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- Maus (61)
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- Krebs <Medizin> (22)
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- Maschinelles Lernen (22)
- Molekulargenetik (22)
- Selbstorganisation (22)
- Supramolekulare Chemie (22)
- Transkriptionsfaktor (21)
- Apoptosis (20)
- Dendritische Zelle (20)
- Drosophila melanogaster (20)
- Fluoreszenzmikroskopie (20)
- Genregulation (20)
- Melanom (20)
- Molekularbiologie (20)
- Molekularstrahlepitaxie (20)
- Kernspintomografie (19)
- Klimaänderung (18)
- Modellierung (18)
- Photoelektronenspektroskopie (18)
- Staphylococcus aureus (18)
- Fluoreszenz (17)
- Optimierung (17)
- Organischer Halbleiter (17)
- Polymere (17)
- Quecksilbertellurid (17)
- Zellzyklus (17)
- Bioinformatik (16)
- Entzündung (16)
- Spektroskopie (16)
- Fernerkundung (15)
- Optimale Kontrolle (15)
- Psychologie (15)
- Stress (15)
- Verhalten (15)
- Virtuelle Realität (15)
- Angst (14)
- Epigenetik (14)
- Exziton (14)
- Farbstoff (14)
- Femtosekundenspektroskopie (14)
- MRI (14)
- Mikroskopie (14)
- Myc (14)
- Netzwerk (14)
- Regulation (14)
- Serotonin (14)
- Trypanosoma brucei (14)
- Ultrakurzzeitspektroskopie (14)
- Vaccinia-Virus (14)
- cancer (14)
- Biodiversität (13)
- Escherichia coli (13)
- Halbleiter (13)
- Hydrogel (13)
- Inhibitor (13)
- Kognition (13)
- Makrophage (13)
- Monte-Carlo-Simulation (13)
- Motoneuron (13)
- Organische Solarzelle (13)
- Spintronik (13)
- miRNS (13)
- Ackerschmalwand (12)
- Apoptose (12)
- Aufmerksamkeit (12)
- Bildgebendes Verfahren (12)
- Chemische Synthese (12)
- DNS-Reparatur (12)
- DNS-Schädigung (12)
- Dichtefunktionalformalismus (12)
- GPCR (12)
- Gedächtnis (12)
- HgTe (12)
- Immunologie (12)
- Immuntherapie (12)
- Konditionierung (12)
- Rezeptor (12)
- Schlaganfall (12)
- Stammzelle (12)
- Theoretische Chemie (12)
- Thrombose (12)
- Topologie (12)
- Zelldifferenzierung (12)
- Aggregation (11)
- Antikörper (11)
- Cancer (11)
- Candida albicans (11)
- Deutschland (11)
- Dünne Schicht (11)
- Gehirn (11)
- Genanalyse (11)
- Knockout <Molekulargenetik> (11)
- Lungenkrebs (11)
- Megakaryozyt (11)
- Merocyanine (11)
- Microscopy (11)
- NFATc1 (11)
- NMR-Spektroskopie (11)
- NMR-Tomographie (11)
- Neisseria meningitidis (11)
- Perylenderivate (11)
- Supersymmetrie (11)
- Synapse (11)
- Zellskelett (11)
- learning (11)
- platelets (11)
- topological insulator (11)
- ARPES (10)
- Ameisen (10)
- Aminosäuren (10)
- Angststörung (10)
- Elektronentransfer (10)
- Entwicklung (10)
- Gefühl (10)
- Immunsystem (10)
- Insekten (10)
- Kutikula (10)
- MAP-Kinase (10)
- Optische Spektroskopie (10)
- Oxidativer Stress (10)
- Perylenbisimid (10)
- Platelets (10)
- Proteine (10)
- Robotik (10)
- Supraleitung (10)
- Transkription <Genetik> (10)
- 3D-Druck (9)
- Arteriosklerose (9)
- Aspergillus fumigatus (9)
- Bakterien (9)
- Bildverarbeitung (9)
- Chlamydia trachomatis (9)
- Computersimulation (9)
- DFT (9)
- Diabetes mellitus (9)
- Einzelmolekülmikroskopie (9)
- Elektronenkorrelation (9)
- Elektrophysiologie (9)
- Elementarteilchenphysik (9)
- Extrazelluläre Matrix (9)
- Festkörperphysik (9)
- Fuchsbandwurm (9)
- G-Protein gekoppelte Rezeptoren (9)
- Geruchswahrnehmung (9)
- HPLC (9)
- Immunreaktion (9)
- Mensch-Maschine-Kommunikation (9)
- Mitose (9)
- Neurobiologie (9)
- Organische Chemie (9)
- Quality of Experience (9)
- Quanten-Hall-Effekt (9)
- Quantenchemie (9)
- Quantenpunkt (9)
- Raman-Spektroskopie (9)
- Ratte (9)
- Small RNA (9)
- Starke Kopplung (9)
- Tagesrhythmus (9)
- Tumor (9)
- Virulenz (9)
- fluorescence (9)
- perylene bisimide (9)
- self-assembly (9)
- signal transduction (9)
- Ökologie (9)
- ADHD (8)
- Affekt (8)
- Arabidopsis thaliana (8)
- Arzneimitteldesign (8)
- Aufmerksamkeits-Defizit-Syndrom (8)
- Bioinformatics (8)
- Biomarker (8)
- Blazar (8)
- DNA damage (8)
- Elektronenspinresonanz (8)
- Elektronischer Transport (8)
- Fluoreszenz-Resonanz-Energie-Transfer (8)
- Fotovoltaik (8)
- Galliumarsenid (8)
- Herzinfarkt (8)
- Heterostruktur (8)
- Induzierte pluripotente Stammzelle (8)
- Infektion (8)
- Inhibition (8)
- Ladungstransfer (8)
- Machine Learning (8)
- Mensch (8)
- Metabolismus (8)
- Microarray (8)
- Muscarinrezeptor (8)
- Nahrungserwerb (8)
- Namibia (8)
- Nanopartikel (8)
- Neisseria gonorrhoeae (8)
- Pflanzen (8)
- Pilzkörper (8)
- Squaraine (8)
- Therapie (8)
- Transkription (8)
- Ultrakurzer Lichtimpuls (8)
- Westafrika (8)
- Zellkultur (8)
- dSTORM (8)
- evolution (8)
- photoelectron spectroscopy (8)
- Übergangsmetallkomplexe (8)
- Aktiver galaktischer Kern (7)
- Alzheimerkrankheit (7)
- Angeregter Zustand (7)
- Angiogenese (7)
- Arzneimittel (7)
- Autonomer Roboter (7)
- Bacteria (7)
- Biofilm (7)
- Biomaterial (7)
- Bioverfügbarkeit (7)
- Calcium (7)
- Chronobiologie (7)
- Cytokine (7)
- Depression (7)
- EEG (7)
- Embryonalentwicklung (7)
- Emotion (7)
- Enzym (7)
- Extremwertstatistik (7)
- FRET (7)
- Fluorescence (7)
- Furcht (7)
- Gammastrahlung (7)
- Geldpolitik (7)
- Genetik (7)
- Genmutation (7)
- Helicobacter pylori (7)
- Hubbard-Modell (7)
- In vitro (7)
- Informationsverarbeitung (7)
- Insulin (7)
- Japankärpfling (7)
- Katalyse (7)
- Kleinsatellit (7)
- Klimawandel (7)
- LHC (7)
- Landnutzung (7)
- Ligand <Biochemie> (7)
- MYC (7)
- Malaria (7)
- Methylierung (7)
- Mobiler Roboter (7)
- Motivation (7)
- NMR-Bildgebung (7)
- Nash-Gleichgewicht (7)
- Neuroethologie (7)
- Nigeria (7)
- Operations Management (7)
- Optogenetik (7)
- Organisches Molekül (7)
- Pathogenität (7)
- Performance Evaluation (7)
- Pheromon (7)
- RNS (7)
- Radioastronomie (7)
- Spinale Muskelatrophie (7)
- Supersymmetry (7)
- Synthese (7)
- Textverstehen (7)
- Thrombosis (7)
- Transcription (7)
- Tuberkelbakterium (7)
- Wahrnehmung (7)
- Zebrabärbling (7)
- Zellmigration (7)
- climate change (7)
- dendritic cells (7)
- fMRI (7)
- femtosecond spectroscopy (7)
- melanoma (7)
- memory (7)
- metabolism (7)
- social insects (7)
- virtual reality (7)
- ATLAS <Teilchendetektor> (6)
- AdS-CFT-Korrespondenz (6)
- Antibiotikum (6)
- Arbeitsteilung (6)
- B-Lymphozyt (6)
- Biologie (6)
- Bor (6)
- Camponotus floridanus (6)
- China (6)
- Chiralität <Chemie> (6)
- Click-Chemie (6)
- Cloud Computing (6)
- DNS (6)
- Elektrochemie (6)
- Elektronenstruktur (6)
- Fibroblastenwachstumsfaktor (6)
- Funktionelle Kernspintomografie (6)
- Gehirn-Computer-Schnittstelle (6)
- Genom (6)
- Geruchssinn (6)
- Graphen (6)
- HIV (6)
- Hochtemperatursupraleiter (6)
- Honigbiene (6)
- Instrumentelle Analytik (6)
- Interaktion (6)
- Komplexitätstheorie (6)
- Konfokale Mikroskopie (6)
- Konjugierte Polymere (6)
- Künstliche Intelligenz (6)
- Laser (6)
- Lithium-Ionen-Akkumulator (6)
- Löslichkeit (6)
- Magnetismus (6)
- Natürliche Killerzelle (6)
- Neuronale Plastizität (6)
- Neutrino (6)
- Newton-Verfahren (6)
- Numerisches Verfahren (6)
- Onkolyse (6)
- Organische Synthese (6)
- Parkinson-Krankheit (6)
- Pharmakokinetik (6)
- Platelet (6)
- Pulsformung (6)
- Raf <Biochemie> (6)
- Rekombination (6)
- Routing (6)
- Röntgen-Photoelektronenspektroskopie (6)
- Röntgenspektroskopie (6)
- Self-assembly (6)
- Soziale Insekten (6)
- Spintronics (6)
- Stoffwechsel (6)
- Symbiose (6)
- Systembiologie (6)
- Transplantat-Wirt-Reaktion (6)
- USA (6)
- Ubiquitin (6)
- Verteiltes System (6)
- Zwei-Sechs-Halbleiter (6)
- apoptosis (6)
- drug delivery (6)
- gene expression (6)
- honeybee (6)
- in vitro (6)
- mesenchymal stem cells (6)
- microRNA (6)
- molecular beam epitaxy (6)
- olfaction (6)
- organic semiconductors (6)
- organic solar cells (6)
- platelet (6)
- pulse shaping (6)
- spectroscopy (6)
- supramolecular chemistry (6)
- vaccinia virus (6)
- Übergangsmetall (6)
- Actin (5)
- Aggregat <Chemie> (5)
- Algorithmus (5)
- Antigen CD8 (5)
- Apis mellifera (5)
- Assoziatives Gedächtnis (5)
- Astrophysik (5)
- Ausbreitung (5)
- BMP (5)
- Bauchspeicheldrüsenkrebs (5)
- Biofabrication (5)
- Blattschneiderameisen (5)
- Blut-Hirn-Schranke (5)
- Borylierung (5)
- CRISPR/Cas-Methode (5)
- CRISPR/Cas9 (5)
- Cataglyphis (5)
- Chlamydia (5)
- Chromatin (5)
- Chromophor (5)
- Coherent Multidimensional Spectroscopy (5)
- Cytoskeleton (5)
- Cytotoxizität (5)
- DNA repair (5)
- Demökologie (5)
- Dendritic cells (5)
- Diffusion (5)
- Echinococcus (5)
- Endothel (5)
- Entscheidungsunterstützung (5)
- Epidermaler Wachstumsfaktor-Rezeptor (5)
- Femtosekundenbereich (5)
- Fermionensystem (5)
- Fluoreszenzspektroskopie (5)
- Flüssigkristall (5)
- Fortpflanzung (5)
- Fourier-Spektroskopie (5)
- Gammaastronomie (5)
- Gephyrin (5)
- Geruch (5)
- Gold (5)
- Graph (5)
- Graphenzeichnen (5)
- Herz (5)
- Herzhypertrophie (5)
- Hippocampus (5)
- Honeybee (5)
- Hubbard model (5)
- Hydrogeologie (5)
- Hypoxie (5)
- Hämostase (5)
- Immunology (5)
- Immunotherapy (5)
- Impurity Profiling (5)
- Invasion (5)
- Klima (5)
- Knochen-Morphogenese-Proteine (5)
- Komplexität (5)
- Kondensierte Materie (5)
- Kondo-Effekt (5)
- LC-MS (5)
- LC-MS/MS (5)
- Latrophilin (5)
- Learning (5)
- Listeria monocytogenes (5)
- MAGIC-Teleskop (5)
- MBE (5)
- Magnetische Resonanz (5)
- Magnetischer Halbleiter (5)
- Makroökonomie (5)
- Manganarsenide (5)
- Manganverbindungen (5)
- Massenspektrometrie (5)
- Meeresschwämme (5)
- Meiose (5)
- Memory (5)
- Metagenom (5)
- Mitochondrium (5)
- Molekulardynamik (5)
- Monitoring (5)
- Monoklonaler Antikörper (5)
- Monte Carlo (5)
- Nahfeldoptik (5)
- Namibia <Nordwest> (5)
- Nanodraht (5)
- Nanostruktur (5)
- Naphthylisochinolinalkaloide (5)
- Nervendegeneration (5)
- Neuroanatomie (5)
- Neurodegeneration (5)
- Neurogenetik (5)
- Nichtlineare Optimierung (5)
- Nichtlineare Spektroskopie (5)
- Non-coding RNA (5)
- Nucleinsäuren (5)
- Oberflächenphysik (5)
- Olfaction (5)
- Optik (5)
- Optogenetics (5)
- Perowskit (5)
- Pharmakodynamik (5)
- Photochemie (5)
- Phylogenie (5)
- Quanteninformation (5)
- RNA (5)
- Rastertunnelmikroskop (5)
- Regulatorischer T-Lymphozyt (5)
- Remote Sensing (5)
- Rhodium (5)
- Ringöffnungspolymerisation (5)
- SMN (5)
- Satellit (5)
- Semiconductor (5)
- Semimagnetischer Halbleiter (5)
- Siliciumcarbid (5)
- Software (5)
- Software Defined Networking (5)
- Sozialpsychologie (5)
- Spin (5)
- Spin-Bahn-Wechselwirkung (5)
- Stabilität (5)
- Standardmodell <Elementarteilchenphysik> (5)
- Stressreaktion (5)
- T cell (5)
- Tanzania (5)
- Theoretical Chemistry (5)
- Theoretische Informatik (5)
- Transkriptomanalyse (5)
- Trypanosomen (5)
- Tumorzelle (5)
- UV-VIS-Spektroskopie (5)
- Ultraschall (5)
- Virulenzfaktor (5)
- Visuelle Aufmerksamkeit (5)
- Wirkstoff (5)
- XPS (5)
- Zellteilung (5)
- Zelltod (5)
- Zellwand (5)
- Zentralnervensystem (5)
- ants (5)
- atherosclerosis (5)
- biodiversity (5)
- biomarker (5)
- charge transfer (5)
- dispersal (5)
- diversity (5)
- division of labor (5)
- ecology (5)
- emotion (5)
- extracellular matrix (5)
- graph drawing (5)
- inflammation (5)
- insects (5)
- land use (5)
- megakaryocyte (5)
- neurobiology (5)
- oncolytic virotherapy (5)
- optimal control (5)
- regulation (5)
- soziale Insekten (5)
- spintronics (5)
- super-resolution microscopy (5)
- virulence (5)
- Actin-bindende Proteine (4)
- AdS/CFT (4)
- Alzheimer-Krankheit (4)
- Ancistrocladaceae (4)
- Antennallobus (4)
- Antimikrobieller Wirkstoff (4)
- Approximationsalgorithmus (4)
- Arbeitsmarkt (4)
- Atherosclerosis (4)
- Aufmerksamkeitsdefizit-Syndrom (4)
- Autoantikörper (4)
- Autoimmunität (4)
- B-Zell-Lymphom (4)
- Bestäubung (4)
- Bienen <Familie> (4)
- Bilanzpolitik (4)
- Biochemie (4)
- Biogenese (4)
- Biologische Uhr (4)
- Biomechanik (4)
- Biotransformation (4)
- Borane (4)
- Brain-derived neurotrophic factor (4)
- Bruchpilot (4)
- Brustkrebs (4)
- CD1d (4)
- Cadherine (4)
- Caenorhabditis elegans (4)
- Calciumkanal (4)
- Catalysis (4)
- Chemische Reinheit (4)
- Cognitive control (4)
- Compressed Sensing (4)
- Computational Chemistry (4)
- Computational chemistry (4)
- Conditioning (4)
- Dark Matter (4)
- Data Mining (4)
- Deep learning (4)
- Dendritic cell (4)
- Dienstgüte (4)
- Differentialgleichung (4)
- Dopamin (4)
- Dotierung (4)
- Drahtloses Sensorsystem (4)
- Dunkle Materie (4)
- Dünndarm (4)
- Electrospinning (4)
- Elektroencephalographie (4)
- Elektronendichte (4)
- Elektronenspin (4)
- Elektronentransport (4)
- Embryonale Stammzelle (4)
- Emotionsregulation (4)
- Endocytose (4)
- Entwicklungsbiologie (4)
- Enzyminhibitor (4)
- Epigenetic (4)
- Erwachsener (4)
- Euler equations (4)
- Expansion Microscopy (4)
- Experimentelle Psychologie (4)
- Extremwerttheorie (4)
- Fanconi-Anämie (4)
- Festkörpertheorie (4)
- Fibroblasten (4)
- Finite-Elemente-Methode (4)
- Fotokatalyse (4)
- Fotophysik (4)
- G-Protein gekoppelter Rezeptor (4)
- GPVI (4)
- Gasionisationsdetektor (4)
- Gelenkknorpel (4)
- Genetics (4)
- Geoinformationssystem (4)
- Geomorphologie (4)
- Graphene (4)
- HPLC-MS (4)
- Heart (4)
- Herzmuskel (4)
- Herzmuskelzelle (4)
- Histone (4)
- Hyaluronsäure (4)
- Hypoxia (4)
- Höhengradient (4)
- Image Processing (4)
- Immunisierung (4)
- Immunmodulation (4)
- Immunsuppression (4)
- Impfung (4)
- Implantat (4)
- Inflammation (4)
- Infrarotspektroskopie (4)
- Innate immunity (4)
- Innovation (4)
- Integrine (4)
- Interleukin 4 (4)
- Ionenkanal (4)
- Jura <Geologie> (4)
- Kilimandscharo (4)
- Kommunikation (4)
- Korrelation (4)
- Kosmologie (4)
- Krebs (4)
- Krebsforschung (4)
- Kristallwachstum (4)
- Kutikularwachs (4)
- LEED (4)
- Landwirtschaft (4)
- Laserspektroskopie (4)
- Leishmania (4)
- Leishmaniose (4)
- Lernverhalten (4)
- Ligand (4)
- Lipide (4)
- Localization (4)
- MMB (4)
- MODIS (4)
- MRSA (4)
- Magnetic Resonance Imaging (4)
- Magnetoelektronik (4)
- Magnetowiderstand (4)
- Makrophagen (4)
- Mathematische Modellierung (4)
- Mathematisches Modell (4)
- Mechanismus (4)
- Medaka (4)
- Mehrkriterielle Optimierung (4)
- Meiosis (4)
- Mensch-Maschine-Schnittstelle (4)
- Mergers and Acquisitions (4)
- Merkel cell carcinoma (4)
- Mesenchymzelle (4)
- Metaanalyse (4)
- Metakognition (4)
- Metallosupramolekulare Chemie (4)
- Metastase (4)
- Mimik (4)
- Mitochondria (4)
- Modell (4)
- Molekül (4)
- Monetary Policy (4)
- Monoschicht (4)
- Mutualismus (4)
- Myatrophische Lateralsklerose (4)
- Myelin (4)
- NEXAFS (4)
- NFAT (4)
- NIR-Spektroskopie (4)
- Nachhaltigkeit (4)
- Nahrung (4)
- Nanooptik (4)
- Naturschutz (4)
- Naturstoff (4)
- Nestbau (4)
- Netzhaut (4)
- Neurogenese (4)
- Neuronales Netz (4)
- Neuropeptide (4)
- Nichtglatte Optimierung (4)
- Nickelverbindungen (4)
- Nitratreduktase (4)
- OLED (4)
- Onkogen (4)
- Optimization (4)
- Orientierung (4)
- Overlay-Netz (4)
- Palökologie (4)
- Parasit (4)
- Parkinson's disease (4)
- Peptide (4)
- Peptidsynthese (4)
- Permeabilität (4)
- Perovskite (4)
- Perylenbisdicarboximide <Perylen-3,4:9,10-bis(dicarboximide)> (4)
- Perylene Bisimide (4)
- Phagozytose (4)
- Photovoltaik (4)
- Physik (4)
- Physiologie (4)
- Phänologie (4)
- Plasmodium falciparum (4)
- Plasmon (4)
- Pollen (4)
- Porin (4)
- Posttranskriptionelle Regulation (4)
- Prescriptive Analytics (4)
- Primaten (4)
- Prognose (4)
- Proliferation (4)
- Protonen-NMR-Spektroskopie (4)
- Pump-Probe-Technik (4)
- Punktwolke (4)
- QM/MM (4)
- Quantenfeldtheorie (4)
- Quantenspinsystem (4)
- ROS (4)
- Raman (4)
- Rashba-Effekt (4)
- Rastertunnelmikroskopie (4)
- Reaktionsmechanismus (4)
- Rechnungslegung (4)
- Renormierungsgruppe (4)
- Resistenz (4)
- Rutheniumkomplexe (4)
- Röntgendiffraktometrie (4)
- SARS-CoV-2 (4)
- SERS (4)
- Salmonella (4)
- Schwämme (4)
- Sekundärmetabolit (4)
- Silicium (4)
- Smad (4)
- Sol-Gel-Verfahren (4)
- Solarzelle (4)
- Soziale Wahrnehmung (4)
- Spectroscopy (4)
- Stratigraphie (4)
- Supply Chain Management (4)
- Supramolekulare Struktur (4)
- Synapsine (4)
- TFIIH (4)
- Targeted drug delivery (4)
- Telekommunikationsnetz (4)
- Theoretische Physik (4)
- Thrombozytenaggregation (4)
- Toxin (4)
- Transcriptome (4)
- Transforming Growth Factor beta (4)
- Transiente Absorption (4)
- Transpiration <Pflanzen> (4)
- Triarylamine (4)
- Triarylborane (4)
- TrkB (4)
- Ubiquitinierung (4)
- Ultrafast spectroscopy (4)
- Ultraschnelle Photochemie (4)
- Ultraviolett-Photoelektronenspektroskopie (4)
- VASP (4)
- VSG (4)
- Venusfliegenfalle (4)
- Verarbeitungsflüssigkeit (4)
- Wasseroxidation (4)
- West Africa (4)
- Wide-gap-Halbleiter (4)
- Wirkstofffreisetzung (4)
- Zeitreihe (4)
- Zelladhäsion (4)
- Zelle (4)
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Institut
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- Physikalisches Institut (208)
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- Institut für Psychologie (110)
- Institut für Pharmazie und Lebensmittelchemie (100)
- Julius-von-Sachs-Institut für Biowissenschaften (89)
Schriftenreihe
Sonstige beteiligte Institutionen
- Fraunhofer-Institut für Silicatforschung ISC (5)
- Helmholtz Institute for RNA-based Infection Research (HIRI) (5)
- Technische Hochschule Nürnberg Georg Simon Ohm (3)
- Deutsches Zentrum für Luft- und Raumfahrt (DLR), Institut für Raumfahrtsysteme (2)
- EMBL Heidelberg (2)
- Institut für Tierökologie und Tropenbiologie (2)
- Lehrkrankenhaus II. Medizinische Klinik Klinikum Coburg (2)
- Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg (2)
- Universität Belgrad, Serbien (2)
- Universitätsklinikum Münster (2)
ResearcherID
- B-1911-2015 (1)
- B-4606-2017 (1)
- C-2593-2016 (1)
- D-1250-2010 (1)
- I-5818-2014 (1)
- J-8841-2015 (1)
- M-1240-2017 (1)
- N-2030-2015 (1)
- N-3741-2015 (1)
EU-Projektnummer / Contract (GA) number
- 311781 (1)
- 320377 (1)
- EU (FP7/ 2007-2013) (1)
The unicellular pathogen Trypanosoma brucei is the causative agent of African
trypanosomiasis, an endemic disease prevalent in sub-Saharan Africa. Trypanosoma brucei alternates between a mammalian host and the tsetse fly vector. The extracellular parasite survives in the mammalian bloodstream by periodically exchanging their ˈvariant surface glycoproteinˈ (VSG) coat to evade the host immune response. This antigenic variation is achieved through monoallelic expression of one VSG variant from subtelomeric ˈbloodstream
form expression sitesˈ (BES) at a given timepoint. During the differentiation from the bloodstream form (BSF) to the procyclic form (PCF) in the tsetse fly midgut, the stage specific surface protein is transcriptionally silenced and replaced by procyclins. Due to their subtelomeric localization on the chromosomes, VSG transcription and silencing is partly regulated by homologues of the mammalian telomere complex such as TbTRF, TbTIF2 and TbRAP1 as well as by ˈtelomere-associated proteinsˈ (TelAPs) like TelAP1. To gain more insights into transcription regulation of VSG genes, the identification and characterization of other TelAPs is critical and has not yet been achieved. In a previous study, two biochemical approaches were used to identify other novel TelAPs. By using ˈco-immunoprecipitationˈ (co-IP) to enrich possible interaction partners of TbTRF and by affinity chromatography using telomeric repeat oligonucleotides, a listing of TelAP candidates has been conducted. With this approach TelAP1 was identified as a novel component of the telomere complex, involved in the kinetics of transcriptional BES silencing during BSF to PCF differentiation. To gain further insights into the telomere complex composition, other previously enriched proteins were characterized through a screening process using RNA interference to deplete potential candidates. VSG expression profile changes and overall proteomic changes after depletion were analyzed by mass spectrometry. With this method, one can gain insights into the functions of the proteins and their involvement in VSG expression site regulation. To validate the interaction of proteins enriched by co-IP with TbTRF and TelAP1 and to identify novel interaction proteins, I performed reciprocal affinity purifications of the four most promising candidates (TelAP2, TelAP3, PPL2 and PolIE) and additionally confirmed colocalization of two candidates with TbTRF via immunofluorescence (TelAP2, TelAP3). TelAP3 colocalizes with TbTRF and potentially interacts with TbTRF, TbTIF2, TelAP1 and TelAP2, as well as with two translesion polymerases PPL2 and PolIE in BSF. PPL2 and PolIE seem to be in close contact to each other at the telomeric ends and fulfill different roles as only PolIE is involved in VSG regulation while PPL2 is not. TelAP2 was previously characterized to be associated with telomeres by partially colocalizing with TbTRF and cells show a VSG derepression phenotype when the protein was depleted. Here I show that TelAP2 interacts with the telomere-binding proteins TbTRF and TbTIF2 as well as with the telomere-associated protein TelAP1 in BSF and that TelAP2 depletion results in a loss of TelAP1 colocalization with TbTRF in BSF.
In conclusion, this study demonstrates that characterizing potential TelAPs is effective in gaining insights into the telomeric complex's composition and its role in VSG regulation in Trypanosoma brucei. Understanding these interactions could potentially lead to new therapeutic targets for combatting African trypanosomiasis.
The current study presents a new a group of Demotic ostraca in the belongings of the Cairo Museum. A large part of this group stem from Medinet Habu in the western bank of modern Luxor in Upper Egypt and was discovered in the beginning of the thirties of the last century by the Chicago Oriental Institute (recently renamed as Institute for the Study of Ancient Cultures ‘ISAC’). A small portion of the collection under consideration come from other Upper Egyptian provenances including Gebelein, Edfu, Kom Ombo, and possibly elsewhere in Thebes. The main goal of the present dissertation is to decipher, translate, and provide a philological, paleographical, and cultural analysis of the group of texts in question. The results of this study are spread over two main parts, the first of which is dedicated to the main and largest part of the collection, i.e. ostraca from Medinet Habu, while the second is concerned with ostraca from other places. The first part comprises of five sections beginning with receipts of money and in-kind payments including some receipts for the payments of the different capitation charges in the Ptolemaic and Roman Periods, a few for land-related payments, as well as others related to different Ptolemaic monopolies or trades such as a receipt for the price of oil, one for the linen tax, in addition to a unique receipt for the rarely attested fish tax. The second section includes accounts and lists of different kinds be it monetary, in-kind, agriculture, or any other type of lists or accounts that record different everyday transactions. The following section presents a relatively different type of lists, namely lists of personal names. The fourth section incorporates a variety of texts of different concerns, e.g. texts of religious nature, letters, temples oaths, or other private documents. Unidentified texts occupy the fifth and final section of the first part. The second part of the study, which comprises texts that originate from different Upper Egyptian localities, includes three sections, i.e. receipts, accounts, and lists of names.
The mold Aspergillus fumigatus (A. fumigatus) is known as human pathogen and can cause life-threatening infections in humans with a weakened immune system. This is a known complication in patients receiving glucocorticoids, e.g. after hematopoietic stem cell transplantation or solid organ transplantation. Although research in the field of immune cell/fungus interaction has discovered key strategies how immune cells fight against infectious fungi, our knowledge is still incomplete. In order to develop effective treatment options against fungal infections, a detailed understanding of their interactions is crucial. Thus, visualization of immune cell and fungus is an excellent approach to gain further knowledge. For a detailed view of such interaction processes, a high optical resolution on nanometer scale is required. There is a variety of super resolution microscopy techniques, enabling fluorescence imaging beyond the diffraction limit. This work combines the use of three complementary super resolution microscopy techniques, in order to study immune cell/fungus interaction from different points of view.
Aim of this work is the introduction of the recently invented imaging technique named expansion microscopy (ExM) for the study of immune cell/fungus interactions. The core aspect of this method is the physical magnification of the specimen, which increases the distance between protein structures that are close to each other and which can therefore be imaged separately.
The simultaneous magnification of primary human natural killer (NK) cells and A. fumigatus hyphae was established in this work using ExM. Reorganization of cytoskeletal components of interacting NK cells was demonstrated here, by expansion of the immunological synapse (IS), formed between NK cells and A. fumigatus. In addition, reorganization of the microtubule-organizing center (MTOC) towards fungal hyphae and an accumulation of actin at the IS has been observed. Furthermore, ExM has been used to visualize lytic granules of NK cells after degranulation. After magnification of the specimen, lysosome associated protein 1 (LAMP1) was shown to surround perforin. In absence of the plasma membrane-exposed degranulation marker LAMP1, a “ring-shaped” structure was often observed for fluorescently labeled perforin. Volume calculation of lytic granules demonstrated the benefit of ExM. Compared to pre-expansion images, analyses of post-expansion images showed two volume distributions for degranulated and non-degranulated NK cells. In addition, this work emphasizes the importance of determining the expansion factor for a structure in each species, as variations of expansion factors have been observed. This factor, as well as possible sample distortions should be considered, when ExM is used in order to analyze the interaction between two species.
A second focus of this work is the visualization of a chimeric antigen receptor (CAR), targeting an epitope on the cell wall of A. fumigatus. Structured illumination microscopy (SIM) revealed that the CAR is part of the immunological synapse of primary human CAR T cells and CAR-NK-92 cells. At the interaction site, an accumulation of the CAR was observed, as well as the presence of perforin. CAR accumulation at fungal hyphae was further demonstrated by automated live cell imaging of interacting CAR-NK-92 cells, expressing a fluorescent fusion protein.
Additionally, the use of direct stochastic optical reconstruction microscopy (dSTORM) gave first insights in CAR expression levels on the basal membrane of CAR-NK-92 cells, with single molecule sensitivity. CAR cluster analyses displayed a heterogeneous CAR density on the basal membrane of transfected NK 92 cells.
In summary, this work provides insights into the application of ExM for studying the interaction of primary human NK cells and A. fumigatus for the first time. Furthermore, this thesis presents first insights regarding the characterization of an A. fumigatus-targeting CAR, by applying super-resolution fluorescence microscopy, like SIM and dSTORM.
Theory and simulation of ultrafast autodetachment dynamics and nonradiative relaxation in molecules
(2024)
In this thesis, theoretical approaches for the simulation of electron detachment processes in molecules following vibrational or electronic excitation are developed and applied. These approaches are based on the quantum-classical surface-hopping methodology, in which nuclear motion is treated classically as an ensemble of trajectories in the potential of quantum-mechanically described electronic degrees of freedom.
This compilation focuses on adolescent mental disorders and their prevention. It comprises three distinct studies, each contributing to a deeper understanding of this critical topic. This work addresses a critical gap in the understanding of, and approach to, adolescent mental health, and as a result reveals a critically important and urgently needed policy implication for action. The thematic structure of these studies begins with an examination of the epidemiology of child and adolescent mental disorders. Baseline data were collected from N = 877 adolescents with a mean age of 12.43 years (SD = 0.65). Mental health problems, such as depressive symptoms, non-suicidal self-injury, suicidal ideation, symptoms of eating disorders, and gender differences, are thoroughly examined. Results revealed a significant portion of our sample displaying mental health problems as early as the 6th and 7th grades, with girls generally being more affected than boys. The findings underscore the importance of early adolescence in the emergence of mental health problems and thereby emphasize the need for preventive measures. Moving beyond prevalence estimates, the compilation delves into the etiology of these disorders, exploring their potential correlation with a COVID-19 infection. Understanding the early signs and risk factors is crucial for timely support. While numerous studies have investigated potential risk and protective factors during the pandemic, our focus shifts to adolescents’ coping when an infection with the virus was involved (N = 2,154, M = 12.31, SD = 0.67). We hypothesized that students infected or with close family members infected, would exhibit an increased psychopathology and a decreased functioning of protective factors such as self-efficacy or self-esteem. We found no connection between infection and the mental health status within our sample, but protective factors and mental well-being were positively associated. Thus, universal primary prevention appears to be the preferred approach for promoting mental health. Lastly, the compilation introduces LessStress, a noteworthy contribution to more evidence-based prevention programs. This universal approach is designed to reduce stress in schools, accompanied by a cluster-randomized trial to evaluate its effectiveness (estimated sample size N = 1,894). Existing studies have demonstrated the effectiveness of stress prevention, leading us to introduce a short and easy-to-implement prevention program. There is positive evidence for one-lesson interventions in schools for promoting well-being and health behaviors among adolescents. LessStress is designed based on a life skills approach that not only imparts psychoeducational content but also teaches skills relevant to everyday life and directly applicable. Throughout these studies, a common thread emerges: the pressing need to address mental disorders during childhood and adolescence. These formative years play a pivotal role in the development of mental health problems. These formative years play a crucial role in the development of mental health problems. They highlight the importance of epidemiological data collection and analysis based on the latest models to develop prevention interventions that are not only effective but also reach young people on a global level.
Dipolar merocyanines are very attractive supramolecular building blocks, as they combine interesting functional properties with strong, directional intermolecular interactions. The pyridine dioxocyano-pyridine (PYOP) chromophore (Chapter 2.2), used in this thesis, stands out because of its exceptionally high ground state dipole moment (g ~ 17 D), in combination with the option to retain good solubility also in unpolar solvents, by decoration with solubilizing groups.
The reliable binding motif of anti-parallel -stacking due to dipole-dipole interactions has allowed the design of molecular building blocks that form assemblies of predictable geometry. The intense unstructured charge transfer UV/Vis absorption band (eg ~ 10.7 D) is a result of the dominant contribution of the zwitterionic resonance structure which brings the PYOP chromophore just beyond the cyanine limit in solvents of low polarity (c2 = 0.60, 1,4 dioxane). The high sensitivity of the S0 – S1 UV/Vis absorption band to the environment manifests itself in a pronounced negative solvatochromism and strong H-type exciton coupling within -stacked PYOP assemblies. In accordance with the classical molecular exciton theory, an increasing hypsochromic shift of the dominant absorption band of these H aggregates can be observed as the stack size increases up to about six chromophores, where it levels out at about max ~ 440 nm (CHCl3). This allows a uniquely simple estimation of the number of interacting chromophores within the self-assembled structure from a single UV/Vis absorption spectrum of an aggregate.
The defined and well investigated PYOP dimer formation was employed in this thesis to probe the applicability and limitations of concentration-, temperature-, and solvent-dependent self-assembly studies (Chapter 3). Straightforward theoretical models to evaluate datasets of concentration-, temperature-, and solvent-dependent UV/Vis absorption by nonlinear regression analysis were derived for the case of dimer formation (Chapter 2.1). Although the dimer model is well known and widely applied in literature, this detailed derivation is helpful to understand assumptions and potential problems of the different approaches for the determination of thermodynamic parameters. This helps to decide on the most appropriate method to analyse a system of interest. In this regard it should be noted that covering a large portion of the self-assembly process with the experimental data is a prerequisite for the accuracy of the analysis. Additionally, many of the insights can also be transferred to other self-assembly systems like supramolecular polymerization or host-guest interactions.
The concentration-dependent analysis is the most straightforward method to investigate self-assembly equilibria. No additional assumptions, besides mass balance and mass action law, are required. Since it includes the least number of parameters (only K, if M/D are known), it is the most, or even only, reliable method, to elucidate the self-assembly mechanism of an unknown system by model comparison. To cover a large concentration range, however, the compound must be soluble enough and generally sample amounts at least in the low mg scale must be available.
The temperature-dependent analysis has the advantage that all thermodynamic parameters G0, H0 and S0 can be obtained from a single sample in one automated measurement. However, the accessible temperature-range is experimentally often quite limited and dependent on the solvent. For systems which do not show the transition from monomer to aggregate in a narrow temperature range, as given for, e.g., cooperative aggregation or processes with a high entropy contribution, often not the entire self-assembly process can be monitored. Furthermore, the assumptions of temperature-independent extinction coefficients of the individual species as well as temperature-independent H0 and S0 must be met. Monte Carlo simulations of data sets demonstrated that even minor changes in experimental data can significantly impact the optimized values for H0 and S0. This is due to the redundancy of these two parameters within the model framework and even small thermochromic effects can significantly influence the results. The G0 value, calculated from H0 and S0, is, however, still rather reliable.
Solvent-dependent studies can often cover the entire self-assembly process from monomeric (agg = 0) to the fully aggregated state (agg = 1). However, for dyes with strong solvatochromic effects, such as the dipolar merocyanines investigated in this thesis, the results are affected. Also, the assumption of a linear relation of the binding energy G0 and the fraction of denaturating solvent f, which is based on linear free energy relationships between G0 and the solvent polarity, can lead to errors. Especially when specific solvent effects are involved.
For the evaluation of experimental data by nonlinear regression, general data analysis software can be used, where user-defined fit models and known parameters can be implemented as desired. Alternatively, multiple specialized programs for analysing self-assembly data are available online. While the latter programs are usually more user-friendly, they have the disadvantage of being a “black box” where only pre-implemented models can be used without the option for the user to adapt models or parameters for a specific system.
In Chapter 3 comprehensive UV/Vis absorption datasets are presented for the dimerization of merocyanine derivative 1 in 1,4-dioxane, which allowed for the first time a direct comparison of the results derived from concentration-, temperature-, and solvent-dependent self-assembly studies.
The results for the binding constant K and corresponding G0 from the concentration- and temperature-dependent analysis were in very good agreement, also in comparison to the results from ITC. For the temperature-dependent analysis, though, multiple datasets of samples with different concentration had to be evaluated simultaneously to cover a meaningful part of the self-assembly process. Furthermore, a significant dependence of the optimized parameters H0 and S0 on the wavelength chosen for the analysis was observed. This can be rationalized by the small thermochromic shifts of both the monomer and the dimer UV/Vis absorption band. The results from the solvent-dependent evaluation showed the largest deviation, as expected for the highly solvatochromic merocyanine dye.
However, even here by evaluation at 491 and 549 nm the deviation for G0 was only 2.5 kJ mol1 (9%) with respect to the results from the concentration-dependent analysis (G0 = 29.1 kJ mol1). Thus, despite the strong solvatochromism of the dipolar chromophore, it can still be considered a reliable method for estimating the binding strength. Furthermore, multiple repetitions of the concentration-, temperature-, and solvent-dependent studies provided insight into the reproducibility of the results and possible sources of experimental errors. In all cases, the deviations of the results were small (G0 < 0.4 kJ mol1) and within the same range as the fit error from the nonlinear regression analysis.
The insights from these studies were an important basis for the in-depth investigation of a more complex supramolecular system in Chapter 4, as a single method is often not enough to capture the full picture of a more complicated self-assembly process. To elucidate the anti-cooperative self-assembly of the chiral merocyanine 2, a combination of multiple techniques had to be applied.
Solvent-dependent UV/Vis absorption studies in CH2Cl2/MCH mixtures showed the step-wise assembly of the merocyanine monomer (max(M) = 549 nm, CH2Cl2) to first a dimer (max(D) = 498 nm, CH2Cl2/MCH 15:85) by dipole-dipole interactions, and then a -stacked higher aggregate (max(H) = 477 nm, MCH), with pronounced H-type coupling.
The thermodynamic evaluation of this data, however, suffered from the severe solvatochromism, especially of the monomeric species (max(M, CH2Cl2) = 549 nm, max(M, MCH) = 596 nm). Therefore, concentration-dependent studies were performed at three different temperatures (298, 323, 353 K) to elucidate the self-assembly mechanism and determine reliable thermodynamic parameters. The studies at elevated temperatures were hereby necessary, to obtain experimental data over a larger agg--range. Due to the pronounced difference in the thermodynamic driving force for dimerization and higher aggregate formation (KD/K5 = 6500) a concentration range exists in MCH where almost exclusively the dimer species of 2 is present, before further self-assembly by dispersion interactions occurs. Therefore, the data could be evaluated independently for the two self-assembly steps. The self-assembly of dimers into the higher aggregate could not be described by the isodesmic model but was fitted satisfactorily to a pentamer model. This rather small size of about ten -stacked PYOP chromophores was, furthermore, consistently indicated by AFM, VPO and DOSY NMR measurements. Based on 1D and 2D NMR data as well as the strong bisignate CD signal of the higher aggregate in combination with TD-DFT calculations, a P-helical stack is proposed as its structure. The small size can be rationalized by the anti-cooperative self-assembly mechanism and the sterical demand of the solubilizing trialkoxyphenyl and the chiral tetralin substituents. Additionally, the aliphatic shell formed by the solubilizing chains around the polar chromophore stack, can account for the exceptionally high solubility of 2 in MCH (> 15 mg mL1). These combined studies of the self-assembly process enabled the identification of suitable conditions for the investigation of fluorescence properties of the individual aggregate species. Aggregation-induced emission enhancement was observed for the almost non-emissive monomer (Fl(M) = 0.23%), which can be rationalized by the increasing rigidification within the dimer (Fl(D) = 2.3%) and the higher aggregate (Fl(H) = 4.5%). The helical chirality of the PYOP decamer stack, furthermore, gave rise to a strong CPL signal with a large glum value of 0.011.
The important conclusion of this thesis is that the temperature- and solvent-dependent analyses are valid alternatives to the classical concentration-dependent analysis to determine thermodynamic parameters of self-assembly equilibria. Although, for a specific supramolecular system, one approach might be favourable over the others for a variety of reasons. The experimental limitations often demand a combination of techniques to fully elucidate a self-assembly process and to gain insights in the aggregate structure. The anti-cooperative merocyanine self-assembly, which was described here for the first time for the PYOP merocyanine 2, is no exception. Besides the interest in the merocyanine assemblies from a structural and functional point of view, the insights gained from the presented studies can also be transferred to other self-assembly systems and be a guide to find the most appropriate analysis technique.
This work aims at elucidating chemical processes involving homogeneous catalysis and photo–physical relaxation of excited molecules in the solid state. Furthermore, compounds with supposedly small singlet–triplet gaps and therefore biradicaloid character are investigated with respect to their electro–chemical behavior. The work on hydroboration catalysis via a reduced 9,10–diboraanthracene (DBA) was preformed in collaboration with the Wagner group in Frankfurt, more specifically Dr. Sven Prey, who performed all laboratory experiments. The investigation of delayed luminescence properties in arylboronic esters in their solid state was conducted in collaboration with the Marder group in Würzburg. The author of this work took part in the synthesis of the investigated compounds while being supervised by Dr. Zhu Wu. The final project was a collaboration with the group of Anukul Jana from Hyderabad, India who provided the experimental data.
In this thesis, we apply the information-theoretic approach in the context of quantum dynamics and wave packet motion: Information-theoretic measures are calculated from position and momentum densities, which are obtained from time-dependent quantum wave functions. The aim of this thesis is to benchmark, analyze and interpret these quantities and relate their features to the wave packet dynamics. Firstly, this is done for the harmonic oscillator (HO) with and without static disorder. In the unperturbed HO, the analytical study of coherent and squeezed states reveals time-dependent entropy expressions related to the localization of the wave function. In the disordered HO, entropies from classical and quantum dynamics are compared for short and long times. In the quantum case, imprints of wave packet revivals are found in the entropy. Then, the energy dependence of the entropy for very long times is discussed. Secondly, this is donefor correlated electron-nuclear motion. Here, entropies derived from the total, electronic and nuclear density, respectively, are calculated in position and momentum space for weak and strong adiabatic electronic coupling. The correlation between electron and nucleus is investigated using different correlation measures, where some of these functions are sensitive to the nodal structure of the wave function. An analytic ansatz to interpret the information-theoretical quantities is applied as well.
This doctoral thesis investigates magneto-optical properties of mercury telluride layers grown tensile strained on cadmium telluride substrates. Here, layer thicknesses start above the usual quantum well thickness of about 20 nm and have a upper boundary around 100 nm due to lattice relaxation effects. This kind of layer system has been attributed to the material class of three-dimensional topological insulators in numerous publications. This class stands out due to intrinsic boundary states which cross the energetic band gap of the layer's bulk.
In order to investigate the band structure properties in a narrow region around the Fermi edge, including possible boundary states, the method of highly precise time-domain Terahertz polarimetry is used. In the beginning, the state of the art of Teraherz technology at the start of this project is discussed, moving on to a detailed description and characterization of the self-built measurement setup. Typical standard deviation of a polarization rotation or ellipticity measurement are on the order of 10 to 100 millidegrees, according to the transmission strength through investigated samples. A range of polarization spectra, depending on external magnetic fields up to 10 Tesla, can be extracted from the time-domain signal via Fourier transformation.
The identification of the actual band structure is done by modeling possible band structures by means of the envelope function approximation within the framework of the k·p method. First the bands are calculated based on well-established model parameters and from them the possible optical transitions and expected ellipticity spectra, all depending on external magnetic fields and the layer's charge carrier concentration. By comparing expected with measured spectra, the validity of k·p models with varying depths of detail is analyzed throughout this thesis. The rich information encoded in the ellipitcity spectra delivers key information for the attribution of single optical transitions, which are not part of pure absorption spectroscopy. For example, the sign of the ellipticity signals is linked to the mix of Landau levels which contribute to an optical transition, which shows direct evidence for bulk inversion asymmetry effects in the measured spectra.
Throughout the thesis, the results are compared repeatedly with existing publications on the topic. It is shown that the models used there are often insufficient or, in worst case, plainly incorrect. Wherever meaningful and possible without greater detours, the differences to the conclusions that can be drawn from the k·p model are discussed.
The analysis ends with a detailed look on remaining differences between model and measurement. It contains the quality of model parameters as well as different approaches to integrate electrostatic potentials that exist in the structures into the model.
An outlook on possible future developments of the mercury cadmium telluride layer systems, as well as the application of the methods shown here onto further research questions concludes the thesis.
mRNA is co- or post-transcriptionally processed from a precursor mRNA to a mature mRNA. In addition to 5'capping and splicing, these modifications also include polyadenylation, the addition of a polyA tail to the 3'end of the mRNA. In recent years, alternative polyadenylation in particular has increasingly been taken into account as a mechanism for regulating gene expression. It is assumed that approximately 70-75 % of human protein coding genes contain alternative polyadenylation signals, which are often located within intronic sequences of protein-coding genes. The use of such polyadenylation signals leads to shortened mRNA transcripts and thus to the generation of C-terminal shortened protein isoforms.
Interestingly, the majority of microRNAs, small non-coding RNAs that play an essential role in post-transcriptional gene regulation, are also encoded in intronic sequences of protein-coding genes and are co-transcriptionally expressed with their host genes. The biogenesis of microRNA has been well studied and is well known, but mechanisms that may influence the expression regulation of mature microRNAs are just poorly understood.
In the presented work, I aimed to investigate the influence of alternative intronic polyadenylation on the biogenesis of microRNAs. The human ion channel TRPM1 could already be associated with melanoma pathogenesis and truncated isoforms of this protein have already been described in literature. In addition, TRPM1 harbors a microRNA, miR211, in its sixth intron, which is assumed to act as a tumor suppressor. Since both, TRPM1 and miR211 have already been associated with melanoma pathogenesis, the shift towards truncated transcripts during the development of various cancers is already known and it has been shown that certain microRNAs play a crucial role in the development and progression of melanoma, melanoma cell lines were used as an in vitro model for these investigations.
Integrative, three-dimensional \(in\) \(silico\) modeling of gas exchange in the human alveolus
(2024)
The lung plays a vital role by exchanging respiratory gases. At the core of this gas exchange is a simple yet crucial passive diffusion process occurring within the alveoli. These balloon-like structures, connected to the peripheral airways, are surrounded by a dense network
of small capillaries. Here, inhaled air comes into close proximity with deoxygenated blood coming from the heart, enabling the exchange of oxygen and carbon dioxide across their concentration gradients.
The efficiency of gas exchange can be measured through indicators such as the diffusion capacity of the lung for oxygen and the reaction half-time. A notable discrepancy exists in humans between physiological estimates of diffusion capacity and the theoretical maximum capacity under optimal structural conditions (morphological estimate). This discrepancy is influenced by a range of interrelated factors, including structural elements like the surface area and thickness of the diffusion barrier, as well as physiological factors such as blood flow dynamics. To unravel the different roles of these factors, we investigated how morphological and physiological properties of the human alveolar micro-environment collectively and individually influence the process of gas exchange. To this end, we developed an integrative in silico approach combining 3D morphological modeling and simulation of blood flow and of oxygen transport.
At the core of our approach lies the simulation software Alvin, serving as an interactive platform for the underlying mathematical model of oxygen transport within the alveolus. Developed by integrating and expanding existing mathematical models, our spatio-temporal model produces results in agreement with experimental data. Alvin allows for real-time parameter adjustments and the execution of multiple simultaneous simulation instances and provides detailed quantitative feedback, offering an immersive exploration of the simulated gas exchange process. The morphological and physiological parameters at play were further investigated with a focus on the microvasculature. By compiling a stereological database from the literature and 3D geometric modeling, we created a sheet-flow model as a realistic representation of the morphology of the human alveolar capillary network. Blood flow was simulated using computational fluid dynamics. Our findings were in line with previous estimations and highlighted the crucial role of viscosity models in predicting pressure drop across the microvasculature. Furthermore, we showcased how our approach can be harnessed to explore structural details, such as the connectivity of the alveolar capillary network with the vascular tree, using blood flow indices. It is important to emphasize that
so far we have relied on different data sources and that experimental validation is needed to move forward.
Integration of our findings into Alvin allowed quantification of the simulated gas exchange process through the diffusion capacity for oxygen and reaction half-time. In addition to evaluating the collective influences of the morphological and physiological properties, our interactive software facilitates the assessment of individual parameter value changes. Exploring blood volume and surface area available for gas exchange revealed linear correlations with diffusion capacity. The blood flow velocity had a positive, non-linear effect on diffusion capacity. The reaction half-time confirmed that under normal conditions, the gas exchange process is not diffusion-limited. Collectively, our alveolar model yielded a diffusion capacity value that fell in the middle of previous physiological and morphological estimates, implying that alveolar-level phenomena contribute to 50% of the diffusion capacity limitations that occur in vivo.
In summary, our integrative in silico approach disentangles various structural and functional influences on alveolar gas exchange, complementing traditional investigations in respiratory
research. We further showcase its utility in teaching and the interpretation of published data. To advance our understanding, future work should prioritize obtaining a cohesive experimental data set and identifying an appropriate viscosity model for blood flow simulations.
π-Conjugated organic polymers have attracted tremendous attention in the last decades, and the interest in these materials is mainly driven by their applicability in next-generation electronic and optoelectronic devices (OLEDs, OFETs, photovoltaics). The partial or complete replacement of carbon atoms by main group elements in conjugated polymers can significantly change the characteristics and applications of these macromolecules. In this work, a class of inorganic polymers comprising a backbone of exclusively boron and nitrogen atoms (poly(iminoborane)s, PIBs) and their monodisperse oligomers is described. In addition, novel inorganic–organic hybrid polymers containing BN units in their polymer backbone were synthesized and characterized.
In chapter 2.1, the development of catalytic B–N coupling routes for the controlled synthesis of macromolecular materials is described. While the reaction of an N-silyl-B-chloro-aminoborane with the electrophilic reagent trimethylsilyl triflate led to effective B–N coupling, the reaction with a silver(I) salt resulted in an intramolecular Cl/Me exchange between the boron and silicon centers.
In chapter 2.2-2.4, the study of oligo- and poly(iminoborane)s is discussed. Monodisperse and cyclolinear oligo(iminoborane)s based on diazaborolidines with up to 7 boron and 8 nitrogen atoms were synthesized by successively extending the B-N main chain. However, the use of benzodiazaborolines only led to limited BN catenation. Furthermore, the redistribution processes resulting from the reaction of longer oligomers with non-stoichiometric amounts of (di)halogenated boranes is reported.
In chapter 2.5-2.6, the synthesis of 1,2,5-azadiborolanes as building blocks for the synthesis of poly(iminoborane)s and inorganic-organic hybrid polymers is described. While the attempt to apply an azadiborolane with sterically demanding groups on the boron-bridging ethylene unit for the construction of PIB was unfeasible, it was successfully incorporated in inorganic-organic hybrid polymers. Photophysical studies indicated π-conjugation along the polymer chain. A first attempt to synthesize PIBs based on azadiborolanes with unsubstituted ethylene units showed promising results.
In chapter 2.7-2.8, a comprehensive study of poly(arylene iminoborane)s, which are BN analogs of poly(arylene vinylene)s is described, and the properties of four polymers as well as twelve monodisperse oligomers were investigated. Photophysical investigations of the monomers, dimers and polymers showed a systematic bathochromic shift of the absorption maximum with increasing chain length and thiophene content. Based on TD-DFT calculations of the model oligomers, the lowest-energy absorption band could be assigned to HOMO to LUMO transitions with π-π* character. The oligo- and poly(arylene iminoborane)s showed only very weak to no emission in solution but they were emissive in the solid state. For four oligomers the aggregation induced emission (AIE) in a THF/water mixture was investigated and DLS studies confirmed the formation of nanoaggregates.
In chapter 2.9, oligo- and polymerizations of sulfur-containing building blocks and subsequent pH-triggered degradation of the products is described. While a sulfilimine-containing oligomer could not be isolated, the sulfone-, sulfoximine-, and sulfoxide-containing molecular oligomers and polymers could be successfully synthesized by B=N or B–O bond formation reactions. The sulfur-containing building blocks were successfully released under acidic or basic conditions, which was confirmed by NMR spectroscopy and mass spectrometry.
Introduction.
Mobile health (mHealth) integrates mobile devices into healthcare, enabling remote monitoring, data collection, and personalized interventions. Machine Learning (ML), a subfield of Artificial Intelligence (AI), can use mHealth data to confirm or extend domain knowledge by finding associations within the data, i.e., with the goal of improving healthcare decisions. In this work, two data collection techniques were used for mHealth data fed into ML systems: Mobile Crowdsensing (MCS), which is a collaborative data gathering approach, and Ecological Momentary Assessments (EMA), which capture real-time individual experiences within the individual’s common environments using questionnaires and sensors. We collected EMA and MCS data on tinnitus and COVID-19. About 15 % of the world’s population suffers from tinnitus.
Materials & Methods.
This thesis investigates the challenges of ML systems when using MCS and EMA data. It asks: How can ML confirm or broad domain knowledge? Domain knowledge refers to expertise and understanding in a specific field, gained through experience and education. Are ML systems always superior to simple heuristics and if yes, how can one reach explainable AI (XAI) in the presence of mHealth data? An XAI method enables a human to understand why a model makes certain predictions. Finally, which guidelines can be beneficial for the use of ML within the mHealth domain? In tinnitus research, ML discerns gender, temperature, and season-related variations among patients. In the realm of COVID-19, we collaboratively designed a COVID-19 check app for public education, incorporating EMA data to offer informative feedback on COVID-19-related matters. This thesis uses seven EMA datasets with more than 250,000 assessments. Our analyses revealed a set of challenges: App user over-representation, time gaps, identity ambiguity, and operating system specific rounding errors, among others. Our systematic review of 450 medical studies assessed prior utilization of XAI methods.
Results.
ML models predict gender and tinnitus perception, validating gender-linked tinnitus disparities. Using season and temperature to predict tinnitus shows the association of these variables with tinnitus. Multiple assessments of one app user can constitute a group. Neglecting these groups in data sets leads to model overfitting. In select instances, heuristics outperform ML models, highlighting the need for domain expert consultation to unveil hidden groups or find simple heuristics.
Conclusion.
This thesis suggests guidelines for mHealth related data analyses and improves estimates for ML performance. Close communication with medical domain experts to identify latent user subsets and incremental benefits of ML is essential.
We analyze the mathematical models of two classes of physical phenomena. The first class of phenomena we consider is the interaction between one or more insulating rigid bodies and an electrically conducting fluid, inside of which the bodies are contained, as well as the electromagnetic fields trespassing both of the materials. We take into account both the cases of incompressible and compressible fluids. In both cases our main result yields the existence of weak solutions to the associated system of partial differential equations, respectively. The proofs of these results are built upon hybrid discrete-continuous approximation schemes: Parts of the systems are discretized with respect to time in order to deal with the solution-dependent test functions in the induction equation. The remaining parts are treated as continuous equations on the small intervals between consecutive discrete time points, allowing us to employ techniques which do not transfer to the discretized setting. Moreover, the solution-dependent test functions in the momentum equation are handled via the use of classical penalization methods.
The second class of phenomena we consider is the evolution of a magnetoelastic material. Here too, our main result proves the existence of weak solutions to the corresponding system of partial differential equations. Its proof is based on De Giorgi's minimizing movements method, in which the system is discretized in time and, at each discrete time point, a minimization problem is solved, the associated Euler-Lagrange equations of which constitute a suitable approximation of the original equation of motion and magnetic force balance. The construction of such a minimization problem is made possible by the realization that, already on the continuous level, both of these equations can be written in terms of the same energy and dissipation potentials. The functional for the discrete minimization problem can then be constructed on the basis of these potentials.
Neisseria meningitidis (the meningococcus) is one of the major causes of bacterial meningitis, a life-threatening inflammation of the meninges. Traversal of the meningeal blood-cerebrospinal fluid barrier (mBCSFB), which is composed of highly specialized brain endothelial cells (BECs), and subsequent interaction with leptomeningeal cells (LMCs) are critical for disease progression. Due to the human-exclusive tropism of N. meningitidis, research on this complex host-pathogen interaction is mostly limited to in vitro studies. Previous studies have primarily used peripheral or immortalized BECs alone, which do not retain relevant barrier phenotypes in culture. To study meningococcal interaction with the mBCSFB in a physiologically more accurate context, BEC-LMC co-culture models were developed in this project using BEC-like cells derived from induced pluripotent stem cells (iBECs) or hCMEC/D3 cells in combination with LMCs derived from tumor biopsies.
Distinct BEC and LMC layers as well as characteristic expression of cellular markers were observed using transmission electron microscopy (TEM) and immunofluorescence staining. Clear junctional expression of brain endothelial tight and adherens junction proteins was detected in the iBEC layer. LMC co-culture increased iBEC barrier tightness and stability over a period of seven days, as determined by sodium fluorescein (NaF) permeability and transendothelial electrical resistance (TEER). Infection experiments demonstrated comparable meningococcal adhesion and invasion of the BEC layer in all models tested, consistent with previously published data. While only few bacteria crossed the iBEC-LMC barrier initially, transmigration rates increased substantially over 24 hours, despite constant high TEER. After 24 hours of infection, deterioration of the barrier properties was observed including loss of TEER and altered expression of tight and adherens junction components. Reduced mRNA levels of ZO-1, claudin-5, and VE-cadherin were detected in BECs from all models. qPCR and siRNA knockdown data suggested that transcriptional downregulation of these genes was potentially but not solely mediated by Snail1. Immunofluorescence staining showed reduced junctional coverage of occludin, indicating N. meningitidis-induced post-transcriptional modulation of this protein, as previous studies have suggested. Together, these results suggest a potential combination of transcellular and paracellular meningococcal traversal of the mBCSFB, with the more accessible paracellular route becoming available upon barrier disruption after prolonged N. meningitidis infection. Finally, N. meningitidis induced cellular expression of pro-inflammatory cytokines and chemokines such as IL-8 in all mBCSFB models. Overall, the work described in this thesis highlights the usefulness of advanced in vitro models of the mBCSFB that mimic native physiology and exhibit relevant barrier properties to study infection with meningeal pathogens such as N. meningitidis.
The demand for LIB with enhanced energy densities leads to increased utilization of the space within the confinements of the battery housing or to the use of electrode material with increased intrinsic specific energy densities. Both requirements result in more stress on the battery electrodes and separator during cycling or aging. However, the effect of mechanical strain on the cell’s electrochemistry and thus the performance of batteries is rather unexplored compared to the impact of current or temperature, for example. The objective of this thesis was to give a better understanding of the electrochemical and mechanical interplay in current- and next-generation lithium based battery cells. Therefore, the thesis was structured into the investigations on SoA and next-generation LIBs. For SoA LIBs, the investigations of the interplay started at laboratory scale. Here, the expansion of various electrodes and also the impact of mechanical pressure and its distribution on the performance of the cells were
studied. The investigations at laboratory scale was followed by an examination of the electrochemical and mechanical interactions on large format commercial LIBs which are used in BEVs. Accordingly, the effect of bracing and its effect on the performance was studied in an aging and post-mortem study. To gain a deeper understanding of the mechanical changes in LIBs, an ultrasonic study was performed for pouch cells. Here, the mechanical changes were further investigated in dependence of SoC and SoH. The effects of the mechanical stress on the performance for next-generation batteries were studied at laboratory scale. In the beginning, the expansion of next-generation anode materials such as silicon and lithium was compared with today’s anode materials. Furthermore, the effect of mechanical pressure and electrolyte on the irreversible dilation and performance was investigated for lithium metal cells. Overall, it was shown that pressure has a significant effect on the performance of today’s and also future LIBs. The interplay of the electrochemical and mechanical effects inside a LIB has a considerable impact on the lifetime, capacity fading and impedance increase of the batteries.
Development Of A Human iPSC-Derived Cortical Neuron Model Of Adaptor- Protein-Complex-4-Deficiency
(2024)
Adaptor-protein-4-deficiency (AP-4-deficiency) is an autosomal-recessive childhood- onset form of complicated hereditary spastic paraplegia (HSP) caused by bi-allelic loss- of-function mutations in one of the four subunits of the AP-4-complex. These four conditions are named SPG47 (AP4B1, OMIM #614066), SPG50 (AP4M1, OMIM #612936), SPG51 (AP4E1, OMIM #613744) and SPG52 (AP4S1, OMIM #614067), respectively and all present with global developmental delay, progressive spasticity and seizures. Imaging features include a thinning of the corpus callosum, ventriculomegaly and white matter changes. AP-4 is a highly conserved heterotetrameric complex, which is responsible for polarized sorting of transmembrane cargo including the autophagy- related protein 9 A (ATG9A). Loss of any of the four subunits leads to an instable complex and defective sorting of AP-4-cargo. ATG9A is implicated in autophagosome formation and neurite outgrowth. It is missorted in AP-4-deficient cells and CNS-specific knockout of Atg9a in mice results in a phenotype reminiscent of AP-4-deficiency. However, the AP-4-related cellular phenotypes including ATG9A missorting have not been investigated in human neurons.
Thus, the aim of this study is to provide the first human induced pluripotent stem cell- derived (iPSC) cortical neuron model of AP-4-deficiency to explore AP-4-related phenotypes in preparation for a high-content screening. Under the hypothesis that AP-4- deficiency leads to ATG9A missorting, elevated ATG9A levels, impaired autophagy and neurite outgrowth in human iPSC-derived cortical neurons, in vitro biochemical and imaging assays including automated high-content imaging and analysis were applied. First, these phenotypes were investigated in fibroblasts from three patients with compound heterozygous mutations in the AP4B1 gene and their sex-matched parental controls. The same cell lines were used to generate iPSCs and differentiate them into human excitatory cortical neurons.
This work shows that ATG9A is accumulating in the trans-Golgi-network in AP-4- deficient human fibroblasts and that ATG9A levels are increased compared to parental controls and wild type cells suggesting a compensatory mechanism. Protein levels of the AP4E1-subunit were used as a surrogate marker for the AP-4-complex and were decreased in AP-4-deficient fibroblasts with co-immunoprecipitation confirming the instability of the complex. Lentiviral re-expression of the AP4B1-subunit rescues this corroborating the fact that a stable AP-4-complex is needed for ATG9A trafficking. Surprisingly, autophagic flux was present in AP-4-deficient fibroblasts under nutrient- rich and starvation conditions. These phenotypic markers were evaluated in iPSC-derived cortical neurons and here, a robust accumulation of ATG9A in the juxtanuclear area was seen together with elevated ATG9A protein levels. Strikingly, assessment of autophagy markers under nutrient-rich conditions showed alterations in AP-4-deficient iPSC- derived cortical neurons indicating dysfunctional autophagosome formation. These findings point towards a neuron-specific impairment of autophagy and need further investigation. Adding to the range of AP-4-related phenotypes, neurite outgrowth and branching are impaired in AP-4-deficient iPSC-derived cortical neurons as early as 24h after plating and together with recent studies point towards a distinct role of ATG9A in neurodevelopment independent of autophagy.
Together, this work provides the first patient-derived neuron model of AP-4-deficiency and shows that ATG9A is sorted in an AP-4-dependent manner. It establishes ATG9A- related phenotypes and impaired neurite outgrowth as robust markers for a high-content screening. This disease model holds the promise of providing a platform to further study AP-4-deficiency and to search for novel therapeutic targets.
In the scope of climate warming and the increase in frequency and intensity of severe heat waves in Central Europe, identification of temperate tree species that are suited to cope with these environmental changes is gaining increasing importance. A number of tree physiological characteristics are associated with drought-stress resistance and survival following severe heat, but recent studies have shown the importance of plant hydraulic and anatomical traits for predicting drought-induced tree mortality, such as vessel diameter, and their potential to predict species distribution in a changing climate.
A compilation of large global datasets is required to determine traits related to drought-induced embolism and test whether embolism resistance can be determined solely by anatomical traits. However, most measurements of plant hydraulic traits are labour-intense and prone to measurement artefacts. A fast, accurate and widely applicable technique is necessary for estimating xylem embolism resistance (e.g., water potential at 50% loss of conductivity, P50), in order to improve forecasts of future forest changes. These traits and their combination must have evolved following the selective pressure of the environmental conditions in which each species occurs. Describing these environmental-trait relationships can be useful to assess potential responses to environmental change and mitigation strategies for tree species, as future warmer temperatures may be compounded by drier conditions.
RNA viruses rely entirely on the host machinery for their protein synthesis and harbor non-canonical translation mechanisms, such as alternative initiation and programmed –1 ribosomal frameshifting (–1PRF), to suit their specific needs. On the other hand, host cells have developed a variety of defensive strategies to safeguard their translational apparatus and at times transiently shut down global translation. An infection can lead to substantial translational remodeling in cells and translational control is critical during antiviral response. Due to their sheer diversity, this control is likely unique to each RNA virus and the intricacies of post-transcriptional regulation are unclear in certain viral species.
Here, we explored different aspects of translational regulation in virus-infected cells in detail. Using ribosome profiling, we extensively characterized the translational landscape in HIV-1 infected T cells, uncovering novel features of gene regulation in both host and virus. Additionally, we show that substantial pausing occurs prior to the frameshift site indicating complex regulatory mechanisms involving upstream viral RNA elements that can act as cis- regulators of frameshifting.
We also characterized the mechanistic details of trans- modulation of frameshifting by host- and virus-encoded proteins. Host antiviral protein ZAP-S binds to the SARS-CoV-2 frameshift site and destabilizes the stimulatory structure, leading to frameshift inhibition. On the other hand, EMCV 2A protein stabilizes the viral frameshift site, thereby, activating EMCV frameshifting. While both proteins were shown to be antagonistic in their mechanism, they interact with the host translational machinery. Furthermore, we showed that frameshifting can be regulated not just by proteins, but also by small molecules. High-throughput screening of natural and synthetic compounds identified two potent frameshift inhibitors that also impeded viral replication, namely trichangion and compound 25. Together, this work largely enhances our understanding of gene regulation mechanisms in virus-infected cells and further validates the druggability of viral –1 PRF site.
Poor or variable oral bioavailability is of major concern regarding safety and efficacy for the treatment of patients with poorly water-soluble drugs (PWSDs). The problem statement of this work involves a pharmaceutical development perspective, the physicochemical basis of the absorption process and physiological / biopharmaceutical aspects. A methodology was developed aiming at closing the gap between drug liberation and dissolution on the one hand and the appearance of drug in the blood on the other. Considering what is out of control from a formulation development perspective, a clear differentiation between bioavailability and bioaccessibility was necessary. Focusing on the absorption process, bioaccessibility of a model compound, a poorly soluble but well permeable weak base, was characterized by means of flux across artificial biomimetic membranes. Such setups can be considered to reasonably mimic relevant oral absorption resistances in vitro in terms of diffusion through an unstirred water layer (UWL) and a lipidic barrier. Mechanistic understanding of the driving force for permeation was gained by differentiating drug species and subsequently linking them to the observed transfer rates using a bioaccessibility concept. The three key species that need to be differentiated are molecularly dissolved drug, drug associated in solution with other components (liquid reservoir) and undissolved drug (solid reservoir). An innovative approach to differentiate molecularly dissolved drug from the liquid reservoir using ultracentrifugation in combination with dynamic light scattering as control is presented. A guidance for rational formulation development of PWSDs is elaborated based on the employed model compound. It is structured into five guiding questions to help drug formulation scientists in selecting drug form, excipients and eventually the formulation principle. Overall, the relevance but also limitations of characterizing bioaccessibility were outlined with respect to practical application e.g. in early drug formulation development.