reconstructions (5x2) and (r3xr3) constitute quasi-one- and two-dimensional Au structures on the Si(111) substrate, respectively. The new reconstruction-related Raman peaks are analyzed with respect to their polarization and temperature behavior. The Raman results are combined with firstprinciples calculations to decide between different proposed structural models. The Au-(5x2)/Si(111) reconstruction is best described by the model of Kwon and Kang, while for Au-(r3xr3)/Si(111) the conjugate honeycomb-chained-trimer model is favored. The Sn-induced reconstructions with 1/3 monolayer on Ge(111) and Si(111) are investigated to reveal their extraordinary temperature behavior. Specific surface phonon modes are identified that are predicted within the dynamical fluctuation model. Contrary to Sn/Si(111), the corresponding vibrational mode of Sn/Ge(111) exhibits a nearly harmonic character. The reversible structural phase transition of Sn/Ge(111) from (r3xr3) to (3x3) is observed, while no phase transition is apparent for Sn/Si(111). Moreover, Raman spectra of the closely related systems Sn-(2r3x2r3)/Si(111) and thin films of a-Sn as well as the clean semiconductor surfaces Si(111)-(7x7) and Ge(111)-c(2x8) are evaluated and compared.
The CePt5/Pt(111) system hosts 4f electrons whose energy levels are modified by the crystal field and are relevant for a description of the observed Kondo physics. In contrast, isostructural LaPt5/Pt(111) has no 4f electrons. For CePt5/Pt(111), distinct Raman features due to electronic Raman scattering can be unambiguously related to transitions between the crystal-field states which are depth-dependent. This assignment is supported by comparison to LaPt5/Pt(111) and group theoretical considerations. Furthermore, the vibrational properties of CePt5 and LaPt5 reveal interesting similarities but also striking differences like an unusual temperature shift of a vibration mode of CePt5, which is related to the influence of 4f electrons.
Active galactic nuclei (AGN) are among the brightest and most frequent sources on the extragalactic X-ray and gamma-ray sky. Their central supermassive blackhole generates an enormous luminostiy through accretion of the surrounding gas. A few AGN harbor highly collimated, powerful jets in which are observed across the entire electromagnetic spectrum. If their jet axis is seen in a small angle to our line-of-sight (these objects are then called blazars) jet emission can outshine any other emission component from the system. Synchrotron emission from electrons and positrons clearly prove the existence of a relativistic leptonic component in the jet plasma. But until today, it is still an open question whether heavier particles, especially protons, are accelerated as well. If this is the case, AGN would be prime candidates for extragalactic PeV neutrino sources that are observed on Earth. Characteristic signatures for protons can be hidden in the variable high-energy emission of these objects. In this thesis I investigated the broadband emission, particularly the high-energy X-ray and gamma-ray emission of jetted AGN to address open questions regarding the particle acceleration and particle content of AGN jets, or the evolutionary state of the AGN itself. For this purpose I analyzed various multiwavelength observations from optical to gamma-rays over a period of time using a combination of state-of-the-art spectroscopy and timing analysis. By nature, AGN are highly variable. Time-resolved spectral analysis provided a new dynamic view of these sources which helped to determine distinct emission processes that are difficult to disentangle from spectral or timing methods alone.
Firstly, this thesis tackles the problem of source classification in order to facilitate the search for interesting sources in large data archives and characterize new transient sources. I use spectral and timing analysis methods and supervised machine learning algorithms to design an automated source classification pipeline. The test and training sample were based on the third XMM-Newton point source catalog (3XMM-DR6). The set of input features for the machine learning algorithm was derived from an automated spectral modeling of all sources in the 3XMM-DR6, summing up to 137200 individual detections. The spectral features were complemented by results of a basic timing analysis as well as multiwavelength information provided by catalog cross-matches. The training of the algorithm and application to a test sample showed that the definition of the training sample was crucial: Despite oversampling minority source types with synthetic data to balance out the training sample, the algorithm preferably predicted majority source types for unclassified objects. In general, the training process showed that the combination of spectral, timing and multiwavelength features performed best with the lowest misclassification rate of \\sim2.4\\%.
The methods of time-resolved spectroscopy was then used in two studies to investigate the properties of two individual AGN, Mrk 421 and PKS 2004-447, in detail. Both objects belong to the class of gamma-ray emitting AGN. A very elusive sub-class are gamma-ray emitting Narrow Line Seyfert 1 (gNLS1) galaxies. These sources have been discovered as gamma-ray sources only recently in 2010 and a connection to young radio galaxies especially compact steep spectrum (CSS) radio sources has been proposed. The only gNLS1 on the Southern Hemisphere so far is PKS2004-447 which lies at the lower end of the luminosity distribution of gNLS1. The source is part of the TANAMI VLBI program and is regularly monitored at radio frequencies. In this thesis, I presented and analyzed data from a dedicated multiwavelength campaign of PKS 2004-447 which I and my collaborators performed during 2012 and which was complemented by individual observations between 2013 and 2016. I focussed on the detailed analysis of the X-ray emission and a first analysis of its broadband spectrum from radio to gamma-rays. Thanks to the dynamic SED I could show that earlier studies misinterpreted the optical spectrum of the source which had led to an underestimation of the high-energy emission and had ignited a discussion on the source class. I show that the overall spectral properties are consistent with dominating jet emission comprised of synchrotron radiation and inverse Compton scattering from accelerated leptons. The broadband emission is very similar to typical examples of a certain type of blazars (flat-spectrum radio quasars) and does not present any unusual properties in comparison. Interestingly, the VLBI data showed a compact jet structure and a steep radio spectrum consistent with a compact steep spectrum source. This classified PKS 2004-447 as a young radio galaxy, in which the jet is still developing.
The investigation of Mrk 421 introduced the blazar monitoring program which I and collaborator have started in 2014. By observing a blazar simultaneously from optical, X-ray and gamma-ray bands during a VHE outbursts, the program aims at providing extraordinary data sets to allow for the generation of a series of dynamical SEDs of high spectral and temporal resolution. The program makes use of the dense VHE monitoring by the FACT telescope. So far, there are three sources in our sample that we have been monitoring since 2014. I presented the data and the first analysis of one of the brightest and most variable blazar, Mrk 421, which had a moderate outbreak in 2015 and triggered our program for the first time. With spectral timing analysis, I confirmed a tight correlation between the X-ray and TeV energy bands, which indicated that these jet emission components are causally connected. I discovered that the variations of the optical band were both correlated and anti-correlated with the high-energy emission, which suggested an independent emission component. Furthermore, the dynamic SEDs showed two different flaring behaviors, which differed in the presence or lack of a peak shift of the low-energy emission hump. These results further supported the hypothesis that more than one emission region contributed to the broadband emission of Mrk 421 during the observations.
Overall,the studies presented in this thesis demonstrated that time-resolved spectroscopy is a powerful tool to classify both source types and emission processes of astronomical objects, especially relativistic jets in AGN, and thus provide a deeper understanding and new insights of their physics and properties.
An experimental setup for probing ultrafast dynamics at the diffraction limit was developed, characterized and demonstrated in the scope of the thesis, aiming for optical investigations while simultaneously approaching the physical limits on the length and timescale.
An overview of this experimental setup was given in Chapter 2, as well as the considerations that led to the selection of the individual components. Broadband laser pulses with a length of 9.3 fs, close to the transform limit of 7.6 fs, were focused in a NA = 1.4 immersion oil objective, to the diffraction limit of below 300 nm (FWHM).
The spatial focus shape was characterized with off-resonance gold nanorod scatterers scanned through the focal volume. For further insights into the functionality and limitations of the pulse shaper, its calibration procedure was reviewed. The deviations between designed and experimental pulse shapes were attributed to pulse-shaper artifacts, including voltage-dependent inter-layer as well as intra-layer LCD-pixel crosstalk, Fabry-Pérot-type reflections in the LCD layers, and space-time coupling. A pixel-dependent correction was experimentally carried out, which can be seen as an extension of the initial calibration to all possible voltage combinations of the two LCD layers.
The capabilities of the experimental setup were demonstrated in two types of experiments, targeting the nonlinearity of gold (Chapter 3) as well as two-dimensional spectroscopy at micro-structured surfaces (Chapter 4).
Investigating thin films, an upper bound for the absolute value for the imaginary part of the nonlinear refractive index of gold could be set to |n′′ 2 (Au)| < 0.6·10−16 m2/W, together with |n′ 2 (Au)| < 1.2·10−16 m2/W as an upper bound for the absolute value of the real part. Finite-difference time-domain simulations on y-shaped gold nanostructures indicated that a phase change of ∆Φ ≥ 0.07 rad between two plasmonic modes would induce a sufficient change in the spatial contrast of emission to the far-field to be visible in the experiment. As the latter could not be observed, this value of ∆Φ was determined as the upper bound for the experimentally induced phase change. An upper bound of 52 GW/cm2 was found for the damage threshold.
In Chapter 4, a novel method for nonlinear spectroscopy on surfaces was presented. Termed coherent two-dimensional fluorescence micro-spectroscopy, it is capable of exploring ultrafast dynamics in nanostructures and molecular systems at the diffraction limit. Two-dimensional spectra of spatially isolated hotspots in structured thin films of fluorinated zinc phthalocyanine (F16ZnPc) dye were taken with a 27-step phase-cycling scheme. Observed artifacts in the 2D maps were identified as a consequence from deviations between the desired and the experimental pulse shapes. The optimization procedures described in Chapter 2 successfully suppressed the deviations to a level where the separation from the nonlinear sample response was feasible.
The experimental setup and methods developed and presented in the scope of this thesis demonstrate its flexibility and capability to study microscopic systems on surfaces. The systems exemplarily shown are consisting of metal-organic dyes and metallic nanostructures, represent samples currently under research in the growing fields of organic semiconductors and plasmonics.
Due to their complex chemical structure transition metal oxides display many fascinating properties which conventional semiconductors lack.
For this reason transition metal oxides hold a lot of promise for novel electronic functionalities.
Just as in conventional semiconductor heterostructures, the interfaces between different materials play a key role in oxide electronics.
The textbook example is the (001) interface between the band insulators LaAlO\(_3\) and SrTiO\(_3\) at which a two-dimensional electron system (2DES) forms.
In order to utilize such a 2DES in prospective electronic devices, it is vital that the electronic properties of the interface can be controlled and manipulated at will.
Employing photoelectron spectroscopy as well as electronic transport measurements, this thesis examines how such interface engineering can be realized in the case of the LaAlO\(_3\)/SrTiO\(_3\) heterostructure:
By photoemission we manage to unambiguously distinguish the different mechanisms by which SrTiO\(_3\) can be doped with electrons.
An electronic reconstruction is identified as the driving mechanism to render stoichiometric LaAlO\(_3\)/SrTiO\(_3\) interfaces metallic.
The doping of the LaAlO\(_3\)/SrTiO\(_3\) heterointerface can furthermore be finely adjusted by changing the oxygen vacancy \(V_{\mathrm{O}}\) concentration in the heterostructure.
Combining intense x-ray irradiation with oxygen dosing, we even achieve control over the \(V_{\mathrm{O}}\) concentration and, consequently, the doping in the photoemission experiment itself.
Exploiting this method, we investigate how the band diagram of SrTiO\(_3\)-based heterostructures changes as a function of the \(V_{\mathrm{O}}\) concentration and temperature by hard x-ray photoemission spectroscopy.
With the band bending in the SrTiO\(_3\) substrate changing as a function of the \(V_{\mathrm{O}}\) concentration, the interfacial band alignment is found to vary as well.
The relative permittivity of the SrTiO\(_3\) substrate and, in particular, its dependence on temperature and electric field is identified as one of the essential parameters determining the electronic interface properties.
That is also why the sample temperature affects the charge carrier distribution.
The mobile charge carriers are shown to shift toward the SrTiO\(_3\) bulk when the sample temperature is lowered.
This effect is, however, only pronounced if the total charge carrier concentration is small.
At high charge carrier concentrations the charge carriers are always confined to the interface, independent of the sample temperature.
The dependence of the electronic interface properties on the \(V_{\mathrm{O}}\) concentration is also investigated by a complementary method, viz. by electronic transport measurements.
These experiments confirm that the mobile charge carrier concentration increases concomitantly to the \(V_{\mathrm{O}}\) concentration.
The mobility of the charge carriers changes as well depending on the \(V_{\mathrm{O}}\) concentration.
Comparing spectroscopy and transport results, we are able to draw conclusions about the processes limiting the mobility in electronic transport.
We furthermore build a memristor device from our LaAlO\(_3\)/SrTiO\(_3\) heterostructures and demonstrate how interface engineering is used in practice in such novel electronic applications.
This thesis furthermore investigates how the electronic structure of the 2DES is affected by the interface topology:
We show that, akin to the (001) LaAlO\(_3\)/SrTiO\(_3\) heterointerface, an electronic reconstruction also renders the (111) interface between LaAlO\(_3\) and SrTiO\(_3\) metallic.
The change in interface topology becomes evident in the Fermi surface of the buried 2DES which is probed by soft x-ray photoemission.
Based on the asymmetry in the Fermi surface, we estimate the extension of the conductive layer in the (111)-oriented LaAlO\(_3\)/SrTiO\(_3\) heterostructure.
The spectral function measured furthermore identifies the charge carriers at the interface as large polarons.
Main focus of the present dissertation was to gain new insight about the interaction between magnetic ions and the conduction band of diluted magnetic semiconductors. This interaction in magnetic semiconductors with carrier concentrations near the metal-insulator transition (MIT) in an external magnetic field is barely researched. Hence, n-doped Zn1−xMnxSe:Cl samples were studied.
Resonant Raman spectroscopy was employed at an external magnetic field between 1T and 7T and a temperature of 1.5K.
The resulting magnetization of the material amplifies the splitting of states with opposite spins both in the valence and the conduction band. This is known as the "giant-Zeeman-effect".
In this thesis, the resonance of the electron spin flip process, i.e. the enhancement of the signal depending on the excitation energy, was used as an indicator to determine the density of states of the charge carriers. The measured resonance profiles of each sample showed a structure, which consist of two partially overlapping Gaussian curves. The analysis of the Gaussian curves revealed that their respective maxima are separated independent of the magnetic field strenght by about 5 meV, which matches the binding energy of the donor bound exciton (D0, X).
A widening of the full width at half maximum of the resonance profile was observed with increasing magnetic field. A detailed analysis of this behavior showed that the donor bound exciton spin flip resonance primarily accounts for the widening for all samples with doping concentrations below the metal insulator transition. A model was proposed for the interpretation of this observation.
This is based on the fundamental assumptions of a spatially random distribution of the manganese ions on the group-II sublattice of the ZnSe crystal and the finite extension of the excitons. Thus, each exciton covers an individual quantity of manganese ions, which manifest as a local manganese concentration. This local manganese concentration is normally distributed for a set of excitons and hence, the evaluation of the distribution allows the determination of exciton radii
Two trends were identified for the (D0, X) radii. The radius of the bound exciton decreases with increasing carrier concentration as well as with increasing manganese concentration. The determination of the (D0, X) radii by the use of resonant spin flip Raman spectroscopy and also the observation of the behavior of the (D0, X) radius depending on the carrier concentration, was achieved for the first time.
For all samples with carrier concentrations below the metal-insulator transition, the obtained (X0) radii are up to a factor of 5.9 larger than the respective (D0, X) radii. This observation is explained by the unbound character of the (X0).
For the first time, such an observation could be made by Raman spectroscopy.Beside the resonance studies, the shape of the Raman signal of the electron spin flip was analyzed. Thereby an obvious asymmetry of the signal, with a clear flank to lower Raman shifts, was observed. This asymmetry is most pronounced, when the spin flip process is excited near the (D0, X) resonance.
To explain this observation, a theoretical model was introduced in this thesis. Based on the asymmetry of the resonantly excited spin flip signal, it was possible to estimate the (D0, X) radii, too. At external magnetic fields between 1.25T and 7T, the obtained radii lie between 2.38nm and 2.75nm.
Additionally, the asymmetry of the electron spin flip signal was observed at different excitation energies. Here it is striking that the asymmetry vanishes with increasing excitation energy. At the highest excitation energy, where the electron spin flip was still detectable, the estimated radius of the exciton is 3.92nm.
Beside the observations on the electron spin flip, the resonance behavior of the spin flip processes in the d-shell of the incorporated Mn ions was studied in this thesis. This was performed for the direct Mn spin flip process as well as for the sum process of the longitudinal optical phonon with the Mn spin flip. For the Stokes and anti-Stokes direct spin flip process and for the Stokes sum process, each the resonance curve is described by considering only one resonance mechanism. In contrast, resonance for the sum process in which an anti-Stokes Mn spin flip is involved, consists of two partially overlapping resonances due to different mechanisms. A detailed analysis of this resonance profile showed that for (Zn,Mn)Se at the chosen experimental parameters, an
incoming and outgoing resonance can be achieved, separated by a few meV.
Hereby, at a specific excitation energy range and a high excitation power, it was possible to achieve an inversion of the anti-Stokes to Stokes intensity, because only the anti-Stokes Mn spin flip process was enhanced resonantly.
An efficient foraging strategy is one of the most important traits for the fitness of animals. The theory of optimal foraging tries to predict foraging behaviour through the overarching question: how animals should forage so as to minimize costs while maximizing profits? Social insects, having occupied nearly every natural niche through widely different strategies, offer themselves as an ideal group to study how well optimal foraging theory can explain their behaviour and success.
Specialization often leads to unique adaptations in morphology and behaviour. I therefore decided to investigate the behaviour of Megaponera analis. This ponerine ant species is specialized on hunting only termites of the subfamily Macrotermitinae at their foraging sites. Their foraging behaviour is regulated by a handful of individual scouts (10-20) that search for termite foraging sites before returning to the nest to recruit a large number of nestmates (200-500 ants). These ants then follow the scout in a column formation to the termites and after the hunt return together to the nest, these raids occur two to five times per day.
Predators of highly defensive prey likely develop cost reducing adaptations. The evolutionary arms race between termites and ants led to various defensive mechanisms in termites, e.g. a caste specialized in fighting predators. As M. analis incurs high injury/mortality risks when preying on termites, some risk mitigating adaptations have evolved. I show that a unique rescue behaviour in M. analis, consisting of injured nestmates being carried back to the nest, reduces combat mortality. These injured ants “call for help” with pheromones present in their mandibular gland reservoirs. A model accounting for this rescue behaviour identifies the drivers favouring its evolution and estimates that rescuing allows for maintaining a 29% larger colony size. Heavily injured ants that lost too many legs during the fight on the other hand are not helped. Interestingly, this was regulated not by the helper but by the uncooperativeness of the injured ant. I further observed treatment of the injury by nestmates inside the nest through intense allogrooming directly at the wound. Lack of treatment increased mortality from 10% to 80% within 24 hours, with the cause of death most likely being infections.
Collective decision-making is one of the main mechanisms in social insects through which foraging is regulated. However, individual decision-making can also play an important role, depending on the type of foraging behaviour. In M. analis only a handful of individuals (the scouts) hold all the valuable information about foraging sites. I therefore looked at predictions made by optimal foraging theory to better understand the interplay between collective and individual decision-making in this obligate group-raiding predator. I found a clear positive relation between raid size and termite abundance at the foraging site. Furthermore, selectivity of the food source increased with distance. The confirmation of optimal foraging theory suggests that individual scouts must be the main driver behind raid size, choice and raiding behaviour. Therefore most central place foraging behaviours in M. analis were not achieved by collective decisions but rather by individual decisions of scout ants. Thus, 1% of the colony (10–20 scouts) decided the fate and foraging efficiency of the remaining 99%.
Division of labour is one of the main reasons for the success of social insects. Worker polymorphism, age polyethism and work division in more primitive ants, like the ponerines, remain mostly unexplored though. Since M. analis specializes on a defensive prey, adaptations to reduce their foraging costs can be expected. I found that the work division, task allocation and column-formation during the hunt were much more sophisticated than was previously thought. The column-formation was remarkably stable, with the same ants resuming similar positions in subsequent raids and front ants even returning to their positions if displaced in the same raid. Most of the raid tasks were not executed by predetermined members of the raid but were filled out as need arose during the hunt, with a clear preference for larger ants to conduct most tasks.
I show that specialization towards a highly defensive prey can lead to very unique adaptations in the foraging behaviour of a species. I explored experimentally the adaptive value of rescue behaviour focused on injured nestmates in social insects. This was not only limited to selective rescuing of lightly injured individuals by carrying them back (thus reducing predation risk) but moreover includes a differentiated treatment inside the nest. These observations will help to improve our understanding of the evolution of rescue behaviour in animals. I further show that most optimal foraging predictions are fulfilled and regulated by a handful of individuals in M. analis. Lastly, I propose that the continuous allometric size polymorphism in M. analis allows for greater flexibility in task allocation, necessary due to the unpredictability of task requirements in an irregular system such as hunting termites in groups. All of my observations help to further understand how a group-hunting predator should forage so as to minimize costs while maximizing profits.
Since its first experimental implementation in 2005, single-molecule localization microscopy (SMLM) emerged as a versatile and powerful imaging tool for biological structures with nanometer resolution. By now, SMLM has compiled an extensive track-record of novel insights in sub- and inter- cellular organization.\\
Moreover, since all SMLM techniques rely on the analysis of emission patterns from isolated fluorophores, they inherently allocate molecular information $per$ $definitionem$.\\
Consequently, SMLM transitioned from its origin as pure high-resolution imaging instrument towards quantitative microscopy, where the key information medium is no longer the highly resolved image itself, but the raw localization data set.\\
The work presented in this thesis is part of the ongoing effort to translate those $per$ $se$ molecular information gained by SMLM imaging to insights into the structural organization of the targeted protein or even beyond. Although largely consistent in their objectives, the general distinction between global or segmentation clustering approaches on one side and particle averaging or meta-analyses techniques on the other is usually made.\\
During the course of my thesis, I designed, implemented and employed numerous quantitative approaches with varying degrees of complexity and fields of application.\\ \\
In my first major project, I analyzed the localization distribution of the integral protein gp210 of the nuclear pore complex (NPC) with an iterative \textit{k}-means algorithm. Relating the distinct localization statistics of separated gp210 domains to isolated fluorescent signals led, among others, to the conclusion that the anchoring ring of the NPC consists of 8 homo-dimers of gp210.\\
This is of particular significance, both because it answered a decades long standing question about the nature of the gp210 ring and it showcased the possibility to gain structural information well beyond the resolution capabilities of SMLM by crafty quantification approaches.\\ \\
The second major project reported comprises an extensive study of the synaptonemal complex (SNC) and linked cohesin complexes. Here, I employed a multi-level meta-analysis of the localization sets of various SNC proteins to facilitate the compilation of a novel model of the molecular organization of the major SNC components with so far unmatched extend and detail with isotropic three-dimensional resolution.\\
In a second venture, the two murine cohesin components SMC3 and STAG3 connected to the SNC were analyzed. Applying an adapted algorithm, considering the disperse nature of cohesins, led to the realization that there is an apparent polarization of those cohesin complexes in the SNC, as well as a possible sub-structure of STAG3 beyond the resolution capabilities of SMLM.\\ \\
Other minor projects connected to localization quantification included the study of plasma membrane glycans regarding their overall localization distribution and particular homogeneity as well as the investigation of two flotillin proteins in the membrane of bacteria, forming clusters of distinct shapes and sizes.\\ \\
Finally, a novel approach to three-dimensional SMLM is presented, employing the precise quantification of single molecule emitter intensities. This method, named TRABI, relies on the principles of aperture photometry which were improved for SMLM.\\
With TRABI it was shown, that widely used Gaussian fitting based localization software underestimates photon counts significantly. This mismatch was utilized as a $z$-dependent parameter, enabling the conversion of 2D SMLM data to a virtual 3D space. Furthermore it was demonstrated, that TRABI can be combined beneficially with a multi-plane detection scheme, resulting in superior performance regarding axial localization precision and resolution.\\
Additionally, TRABI has been subsequently employed to photometrically characterize a novel dye for SMLM, revealing superior photo-physical properties at the single-molecule level.\\
Following the conclusion of this thesis, the TRABI method and its applications remains subject of diverse ongoing research.
The number of active pharmaceutical ingredients (APIs) exhibiting a low solubility in aqueous media or a slow dissolution rate kept rising over the past years urging formulation scientists to explore new ways to tackle poor solubility and to enable oral absorption from such compounds. Bioavailability of poorly water-soluble compounds can be improved by increasing the dissolution rate and/or by increasing the gastro intestinal concentration through transient supersaturation. The dissolution rate of the API can be typically modified by the choice of the physical form, the polymorphic form, the powder surface area, and the local pH, while a transient supersaturation can be extended mainly by nucleation or crystallization inhibiting effects. In the present thesis, three strategies were explored to tailor the dissolution rate, the supersaturation and the hydrotropic solubilization of APIs, weak bases, respectively.
The first part of this thesis followed a bioinspired approach to extend the kinetic solubility of salts and co-crystals. API salts and co-crystals are high energy forms that can generate supersaturated solutions with respect to any more stable form, typically the most stable API form in physiological environment. The transient kinetic stabilization of supersaturated states, also termed “parachute effect”, is considered to improve bioavailability and is one aspect of the formulation that can be tailored. Inspiration from plants, which store high concentrations of aromatic bases in their vacuoles via complexation with polyphenols, sparked the evaluation to use hydroxybenzoic acid derivatives for salt or co-crystal engineering. Imatinib was chosen as the model compound for this investigation as its aromaticity and flat molecular architecture could favor interactions with hydroxybenzoic acid derivatives. One 1:1 Imatinib syringate co-crystal (I-SYA (1:1)) and one 1:2 Imatinib syringate co-crystal salt (I-SYA (1:2)) were obtained. Their dissolution assays in simulated intestinal fluid (SIF; a 50 mM phosphate buffer of pH 6.8) revealed that they formed stable solutions for several hours and days, respectively, in contrast to the marketed Imatinib mesylate salt (approx. 1h). This kinetic stability in solution was linked to the nucleation inhibition of the less soluble Imatinib hydrate by syringic acid (SYA). In solution 1H-NMR studies evidenced the aggregation of Imatinib and SYA. The amphiphilic nature of both Imatinib and SYA is considered to drive their association in solution, additionally, multiple intermolecular interactions such as hydrogen bonds and π-π stacking are likely to contribute. The association in solution enabled a phase of extended supersaturation, i.e., a parachute against desupersaturation, while no negative impact of aggregation on the permeability of both Imatinib and SYA was observed.
A prerequisite to reach supersaturation is a rapid dissolution and release of the API from the formulation. Accordingly, the second and third part of this thesis is focused on the so-called “spring effect” of amorphous solid dispersions (ASDs). The addition of a hydrotropic agent, meaning a molecule that can solubilize poorly water-soluble APIs in aqueous solutions (well-known examples of hydrotropes are benzoic acid and nicotinamide) into an amorphous Ciprofloxacin-polymer matrix led to ternary systems with a significantly faster release and higher concentration of the API in SIF as compared to binary ASDs consisting of Ciprofloxacin (CPX) and polymer only. The stronger spring could be rationalized by an improved wetting of the ASD, or/and by a hydrotropic solubilization effect, although these hypotheses need further investigation. Marked differences in the dissolution profiles of binary ASDs were observed in biorelevant fasted simulated intestinal fluid (FaSSIF; a medium containing Na taurocholate (3 mM) and lecithin (0.75 mM) at pH 6.5) as compared to SIF. In FaSSIF, API release from binary polymeric ASDs was largely improved, and the duration of supersaturation was extended. This suggests that the bile salt Na taurocholate and lecithin present in FaSSIF do improve both dissolution rate and supersaturation of ASDs, the two pillars of ASDs as oral enabling formulations. Indeed, bile salts are endogenous surfactants which, together with phospholipids, play an important role in the wetting, solubilization, and absorption of lipophilic compounds.
The aim of the third part of the present thesis was to study ASDs as formulation principles reducing the strong positive food effect of Compound A. By inclusion of Na taurocholate (NaTC) within the matrix of polymeric ASDs a significant improvement of the dissolution rate and the kinetic solubility in SIF were achieved. Transient supersaturated states of up to four orders of magnitude over the equilibrium solubility were obtained. Two ASDs were selected for further in vivo evaluation in dog. The first was a NaTC/Eudragit E based ASD meant to dissolve and release Compound A in the acidic environment of the stomach, where its solubility is the highest. The second relied on the release of Compound A in the neutral environment of the duodenum and jejunum by using an enterically dissolving polymer, HPMC-P. Releasing the API at the site of its putative absorption was an attempt to control supersaturation levels in the duodenum and to prevent portioning and thus dilution effects during transfer from the stomach. In fasted dogs, exposure from the NaTC/HPMC-P ASD was close to that of the reference Compound A formulation under fed conditions, which suggests an improved dissolution rate and kinetic solubility under fasted conditions (historical data). The exposure from the NaTC/Eudragit E ASD was twice as low as from the NaTC/HPMC-P ASD, and also lower compared to Compound A reference formulation, whereas in vitro the parachute effect of the NaTC/Eudragit E ASD was largely superior to that of the NaTC/HPMC-P ASD. A difference in the extend of the parachute could be related to differences in the thermodynamic activity of dissolved molecules from the two ASDs. Indeed, the high instability of the NaTC/HPMC-P ASD could stem from a high thermodynamic activity driving diffusion through membranes, whereas less instable solutions of NaTC/Eudragit E could indicate solubilization effects which often translate into a lower flux through the biological membrane. Additionally, the pH of the environment where dissolution takes place might be an important factor for absorption, and could also account for the difference in exposure from the two ASDs.
The aim of this thesis was to explore how the intimate environment of weak, poorly soluble bases could be functionalized to improve dissolution rate and kinetic solubility. The investigations highlighted that the performance of enabling oral delivery formulations of weak bases in aqueous media can be enhanced at different levels. At one end initial dissolution rate of ASDs can be tailored by introducing hydrotropes or/and bile salts within the polymeric matrix of ASDs. Bile salts, when combined with appropriate polymers, had also a precipitation inhibition effect enabling the maintenance of supersaturation for a bio-relevant period of time. These results set the ground for further investigations to comprehend specific interactions between bile salts and APIs, and potentially polymers at the molecular level. It will be interesting to explore how such complex systems can be exploited in the formulation design of poorly water-soluble APIs. In addition, it was observed that the duration of supersaturation generated by salts/co-crystals can be extended by the pertinent selection of counterions or coformers. The in vivo relevance of these tunings remains to be evaluated, as translation from closed, in vitro systems to the highly dynamic gastrointestinal environment is not straightforward. A better understanding of the contribution of each kinetic stage (dissolution, supersaturation, and precipitation) and their interplay with physiological factors impacting absorption is essential to facilitate the design of formulations with improved pharmacokinetics.
Wilms tumor (WT) is the most common kidney cancer in childhood. It is a genetically heterogeneous tumor and several genetic alterations have been identified in WT patients. Recurrent mutations were found in the homeo-domain of SIX1 and SIX2 in high proliferative tumors (18.1% of the blastemal-type tumors) as well as in the microprocessor genes DROSHA and DGCR8 (18.2% of the blastemal-type tumors), indicating a critical role of the SIX-SALL pathway and aberrant miRNA processing in WT formation. Underlined by the fact that a significant overlap between mutations in DROSHA and SIX1 was found, indicating a synergistic effect.
To characterize the in vivo role of DROSHA and SIX mutations during kidney development and their oncogenic potential, I analyzed mouse lines with either a targeted deletion of Drosha or an inducible expression of human DROSHA or SIX1 carrying a tumor-specific E1147K or Q177R mutation, respectively.
The DROSHA mutation E1147K was predicted to act in a dominant negative manner. Six2-cre mediated deletion of Drosha in nephron progenitors led to a lethal phenotype with apoptotic loss of progenitor cells and early termination of nephrogenesis. Mosaic deletions via Wt1-creERT2 resulted in a milder phenotype with viable offspring that developed proteinuria after 2-4 weeks, but no evidence of tumor formation. Activation of the DROSHA-E1147K transgene via Six2-cre, on the other hand, induced a more severe phenotype with apoptosis of progenitor cells, proteinuria and glomerular sclerosis. The severely growth-retarded mice died within the first two months. This strong phenotype was consistent with the predicted dominant-negative effect of DROSHA-E1147K.
Analysis of the SIX1-Q177R mutation suggested that the mutation leads to a shift in DNA binding specificity instead of a complete loss of DNA binding. This may end up in subtle changes of the gene regulatory capacity of SIX1. Six2-cre mediated activation of SIX1-Q177R lead to a viable phenotype with no alterations or shortened life span. Yet a global activation of SIX1-Q177R mediated by Zp3-cre resulted in bilateral hydronephrosis and juvenile death of the mice.
To mimic the synergistic effect of DROSHA and SIX1 mutations, I generated compound mutants in two combinations: A homozygous deletion of Drosha combined with an activation of SIX1-Q177R and a compound mutant with activation of DROSHA-E1147K and SIX1-Q177R. Each mouse model variant displayed new phenotypical alterations. Mice with Six2-cre mediated homozygous deletion of Drosha and activation of SIX1-Q177R were not viable, yet heterozygous deletion of Drosha and activation of SIX1-Q177R led to hydronephrosis, proteinuria and an early death around stage P28. Combined activation of DROSHA-E1147K and SIX1-Q177R under Six2-cre resulted in proteinuria, glomerulosclerosis and lesions inside the kidney. These mice also suffered from juvenile death. Both mouse models could confirm the predicted synergistic effect.
While these results underscore the importance of a viable self-renewing progenitor pool for kidney development, there was no evidence of tumor formation. This suggests that either additional alterations in mitogenic or antiapoptotic pathways are needed for malignant transformation, or premature loss of a susceptible target cell population and early lethality prevent WT formation.
Viral infections induce a significant impact on various functional categories of biological processes in the host. The understanding of this complex modification of the infected host immune system requires a global and detailed overview on the infection process. Therefore it is essential to apply a powerful approach which identifies the involved components conferring the capacity to recognize and respond to specific pathogens, which in general are defeated in so-called compatible virus-plant infections. Comparative and integrated systems biology of plant-virus interaction progression may open a novel framework for a systemic picture on the modulation of plant immunity during different infections and understanding pathogenesis mechanisms. In this thesis these approaches were applied to study plant-virus infections during two main viral pathogens of cassava: Cassava brown streak virus and African cassava mosaic virus.
Here, the infection process was reconstructed by a combination of omics data-based analyses and metabolic network modelling, to understand the major metabolic pathways and elements underlying viral infection responses in different time series, as well as the flux activity distribution to gain more insights into the metabolic flow and mechanism of regulation; this resulted in simultaneous investigations on a broad spectrum of changes in several levels including the gene expression, primary metabolites, and enzymatic flux associated with the characteristic disease development process induced in Nicotiana benthamiana plants due to infection with CBSV or ACMV.
Firstly, the transcriptome dynamics of the infected plant was analysed by using mRNA-sequencing, in order to investigate the differential expression profile according the symptom developmental stage. The spreading pattern and different levels of biological functions of these genes were analysed associated with the infection stage and virus entity. A next step was the Real-Time expression modification of selected key pathway genes followed by their linear regression model. Subsequently, the functional loss of regulatory genes which trigger R-mediated resistance was observed. Substantial differences were observed between infected mutants/transgenic lines and wild-types and characterized in detail. In addition, we detected a massive localized accumulation of ROS and quantified the scavenging genes expression in the infected wild-type plants relative to mock infected controls.
Moreover, we found coordinated regulated metabolites in response to viral infection measured by using LC-MS/MS and HPLC-UV-MS. This includes the profile of the phytohormones, carbohydrates, amino acids, and phenolics at different time points of infection with the RNA and DNA viruses. This was influenced by differentially regulated enzymatic activities along the salicylate, jasmonate, and chorismate biosynthesis, glycolysis, tricarboxylic acid cycle, and pentose phosphate pathways, as well as photosynthesis, photorespiration, transporting, amino acid and fatty acid biosynthesis. We calculated the flux redistribution considering a gradient of modulation for enzymes along different infection stages, ranging from pre-symptoms towards infection stability.
Collectively, our reverse-engineering study consisting of the generation of experimental data and modelling supports the general insight with comparative and integrated systems biology into a model plant-virus interaction system. We refine the cross talk between transcriptome modification, metabolites modulation and enzymatic flux redistribution during compatible infection progression. The results highlight the global alteration in a susceptible host, correlation between symptoms severity and the alteration level. In addition we identify the detailed corresponding general and specific responses to RNA and DNA viruses at different stages of infection. To sum up, all the findings in this study strengthen the necessity of considering the timing of treatment, which greatly affects plant defence against viral infection, and might result in more efficient or combined targeting of a wider range of plant pathogens.
The evolutionary conserved Myb-MuvB (MMB) multiprotein complex is a transcriptional master regulator of mitotic gene expression. The MMB subunits B-MYB, FOXM1 as well as target genes of MMB are often overexpressed in different cancer types. Elevated expression of these genes correlates with an advanced tumor state and a poor prognosis for patients. Furthermore, it has been reported that pathways, which are involved in regulating the mitotic machinery are attractive for a potential treatment of cancers harbouring Ras mutations (Luo et al., 2009).
This suggest that the MMB complex could be required for tumorigenesis by mediating overactivity of mitotic genes and that the MMB could be a useful target for lung cancer treatment. However, although MMB has been characterized biochemically, the contribution of MMB to tumorigenesis is largely unknown in particular in vivo.
In this thesis, it was demonstrated that the MMB complex is required for lung tumorigenesis in vivo in a mouse model of non small cell lung cancer. Elevated levels of B-MYB, NUSAP1 or CENPF in advanced tumors as opposed to low levels of these proteins levels in grade 1 or 2 tumors support the possible contribution of MMB to lung tumorigenesis and the oncogenic potential of B-MYB.The tumor growth promoting function of B-MYB was illustrated by a lower fraction of KI-67 positive cells in vivo and a significantly high impairment in proliferation after loss of B-Myb in vitro. Defects in cytokinesis and an abnormal cell cycle profile after loss of B-Myb underscore the impact of B-MYB on proliferation of lung cancer cell lines. The incomplete recombination of B-Myb in murine lung tumors and in the tumor derived primary cell lines illustrates the selection pressure against the complete loss of B-Myb and further demonstrats that B-Myb is a tumor-essential gene. In the last part of this thesis, the contribution of MMB to the proliferation of human lung cancer cells was demonstrated by the RNAi-mediated depletion of B-Myb. Detection of elevated B-MYB levels in human adenocarcinoma and a reduced proliferation, cytokinesis defects and abnormal cell cycle profile after loss of B-MYB in human lung cancer cell lines underlines the potential of B-MYB to serve as a clinical marker.
Modulation of insulin-induced genotoxicity in vitro and genomic damage in gestational diabetes
(2019)
Diabetes mellitus is a global health problem, where the risk of diabetes increases rapidly
due to the lifestyle changes. Patients with type II diabetes have many complications
with increased risk of morbidity and mortality. High levels of insulin may lead to DNA
oxidation and damage. Several studies proposed that hyperinsulinemia may be an
important risk factor for various types of cancer. To investigate insulin signaling
pathway inducing oxidative stress and genomic damage, pharmaceutical and natural
compounds which can interfere with the insulin pathway including PI3K inhibitors,
resveratrol, lovastatin, and RAD-001 were selected due to their beneficial effects
against metabolic disorder. Thus, the anti-genotoxic potential of these compounds
regarding insulin-mediated oxidative stress were investigated in normal rat kidney cells
in vitro. Our compounds showed protective effect against genotoxic damage and
significantly decreased reactive oxygen specious after treatment of cells with insulin
with different mechanisms of protection between the compounds. Thus, these
compounds may be attractive candidates for future support of diabetes mellitus therapy.
Next, we explored the link between gestational diabetes mellitus and genomic damage
in cells derived from human blood. Moreover, we investigated the influence of
estradiol, progesterone, adrenaline and triiodothyronine on insulin-induced genomic
damage in vitro. First, we studied the effect of these hormones in human promyelocytic
leukemia cells and next ex vivo with non-stimulated and stimulated peripheral blood
mononuclear cells. In parallel, we also measured the basal genomic damage using three
conditions (whole blood, non-stimulated and stimulated peripheral blood mononuclear
cells) in a small patient study including non-pregnant controls with/without hormonal
contraceptives, with a subgroup of obese women, pregnant women, and gestational
diabetes affected women. A second-time point after delivery was also applied for
analysis of the blood samples. Our results showed that GDM subjects and obese
individuals exhibited higher basal DNA damage compared to lower weight nonpregnant
or healthy pregnant women in stimulated peripheral blood mononuclear cells
in both comet and micronucleus assays. On the other hand, the DNA damage in GDM
women had decreased at two months after birth. Moreover, the applied hormones also
showed an influence in vitro in the enhancement of the genomic damage in cells of the control and pregnant groups but this damage did not exceed the damage which existed
in obese and gestational diabetes mellitus patients with high level of genomic damage.
In conclusion, insulin can induce genomic damage in cultured cells, which can be
modulated by pharmaceutical and naturals substances. This may be for future use in the
protection of diabetic patients, who suffer from hyperinsulinemia during certain disease
stages. A particular form of diabetes, GDM, was shown to lead to elevated DNA
damage in affected women, which is reduced again after delivery. Cells of affected
women do not show an enhanced, but rather a reduced sensitivity for further DNA
damage induction by hormonal treatment in vitro. A potential reason may be an
existence of a maximally inducible damage by hormonal influences.
The role of multicellularity as the predominant microbial lifestyle has been affirmed by studies on the genetic regulation of biofilms and the conditions driving their formation. Biofilms are of prime importance for the pathology of chronic infections of the opportunistic human pathogen Staphylococcus aureus.
The recent development of a macrocolony biofilm model in S. aureus opened new opportunities to study evolution and physiological specialization in biofilm communities in this organism. In the macrocolony biofilm model, bacteria form complex aggregates with a sophisticated spatial organization on the micro- and macroscale. The central positive and negative regulators of this organization in S. aureus are the alternative sigma factor σB and the quorum sensing system Agr, respectively. Nevertheless, nothing is known on additional factors controlling the macrocolony morphogenesis.
In this work, the genome of S. aureus was screened for novel factors that are required for the development of the macrocolony architecture. A central role for basic metabolic pathways was demonstrated in this context as the macrocolony architecture was strongly altered by the disruption of nucleotide and carbohydrate synthesis. Environmental signals further modulate macrocolony morphogenesis as illustrated by the role of an oxygen-sensitive gene regulator, which is required for the formation of complex surface structures. A further application of the macrocolony biofilm model was demonstrated in the study of interstrain interactions. The integrity of macrocolony communities was macroscopically visibly disturbed by competitive interactions between clinical isolates of S. aureus.
The results of this work contribute to the characterization of the macrocolony biofilm model and improve our understanding of developmental processes relevant in staphylococcal infections. The identification of anti-biofilm effects exercised through competitive interactions could lead to the design of novel antimicrobial strategies targeting multicellular bacterial communities.
Hematopoietic stem cell transplantation is a curative therapy for malignant diseases of the haematopoietic system. The patients first undergo chemotherapy or irradiation therapy which depletes the majority of tumour cells before they receive the transplant, consisting of haematopoietic stem cells and mature T cells from a healthy donor. The donor T cells kill malignant cells that have not been eliminated by the conditioning therapy (graft versus leukaemia effect, GvL), and, therefore, are crucially required to prevent relapse of the tumour. However, the donor T cells may also severely damage the patient’s organs causing acute graft versus host disease (aGvHD). In mice, aGvHD can be prevented by interfering with the co-stimulatory CD28 signal on donor T cells. However, experimental models using conventional CD28 knockout mice as T cell donors or αCD28 antibodies have some disadvantages, i.e. impaired T cell development in the thymus of CD28 knockout mice and systemic CD28 blockade with αCD28 antibodies. Thus, it remains unclear how CD28 co-stimulation on different donor T cell subsets contributes to the GvL effect and aGvHD, respectively.
We developed mouse models of aGvHD and the GvL effect that allowed to selectively delete CD28 on certain donor T cell populations or on all donor T cells. CD4+ conventional T cells (Tconv cells), regulatory T cells (Treg cells) or CD8+ T cells were isolated from either Tamoxifen-inducible CD28 knockout (iCD28KO) mice or their wild type (wt) littermates. Allogeneic recipient mice were then transplanted with T cell depleted bone marrow cells and different combinations of iCD28KO and wt T cell subsets. Tamoxifen treatment of the recipients caused irreversible CD28 deletion on the iCD28KO donor T cell population. In order to study the GvL response, BCL-1 tumour cells were injected into the mice shortly before transfer of the T cells.
CD4+ Tconv mediated aGvHD was efficiently inhibited when wt Treg cells were co-transplanted. In contrast, after selective CD28 deletion on donor Treg cells, the mice developed a late and lethal flare of aGvHD, i.e. late-onset aGvHD. This was associated with a decline in iCD28KO Treg cell numbers around day 20 after transplantation. CD28 ablation on either donor CD4+ Tconv cells or CD8+ T cells reduced but did not abrogate aGvHD. Moreover, iCD28KO and wt CD8+ T cells were equally capable of killing allogeneic target cells in vivo and in vitro. Due to this sufficient anti-tumour activity of iCD28KO CD8+ T cells, they had a therapeutic effect in our GvL model and 25% of the mice survived until the end of the experiment (day 120) without any sign of the malignant disease. Similarly, CD28 deletion on all donor T cells induced long-term survival. This was not the case when all donor T cells were isolated from wt donor mice. In contrast to the beneficial outcome after CD28 deletion on all donor T cells or only CD8+ T cells, selective CD28 deletion on donor CD4+ Tconv cells completely abrogated the GvL effect due to insufficient CD4+ T cell help from iCD28KO CD4+ Tconv cells.
This study demonstrates that therapeutic inhibition of the co-stimulatory CD28 signal in either all donor T cells or only in CD8+ T cells might protect patients from aGvHD without increasing the risk of relapse of the underlying disease. Moreover, deletion of CD28 on donor Treg cells constitutes a mouse model of late-onset aGvHD which can be a useful tool in aGvHD research.
Functional analysis of polarization and podosome formation of murine and human megakaryocytes
(2019)
In mammals, blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MK) that extend polarized cell protrusions (proplateles) into BM sinusoids. Proplatelet formation (PPF) requires substantial cytoskeletal rearrangements that have been shown to involve the formation of podosomes, filamentous actin (F-actin) and integrin-rich structures. However, the exact molecular mechanisms regulating MK podosome formation, polarization and migration within the BM are poorly defined. According to current knowledge obtained from studies with other cell types, these processes are regulated by Rho GTPase proteins like RhoA and Cdc42.
In this thesis, polarization and podosome formation were investigated in MKs from genetically modified mice, as well as the cell lines K562 and Meg01 by pharmacological modulation of signaling pathways.
The first part of this thesis describes establishment of the basic assays for investigation of MK polarization. Initial data on polarization of the MK-like erythroleukemia cell line K562 revealed first insights into actin and tubulin dynamics of wild type (WT) and RhoA knock-out (RhoA-/-) K562 cells. Phorbol 12-myristate 13-acetate (PMA)-induction of K562 cells led to the expected MK-receptor upregulation but also RhoA depletion and altered polarization patterns.
The second part of this thesis focuses on podosome formation of MKs. RhoA is shown to be dispensable for podosome formation. Cdc42 is revealed as an important, but not essential regulator of MK spreading and podosome formation. Studies of signaling pathways of podosome formation reveal the importance of the tyrosine kinases Src, Syk, as well as glycoprotein (GP)VI in MK spreading and podosome formation.
This thesis provides novel insights into the mechanisms underlying polarization and podosome formation of MKs and reveals new, important information about cytoskeletal dynamics of MKs and potentially also platelets.
Besides a growing tendency for delayed parenthood, sedentary lifestyle coupled with overnutrition has dramatically increased worldwide over the last few decades. Epigenetic mechanisms can help us understand the epidemics and heritability of complex traits like obesity to a significant extent. Majority of the research till now has focused on determining the impact of maternal factors on health and disease risk in the offspring(s).
This doctoral thesis is focused on deciphering the potential effects of male aging and obesity on sperm methylome, and consequences/transmission via germline to the next generation. In humans, this was assessed in a unique cohort of ~300 sperm samples, collected after in vitro fertilization/intracytoplasmic sperm injection, as well as in conceived fetal cord blood samples of the children. Furthermore, aging effect on sperm samples derived from a bovine cohort was analyzed.
The study identified that human male aging significantly increased the DNA methylation levels of the promoter, the upstream core element, the 18S, and the 28S regions of ribosomal DNA (rDNA) in sperm. Prediction models were developed to anticipate an individual’s age based on the methylation status of rDNA regions in his sperm. Hypermethylation of alpha satellite and LINE1 repeats in human sperm was also observed with aging. Epimutations, which are aberrantly methylated CpG sites, were significantly higher in sperm of older males compared to the younger ones. These effects on the male germline had a negative impact on embryo quality of the next generation. Consistent with these results, DNA methylation of rDNA regions, bovine alpha satellite, and testis satellite repeats displayed a significant positive correlation with aging sperm samples within the same individual and across different age-grouped bulls.
A positive association between human male obesity/body mass index (BMI) and DNA methylation of the imprinted MEG3 gene and the obesity-related HIF3A gene was detected in sperm. These BMI-induced sperm DNA methylation signatures were transmitted to next generation fetal cord blood (FCB) samples in a gender-specific manner. Males, but not female offsprings exhibited a significant positive correlation between father’s BMI and FCB DNA methylation in the two above-mentioned amplicons. Additionally, hypomethylation of IGF2 with increased paternal BMI was observed in female FCB samples. Parental allele-specific in-depth methylation analysis of imprinted genes using next generation sequencing technology also revealed significant correlations between paternal factors like age and BMI, and the corresponding father’s allele DNA methylation in FCB samples.
Deep bisulphite sequencing of imprinted genes in diploid somatic cord blood cells of offspring detected that the levels of DNA methylation signatures largely depended on the underlying genetic variant, i.e. sequence haplotypes. Allele-specific epimutations were observed in PEG1, PEG5, MEG3, H19, and IGF2 amplicons. For the former three genes, the non-imprinted unmethylated allele displayed more epimutations than the imprinted methylated allele. On the other hand, for the latter two genes, the imprinted allele exhibited higher epimutation rate than that of the non-imprinted allele.
In summary, the present study proved that male aging and obesity impacts the DNA methylome of repetitive elements and imprinted genes respectively in sperm, and also has considerable consequences on the next generation. Nevertheless, longitudinal follow-up studies are highly encouraged to elucidate if these effects can influence the risk of developing abnormal phenotype in the offspring during adulthood.
Errors in Prospective Memory
(2019)
Prospective memory is the ability to implement intentions at a later point in time in response to a specified cue. Such prospective memory tasks often occur in daily living and workplace situations. However, in contrast to retrospective memory there has been relatively little research on prospective memory. The studies by Harris (1984) and Einstein and MacDaniel (1990) served as a starting point for a now steadily growing area of research. Based on this emerging field of study this dissertation presents and connects and five journal articles, which further explore prospective memory by focusing on its potential errors.
The first article addresses the question if additional cognitive resources are needed after a prospective memory cue occurs to keep the intention active until it is implemented. The theory by Einstein, McDaniel, Williford, Pagan and Dismukes (2003), which suggested this active maintenance, could not be replicated. The second article demonstrated that interruptions between cue and the window of opportunity to implement the intention reduce prospective memory performance, especially if the interruption is tied with a change of context. Article three to five were focused on the erroneous implementation of a no longer active prospective memory task, so called commission errors. The suggested mechanism for their occurrence, the dual-mechanism account (Bugg, Scullin, & Rauvola, 2016), was not suited to explain the present results. A modification for the dual-mechanism account was formulated, which can account for prior work, as well as for the present data.
The results of all five articles also indicate that the moment of cue retrieval is even more relevant for prospective memory and its errors than previously accounted for.
Two chiral chemical molecules being mirror images of each other, also referred to as enantiomers, may have different pharmacokinetic, pharmacodynamic, and toxicological effects. Thus, pharmaceutical manufacturers and authorities are increasingly interested in the approval of enantiopure drugs. However, the isomeric purity and the limits for isomeric impurities have to be specified applying enantioselective analytical methods, such as capillary electrophoresis.
The separation of enantiomers in capillary electrophoresis may be improved by the addition of ionic liquids to the background electrolyte. The aim of this work was to investigate the influence of different separation conditions on the enantioseparation of phenethylamines in background electrolytes containing ionic liquids based on tetrabutylammonium cations.
Best chiral separations were achieved at acidic pH values using phosphate buffers containing 125 mmol/L tetrabutylammonium based salts. Different reasons explaining enhanced enantioseparations in buffers containing ionic liquids were found. First, due to an improvement of the cyclodextrin solubility, the addition of ionic liquids to the background electrolyte enables the use of higher concentrations of these chiral selector. Furthermore, the adsorption of tetrabutylammonium cations to the negatively charged capillary surface results in a reduction of the electroosmotic flow. Hence, the resulting prolongation of migration times leads to a longer period of time for the separation of temporarily formed diastereomeric analyte cyclodextrin complexes, which yields improved enantioseparation. Additionally, due to a decrease of the adsorption of positively charged phenethylamine analyte molecules to capillary surface silanol groups, the adsorption of ionic liquid cations inhibits peak broadening. A further reason explaining an enhanced enantioseparation by the addition of ionic liquids to the background electrolyte is a competition between tetrabutylammonium cations and analyte enantiomers for the inclusion into cyclodextrin cavities.
Furthermore, the influence of different chiral counterions, combined with tetrabutylammonium cations, on the enantioseparation of phenethylamines was investigated. Solely anions based on the basic proteinogenic amino acids L lysine and L arginine yielded chiral separation results superior to those achieved using achiral tetrabutylammonium chloride as background electrolyte additive. Especially the application of tetrabutylammonium L argininate gave very good enantioseparations of all investigated ephedrine derivatives, which might be explained by the ability of L arginine to affect the formation of complexes between analytes and cyclodextrins.
Besides the investigation of the influence of ionic liquids on the enantioseparation, complexes between phenethylamine enantiomers and β cyclodextrin derivatives were characterized by affinity capillary electrophoresis. The binding constants between analyte enantiomers and cyclodextrins and the electrophoretic mobilities of the temporarily formed complexes were determined and compared to the observed chiral resolution values. While neither the calculated binding constants nor their differences correlated with the quality of the enantioseparation, a strong correlation between the differences of the electrophoretic mobilities of the complexes and the chiral resolution values was found.
Development of Novel Quinolone Amides Against the African Sleeping Sickness - A Fluorine Walk
(2019)
In recent years the transmission of the Human African Trypanosomiasis could be significantly reduced. The reported cases in 2016 reached a historic low level of 2184 cases and these achievements can be ascribed to intense control and surveillance programmes.118 However, most of the reported cases (>1000 in 2015) occurred in the Democratic Republic of the Congo and thus, need to be treated adequately. In particular, when the parasites have traversed the blood-brain barrier (BBB), treatment proved to be even more difficult. In addition, the number of cases always came in waves due to many reasons, e.g., development of resistances. Thus, it can be expected from experiences of the past that the number of cases will increase again. Hence, novel chemical entities are desperately needed in order to overcome the drawbacks which are associated with the current treatment options.
Our drug discovery approach included an initial drug repurposing strategy combined with a phenotypic screening. S. Niedermeier found novel active compounds derived from commercial fluoroquinolones. The most promising hit compound was further developed by G. Hiltensperger resulting in the lead quinolone amide GHQ168 (IC50 = 0.047 µM).
This doctoral thesis is about new insights into the SAR of the quinolone amides and the enhancement of the lead compound. Special consideration was given to the fluorine atom in the quinolone amides and how certain fluorine substitution patterns influence the antitrypanosomal activity, physicochemical properties and pharmacokinetics (i.e. ‘fluorine walk’). Moreover, the ability of the compound class crossing the BBB should be investigated. This feature is inevitable necessary in order to potentially treat African sleeping sickness stage II.
The Gould-Jacobs protocol was predominantly used for the synthesis of the quinolone core. Since former SAR studies mainly concentrated on the variation in positions 1, 3 and 7, quinolone scaffolds (2a-i) with diverse substitution patterns regarding positions 5, 6, 7 and 8 were synthesised in this thesis. The resulting quinolone amides were evaluated for their antitrypanosomal activity.
Voluminous residues in position C-5 resulted in diminished activities (compounds 13, 16 and 18) and solely small-sized moieties were tolerated. In particular the fluorine atom in position 5 revealed beneficial trypanocidal effects as shown for compounds 6 (IC50 = 0.05 µM), 8 (IC50 = 0.04 µM), and 24 (IC50 = 0.02 µM). Furthermore, having fluorine only in position 5 of the quinolone core could considerably reduce the cytotoxic effects (CC50 >100 µM, SI = >2000 for 6). Hence, the 5-fluoro-substituted quinolone amides were considered superior to GHQ168.
Regarding the C-6 position all other moieties (e.g., H in 9, OCH3 in 10, CF3 in 12) except of a fluorine atom decreased the activity against Trypanosoma brucei brucei. A double fluorination in C-6 and C-8 was not beneficial (IC50 = 0.06 µM for 7) and a single fluorine atom in C-8 even showed a negative effect (IC50 = 0.79 µM for 5).
The logP value is considered a surrogate parameter for lipophlicity and thus, affecting permeability and solubility processes. In particular the fluorine atom influences the lipophilicity due to versatile effects: Lipophilicity is increased by additional fluorine atoms on aromatic rings (7, 23) and reduced by fluorine atoms at an alkyl chain (49), respectively. Additionally, the 5-fluoro-substituted quinolone amides (6, 8, and 24) could prove the contrary effect of decreasing lipophilicity when the aromatic fluorine substituent is in vicinity to a carbonyl group.
For the most promising drug candidates 6, 23, and 24 the respective metabolites and the metabolic turnover were investigated by C. Erk. In comparison to GHQ168 the hydroxylation of the benzylamide was prevented by the para-fluorine atom. Hence, half-life was extended for compound 23 (t1/2 = 6.4 h) and N-desalkylation was the predominant pathway. Moreover, the respective fluorine substitution pattern of the quinolone core affected the metabolism of compound 6. The 5-fluoro-substituted quinolone amide was less prone for biotransformation (t1/2 = 7.2 h) and half-life could even be further prolonged for compound 24 (t1/2 = 7.7 h).
Due to the most appropriate safety profile of compound 6, this particular drug candidate was considered for in vivo study. Its poor solubility made a direct intraperitoneal administration unfeasible. Thus, an amorphous solid dispersion of 6 was generated using the spray-drying method according to the previous protocol. Unfortunately, the required solubility for the predicted in vivo study was not achieved.
Furthermore, the compound class of the quinolone amide was evaluated for its ability for brain penetration. The methanesulfonyl precursor 48 was synthesised and subsequently radiofluorinated in the group of Prof. Dr. Samnick (Department of Nuclear Medicine, University Hospital of Würzburg). The labelled compound [18F]49 was administered to mice, and its distribution throughout the body was analysed using positron emission tomography and autoradiography, respectively. The autoradiography of the murine brains revealed medium to high concentrations of [18F]49. Therefore, the quinolone amides are generally suitable for treating Human African Trypanosomiasis stage II.
A scaffold hopping approach was performed starting from the quinolone amides and concluding with the compound class of pyrazoloquinolin-3-ones. The intramolecular hydrogen bond between the sec. amide and the C-4 carbonyl moiety was replaced by a covalent bond. The two compound classes were comparable regarding the antitrypanosomal activity to some degree (IC50 = 7.9 µM (EK02) vs. 6.37 µM (53a)). However, a final evaluation of 59 was not possible due to poor solubility.