Refine
Has Fulltext
- yes (151)
Is part of the Bibliography
- yes (151)
Year of publication
- 2024 (151) (remove)
Document Type
- Doctoral Thesis (117)
- Journal article (23)
- Preprint (4)
- Working Paper (3)
- Master Thesis (2)
- Book (1)
- Report (1)
Language
- English (151) (remove)
Keywords
- Maschinelles Lernen (6)
- Tissue Engineering (6)
- Trypanosoma brucei (4)
- CRISPR/Cas-Methode (3)
- Cognition (3)
- Entzündung (3)
- Immuntherapie (3)
- Induzierte pluripotente Stammzelle (3)
- Kognition (3)
- Myc (3)
- Nanopartikel (3)
- Simulation (3)
- Thrombozyt (3)
- Topologie (3)
- 3D-Druck (2)
- Biene (2)
- Bildgebendes Verfahren (2)
- Bioinks (2)
- Bioverfügbarkeit (2)
- CRISPR/Cas9 (2)
- Cancer (2)
- Infektion (2)
- Kernspintomografie (2)
- Klimaänderung (2)
- Leistungsbewertung (2)
- Lithium-Ionen-Akkumulator (2)
- LoRaWAN (2)
- Machine Learning (2)
- Magnetohydrodynamik (2)
- Metaanalyse (2)
- Platelets (2)
- Quality of Experience (2)
- ROS (2)
- Streaming <Kommunikationstechnik> (2)
- Supramolekulare Chemie (2)
- T-Lymphozyt (2)
- Topology (2)
- Transkription (2)
- Transplantat-Wirt-Reaktion (2)
- Trust (2)
- Ubiquitin (2)
- Variant surface glycoprotein (2)
- Vertrauen (2)
- Video Streaming (2)
- absorption (2)
- cell biology (2)
- machine learning (2)
- mental health (2)
- translation (2)
- 19F-NMR (1)
- 2D (1)
- 3 D bioprinting (1)
- 3D muscle (1)
- 3D printing (1)
- 3D tumour model (1)
- 7 T (1)
- 7,8-dihydroxyflavone (7,8-DHF) (1)
- ALS (1)
- ARPES (1)
- ATF4 (1)
- Academic Professionalisation (1)
- Accounts (1)
- Acenes (1)
- AdS-CFT-Korrespondenz (1)
- Adaptorproteine (1)
- Adhesive Hydrogels (1)
- Adult Education (1)
- Akupunktur (1)
- Albendazol (1)
- Algorithmik (1)
- Algorithmische Geometrie (1)
- Algorithmus (1)
- Alpha (1)
- Alpha power (1)
- Alternative polyadenylation (1)
- Altersunterschied (1)
- Alzheimerkrankheit (1)
- Amyotrophic lateral sclerosis (1)
- Angststörung (1)
- Anorganische Polymere (1)
- Antibody (1)
- Antimon (1)
- Anxiety disorder (1)
- Apis mellifera (1)
- Approved immunomodulators (1)
- Arabidopsis thaliana (1)
- Arene-Fluoroarene (1)
- Arteriosklerose (1)
- Artery Models (1)
- Arthrose (1)
- Artificial Base Pair (1)
- Arzneimittelüberwachung (1)
- Aspergillus fumigatus (1)
- Astrophysics (1)
- Astrophysik (1)
- Atherosclerosis (1)
- Atomgitter (1)
- AuNPs (1)
- Audiologie (1)
- Autodetachment (1)
- Automation (1)
- Automobilindustrie (1)
- Automorphismengruppe (1)
- Außenhandel (1)
- Avionik (1)
- Avoidance (1)
- B0 (1)
- BCA (1)
- Bacteria (1)
- Bakterielle Hirnhautentzündung (1)
- Bakterien (1)
- Band Structure (1)
- Bandstruktur (1)
- Barth Syndrome (1)
- Baumphysiologie (1)
- Bayerische Alpen <Motiv> (1)
- Begrenzte Staatlichkeit (1)
- Bericht (1)
- Bestandsmanagement (1)
- Bias (1)
- Bile (1)
- BioID (1)
- Bioaccessibility (1)
- Bioavailability (1)
- Biodistribution (1)
- Biofabrication (1)
- Biogenese (1)
- Biomechanics (1)
- Biomedicine (1)
- Biomedizin (1)
- Biopsychosocial (1)
- Biotransformation (1)
- Blazar (1)
- Blut-Liquor-Schranke (1)
- Bodengeografie (1)
- Body movement (1)
- Bone marrow transplantation (1)
- Bor-Stickstoff Bindung (1)
- Brain endothelial cells (1)
- Breeding (1)
- C-type natriuretic peptide (1)
- C.376A>G (p.S126G) (1)
- C4da (1)
- CAR T cell (1)
- CAR-T cell (1)
- CAR-T-Zell-Therapie (1)
- CD4+ T cell activation (1)
- CD8+ T cell differentiation (1)
- CE Proteaes (1)
- COVID-19 (1)
- CRISPR (1)
- CRISPR-Cas (1)
- Cancer Metabolism (1)
- Cardiac MRI (1)
- Cartiage Integration (1)
- Cartilage defect (1)
- Cell culture (1)
- Cell migration (1)
- Central limit theorem under dependence (1)
- Chemie (1)
- Chemometric (1)
- Child Development (1)
- China (1)
- Chirality (1)
- Chlamydia trachomatis (1)
- Climate change (1)
- Co-culture (1)
- Cognitive Load (1)
- Cognitive consistency (1)
- Cognitive processing (1)
- Cognitive profile (1)
- Coherent Multidimensional Spectroscopy (1)
- Coherent Two-dimensional Nanoscopy (1)
- Collaborative Research Center (1)
- Colloidal stability (1)
- Colorectal Cancer (1)
- Computational Chemistry (1)
- Convolutional Neural Network (1)
- Corti-Organ (1)
- Cosmology (1)
- Covid-19 (1)
- Crosslinking (1)
- Cytokine (1)
- DCM genetic background (1)
- DExD/H box protein (1)
- DNA (1)
- DNA double-strand breaks (1)
- DNA-Methylation (1)
- DNA-encoded library synthesis (1)
- DNA-tagged amines (1)
- DNS (1)
- DUB (1)
- DYT-TOR1A (1)
- Darm (1)
- Darmepithel (1)
- Data-driven Operations Management (1)
- Deep learning (1)
- Degradation (1)
- Demotic (1)
- Density Functional Theory (1)
- Depression (1)
- Deubiquitination (1)
- Dichtefunktionalformalismus (1)
- Differential Shannon Entropy (1)
- Diffusion coefficient (1)
- Diffusionskoeffizient (1)
- Dilation (1)
- Dionaea muscipula (1)
- Diskriminationslernen (1)
- Diskriminationstraining (1)
- Domain Knowledge (1)
- Donor-Akzeptor Triaden (1)
- Drama (1)
- Drosophila (1)
- Drug Delivery (1)
- Drug delivery system (DDS) (1)
- Drug form selection (1)
- Dystonie (1)
- Dürrestress (1)
- East Africa (1)
- Eclosion (1)
- Eclosion hormone (1)
- Ecological Momentary Assessments (1)
- Einzelmolekülmikroskopie (1)
- Einzelzellanalyse (1)
- Electrochemical Impedance Spectroscopy (1)
- Electrochemical and Mechanical Interplay (1)
- Electrode (1)
- Electronic Structure (1)
- Elektrochemie (1)
- Elektromobilität (1)
- Elektrophysiologie (1)
- Emotional Affect (1)
- Endobrachyösophagus (1)
- Energiehyperfläche (1)
- Energy Efficiency (1)
- Entropie (1)
- Entzündungsreaktion (1)
- Epidemiologie (1)
- Epigenetik (1)
- Epithelial lineage (1)
- Erwachsenenbildung (1)
- Esophageal adenocarcinoma (1)
- Esophageal disease (1)
- Evolutionspsychologie (1)
- Excipient selection (1)
- Executive Functions (1)
- Exekutive Funktionen (1)
- Expansion Microscopy (1)
- Experimental Biomedicine (1)
- Explainable AI (1)
- Explainable Artificial Intelligence (1)
- Fabry disease (1)
- Femtosecond Pulse Shaping (1)
- Ferromagnetism (1)
- Festelektrolyt (1)
- Festkörperakkumulator (1)
- Festkörperbatterie (1)
- Festkörperelektrolyt (1)
- Fibrinogen (1)
- Finite-Elemente-Methode (1)
- Finite-Volumen-Methode (1)
- Fluid-Struktur-Wechselwirkung (1)
- Fluid-structure interaction (1)
- Fluorescence (1)
- Fluoreszenz (1)
- Fluoreszenzmikroskopie (1)
- Flux (1)
- Fokker-Planck-Gleichung (1)
- Formulation (1)
- Formulierung (1)
- Fourier-transform spectral interferometry (1)
- FoxO3 (1)
- Fragile Staaten (1)
- Fragility (1)
- Fragilität (1)
- Funktechnik (1)
- Furcht (1)
- GPI-anchored protein (1)
- GPVI (1)
- Galle <Sekret> (1)
- Gasaustausch (1)
- Gastroesophageal reflux (1)
- Gauge/Gravity Duality (1)
- Gelenkknorpel (1)
- Generalisierung (1)
- Generative Adversarial Networks (1)
- Genexpression (1)
- Geoarchäologie (1)
- Germany (1)
- Geschlecht (1)
- Gesichtsschmerz (1)
- Gewebemodell (1)
- Gewohnheit (1)
- Glutamine (1)
- Gold Nanoparticles (1)
- Gold- und Silbernanopartikel (1)
- Graft versus Host disease (1)
- Graft-versus-host disease (1)
- Graphen (1)
- Graphenzeichnen (1)
- HDAC (1)
- HFO-1123 (1)
- Habits (1)
- Haemophilus influenzae (1)
- Hebamme (1)
- Helicene (1)
- Hematopoietic cell transplantation (1)
- Hemodynamics (1)
- Hemofiltration (1)
- Hereditary spastic paraplegia (1)
- Hereditäre spastsiche Paraplegie (1)
- Herzinfarkt (1)
- Herzmuskelkrankheit (1)
- Heterostructure Growth (1)
- Heuschrecken (1)
- High-frequency data (1)
- Hirnendothelzellen (1)
- Histon-Deacetylase (1)
- Hochschule (1)
- Honeybee (1)
- Host-Guest Chemistry (1)
- Host-Pathogen Interactions (1)
- Host-pathogen interaction (1)
- Human-Computer-Interaction (1)
- Hyaliner Knorpel (1)
- Hydrogel (1)
- Hydrogels (1)
- Hyrogels (1)
- Hämodynamik (1)
- Hôtel-Dieu de Paris (1)
- IENFD (1)
- IMEX scheme (1)
- ISS <Raumfahrt> (1)
- Idiopathische pulmonale Fibrose (1)
- Immune cells (1)
- Immune evasion (1)
- Immunevasion (1)
- Immunmodulation (1)
- Immunohistochemistry (1)
- Immunology (1)
- Immunotherapy (1)
- In vitro model (1)
- In-Orbit demonstration (1)
- In-vitro-Kultur (1)
- Index (1)
- Indikator (1)
- Individual differences (1)
- Induced pluripotent stem cells (1)
- Infektionsmodell (1)
- Infektionsprozess (1)
- Inflamamtion (1)
- Inflammation (1)
- Inhibitionskontrolle (1)
- Inhibitor (1)
- Inhibitory Control (1)
- Institutionenökonomie (1)
- Insulinsekretion (1)
- Integrated Defensive States (1)
- International LOFAR Telescope (1)
- Intestinal metaplasia (1)
- Intra-Spacecraft Communication (1)
- Inversion Symmetry Breaking (1)
- Ischemic stroke (1)
- Jasmonate info (1)
- Jugend (1)
- Kaliumkanal (1)
- Katalyse (1)
- Kinderentwicklung (1)
- Kindliche Entwicklung (1)
- Klassische Konditionierung (1)
- Klimawandel (1)
- Kniegelenkarthrose (1)
- Knorpel (1)
- Kognitive Entwicklung (1)
- Kognitive Verhaltenstherapie (1)
- Kommunikationstraining (1)
- Konfokale Mikroskopie (1)
- Konjugierte Polymere (1)
- Kosmologie (1)
- Kraftfahrzeugindustrie (1)
- Krebs <Medizin> (1)
- Kutikula (1)
- Kutikularwachs (1)
- LC-MS/MS (1)
- LOFAR (1)
- Langerhans cells (1)
- Lasertherapie (1)
- Learning (1)
- Learning Settings (1)
- Least squares estimation (1)
- Lebenslauf (1)
- Lehrstoff (1)
- Leptomeningeal cells (1)
- Leptomeningealzellen (1)
- Lernen (1)
- Linear Gemischte Modelle (1)
- Linear-Mixed Models (1)
- Lists (1)
- Lithium-Ion Battery (1)
- Lithium-Ionen Batterie (1)
- Localization (1)
- Lumineszenz (1)
- Lung Cancer (1)
- Lung squamous cancer cells (1)
- Lungenkrebs (1)
- Lymphknoten (1)
- MND (1)
- MRI (1)
- Magnetischer Röntgenzirkulardichroismus (1)
- Magnetismus (1)
- Magnetoelasticity (1)
- Magnetoelastizität (1)
- Magnetohydrodynamics (1)
- Measurement (1)
- Mebendazol (1)
- Media Equation (1)
- Media Research (1)
- Medinet Habu (1)
- Medizinprodukt (1)
- Melanom (1)
- Melt Electrowriting (1)
- Melt electrowriting (1)
- Membranproteine (1)
- Mensch-Maschine-Kommunikation (1)
- Mercapturic acid pathway (1)
- Mercury telluride (1)
- Merocyanine (1)
- Messung (1)
- Metabolismus (1)
- Metakognition (1)
- Methylierung (1)
- Mevalonate Pathway (1)
- Microscopy (1)
- Mikroben (1)
- Mikrobiom <Genetik> (1)
- Mikroklima (1)
- Mikromorphologie (1)
- Mikroorganismus (1)
- Mikropartikel (1)
- Mikroskopie (1)
- Mikrotubuli (1)
- Mikrotubulus (1)
- Minimizing movements (1)
- Mitochondrium (1)
- Mobie EEG (1)
- Mobile Crowdsensing (1)
- Mobile Health (1)
- Model-Agnostic (1)
- Modification (1)
- Molekularstrahlepitaxie (1)
- Molekül (1)
- Mondfahrzeug (1)
- Monitoring (1)
- Motoneuron (1)
- Motoneuron-Krankheit (1)
- Motor neuron disease (1)
- Motorische Endplatte (1)
- Mouse Model (1)
- Mucus (1)
- Multi-dimensional SPDEs (1)
- Myatrophische Lateralsklerose (1)
- N-Myc (1)
- N6-methyladenosine (m6A) (1)
- NMJ (neuromuscular junction) (1)
- NMR spectroscopy (1)
- NMR-Spektroskopie (1)
- NONO (1)
- NRF2 (1)
- NSCLC (1)
- Nachtschattengewächse (1)
- Nahrung (1)
- Nanoparticles (1)
- Nanoribbon (1)
- Natriuretisches Hormon (1)
- Natural walking (1)
- Natürliche Killerzelle (1)
- Navier-Stokes equations (1)
- Navier-Stokes-Gleichung (1)
- Neisseria meningitidis (1)
- Nervendegeneration (1)
- Neue Institutionenökonomik (1)
- Neue Medien (1)
- Neurodegenerative Erkrankung (1)
- Neuroendokrines System (1)
- Neuromuskuläre Endplatte (1)
- Neuronales Netz (1)
- Neuropeptide (1)
- Neutrophiler Granulozyt (1)
- Nicht-kleinzelliges Bronchialkarzinom (1)
- Nonadiabatic Dynamics (1)
- Numerische Strömungssimulation (1)
- OXPHOS (1)
- Oberfläche (1)
- Oncoprotein (1)
- One-dimensional SPDEs (1)
- Onkoprotein (1)
- Optimale Kontrolle (1)
- Optimalitätsbedingung (1)
- Organ of Corti (1)
- Organoid (1)
- Ostraca (1)
- Oxidativer Stress (1)
- Oxytosis (1)
- PAF1c (1)
- PDXP inhibitors (1)
- PLEKHG5 (1)
- PROTACs (1)
- Paläopedologie (1)
- Parabolische Differentialgleichung (1)
- Parameter Quality Oil (1)
- Parkinson-Erkrankung (1)
- Parkinson-Krankheit (1)
- Parkinson’s Disease (1)
- Patch-Clamp-Methode (1)
- Paternal age effect (1)
- Pause Release (1)
- Perfusion Bioreactor (1)
- Perianova, Irina (1)
- Periaqueductal gray (1)
- Permeabilität (1)
- Personalisierung (1)
- Personality (1)
- Personalization (1)
- Persönlichkeit (1)
- Peyer's patch (1)
- Pflanzenhydraulik (1)
- Pflanzenökologie (1)
- Pharmacokinetic (1)
- Pharmazeutischer Hilfsstoff (1)
- Phase separation (1)
- Phosphoresence (1)
- Photoemissionselektronenmikroskopie (1)
- Photoswitch (1)
- Plant Biology (1)
- Plant Ecology (1)
- Plant hydraulic (1)
- Platelet-Membranglykoprotein p62 (1)
- Polyadenylierung (1)
- Polyarylenvinylene (1)
- Polygonzüge (1)
- Polyiminoboranes (1)
- Poorly water-soluble drug (1)
- Pornografie (1)
- Posttranslationale Änderung (1)
- Praziquantel (1)
- Primärprevention (1)
- Professionalisierung (1)
- Protein corona (1)
- Prothoracic gland (1)
- Prothoracicotropic hormone (1)
- Psychische Belastung (1)
- Psychische Gesundheit (1)
- Psychological factors (1)
- Psychologie (1)
- Psychotherapie (1)
- Pyren (1)
- Pyrene (1)
- Quantitative 1H NMR (1)
- Quantum Chemistry (1)
- Quantum Information (1)
- Quantum Plasmonics (1)
- Quantum Spin Hall (1)
- Quantum dynamics (1)
- Quasiconformal automorphism (1)
- Quasikonforme Abbildung (1)
- Quecksilbertellurid (1)
- RBM20 mutations (1)
- RNA Polymerase II (RNAPII) (1)
- RNA virus (1)
- RNS-Viren (1)
- ROR2 (1)
- Rac1 (1)
- Radioastronomie (1)
- Radioastronomy (1)
- Ratte (1)
- Raumfahrttechnik (1)
- Reaction Mechanism (1)
- Real-Space Obstruction (1)
- Red Fruit Oil (1)
- Regulation of expression (1)
- Reinforcement Learning (1)
- Relaxation (1)
- Resilienz (1)
- Resistenz (1)
- Retinoesäure (1)
- Retinoic acid (1)
- Rheologie (1)
- Ribosome (1)
- Ribosome biogenesis (1)
- Risikoanalyse (1)
- Rotation (1)
- Rothe method (1)
- SGLT2 inhibitors (1)
- SOD1 (1)
- SV/TPC1 (1)
- Salmonella typhimurium (1)
- Scherverhalten (1)
- Schlaganfall (1)
- Schleim (1)
- Self-Assembly (1)
- Sex/Gender (1)
- Shear stress indicator (1)
- Shimming (1)
- Silicon-Boron Exchange (1)
- Silizium-Bor Austausch (1)
- Single-cell sequencing (1)
- Single-molecule fluorescence microscopy (1)
- Single-molecule tracking (1)
- Sinneszelle (1)
- Small intestine (1)
- Solanaceae (1)
- Solanum species (1)
- Solubilisation (1)
- Sonderforschungsbereich Transregio 240 (1)
- Spaltöffnung (1)
- Spermium (1)
- Sphingolipid biology (1)
- Sphingolipide (1)
- Spin-Bahn-Wechselwirkung (1)
- Spin-Orbit Coupling (1)
- Spinchemie (1)
- Staat (1)
- Stammzellen (1)
- Staphylococcus aureus (1)
- Stat3 (1)
- State (1)
- Stochastische partielle Differentialgleichung (1)
- Stoffwechsel (1)
- Stomaschluss (1)
- Strategisches Management (1)
- Strecken (1)
- Streptavidin (1)
- Stress (1)
- Stressbewältigung (1)
- Stressreaktion (1)
- Stroma (1)
- Structured Illumination Microscopy (1)
- Störungstheorie (1)
- Supersaturation (1)
- Supramolecular Interaction (1)
- Supraparticle (1)
- Surface (1)
- Symmetrie (1)
- Symmetry Resolution (1)
- Synthetische Daten (1)
- T-cell (1)
- THz (1)
- TMD (1)
- TNBC (1)
- TNF (1)
- Targeted drug delivery (1)
- Targeted therapies (1)
- Taufliege (1)
- Tax Receipts (1)
- Telomer <Molekulargenetik> (1)
- Theoretical Chemistry (1)
- Theoretische Chemie (1)
- Thioether-Poly(glycidol)-Beschichtung (1)
- Thrombo-inflammation (1)
- Topological Insulator (1)
- Training von Patienten und Angehörigen (1)
- Transcription Regulation (1)
- Transcription elongation (1)
- Transcriptional Stress Response (1)
- Transfer (1)
- Transgener Organismus (1)
- Transkriptionsfaktor (1)
- Translation regulation (1)
- Transpiration <Pflanzen> (1)
- Trauma (1)
- Tree physiology (1)
- Trifluoroethene (1)
- Trockenstress (1)
- Trust Measurement (1)
- Trypanosoma vivax (1)
- Tumor models (1)
- Tumormikroumgebung (1)
- U1 snRNA (1)
- Ubiquitin Specific Protease 11 (1)
- Ugi-azide reaction (1)
- Ultrahigh field (1)
- Ultraweitband (1)
- Umweltpolitik (1)
- Unconventional T cells (1)
- Uniform topology (1)
- VSG (1)
- VSG structure (1)
- Valscularization (1)
- Variant Surface Glycoprotein (1)
- Varroa destructor (1)
- Varroa mites (1)
- Varroa resistance (1)
- Vascular system (1)
- Venusfliegenfalle (1)
- Vermeidungsreaktion (1)
- Vertisol (1)
- Vicia faba (1)
- Virtual Human (1)
- Virtual Reality (1)
- Virtuelle Realität (1)
- Voice Assistants (1)
- Walking (1)
- West Africa (1)
- Wireless Network (1)
- Wirt-Erreger Interaktion (1)
- Wurmmittel (1)
- XNA (1)
- YTH reader proteins (1)
- Zeitdiskrete Approximation (1)
- Zelle (1)
- Zellkultur (1)
- Zellmigration (1)
- Zellskelett (1)
- Zentralnervensystem (1)
- Zersetzungsprozess (1)
- Zytoskelett (1)
- Züchtung (1)
- aberrant transcripts (1)
- accuracy estimate (1)
- action potential (1)
- adaptivity (1)
- adjustment (1)
- adolescents (1)
- adult development (1)
- agar (1)
- albumin (1)
- algorithms (1)
- all solid-state battery (1)
- alternative intronic polyadenylation (1)
- alveolar gas exchange (1)
- alveolarer Gasaustausch (1)
- amyloidosis (1)
- angle resolved photoemission spectroscopy (1)
- antibody fluorescence signals (1)
- antimony (1)
- atomic mutagenesis (1)
- autoantibody (aAb) (1)
- automotive industry (1)
- belief bias (1)
- biotechnical Varroa control (1)
- biotic interactions (1)
- boron-nitrogen bond (1)
- boronate esters (1)
- brain tumor (1)
- bush ecotone (1)
- cMYC regulation (1)
- cancer therapy (1)
- cardiac imaging (1)
- carnivorous plants (1)
- catalysis (1)
- catalysts (1)
- catalytic activity (1)
- cell therapy (1)
- chemistry (1)
- childbirth (1)
- chronic constriction nerve injury (1)
- chronic kidney disease (1)
- chronic pain (1)
- classical conditioning (1)
- clay (1)
- clinical neurology (1)
- clinical phenotype (1)
- cognitive-behavioral therapy (1)
- communication training (1)
- complex regional pain syndrome (1)
- complexity (1)
- condensed matter (1)
- conditional Knockout (1)
- contractility (1)
- convolutional neural network (1)
- coordination oligomers (1)
- core outcome set (1)
- coupled electron-nuclear motion (1)
- covalent inhibition (1)
- crystallization (1)
- cuticular transpiration barrier (1)
- cuticular waxes (1)
- cyclophane (1)
- data harmonization (1)
- data-driven in silico modeling (1)
- datengesteuerte in silico Modellierung (1)
- dead organic material (1)
- decoherence (1)
- decomposition (1)
- deep brain stimulation (1)
- defence mechanisms (1)
- demethylase enzymes FTO and ALKBH5 (1)
- depression (1)
- depressiveness (1)
- dermal B cells (1)
- developmental biology (1)
- diabetes (1)
- differential diagnosis (1)
- dilated cardiomyopathy with ataxia (1)
- dilated cardiomyopathy with ataxia (DCMA) (1)
- discrimination training (1)
- disease model (1)
- donor-acceptor triads (1)
- dopamine (1)
- drug delivery (1)
- drug formulation (1)
- drug repurposing (1)
- early cosmology (1)
- early-onset isolated dystonia (1)
- electric mobility (1)
- electrocatalysis (1)
- electrochemistry (1)
- electron density (1)
- electron transfer (1)
- electrophoresis (1)
- elevational gradients (1)
- emissions leakage (1)
- emotional dysregulation (1)
- enantioselectivity (1)
- entropy (1)
- environmental policy (1)
- epidemiology (1)
- epitaxial growth (1)
- etiology (1)
- experimental physics (1)
- extraoral intervention (1)
- face perception (1)
- fear generalization (1)
- fibromyalgia syndrome (1)
- frameshifting (1)
- fruit cuticle (1)
- g-factor (1)
- gene-environmental interaction (1)
- general medicine (1)
- generalized anxiety disorder (1)
- genetics (1)
- genome integrity (1)
- geoarcheology (1)
- globotriaosylceramide (1)
- glycine receptor (GlyR) (1)
- graph drawing (1)
- graphs (1)
- guide effiiciency (1)
- haemophilus influenzae (1)
- haemostasis (1)
- hazard avoidance (1)
- hearing (1)
- heart failure (1)
- hedge index (1)
- hedgerow (1)
- hereditary spastic paraplegia (1)
- heritability (1)
- heterogeneous catalysis (1)
- heterogeneous firms (1)
- history of midwifery (1)
- honeybees (1)
- host-guest (1)
- human behaviour (1)
- human intestinal epithelium (1)
- hydrocarbons (1)
- iPSC (1)
- iPSC-derived CMs (iPSC-CMs) (1)
- immunofluorescence detection (1)
- immunology (1)
- immunotherapy (1)
- in vitro Testmodell (1)
- in vitro model system of inherited cardiomyopathies (1)
- in vivo (1)
- in vivo genome editing (1)
- inclusion (1)
- income inequality (1)
- individual characteristics (1)
- induced pluripotent stem cells (1)
- induced pluripotent stem cells (iPSCs) (1)
- infection (1)
- infectionmodel (1)
- infectionprocess (1)
- inflammation (1)
- information-theoretical (1)
- insulin (1)
- interactive simulation (1)
- interaktive Simulation (1)
- intestinal mucus (1)
- intestinal permeability (1)
- iron deficiency (1)
- iron deficiency anemia (1)
- isocyanide multicomponent reactions (1)
- jasmonic acid (1)
- kagome lattice (1)
- lactams (1)
- leaf cuticle (1)
- ligands (1)
- lithium-ion battery (1)
- local point-spread function (1)
- low Mach number (1)
- luminal Ca2+ sensing sites (1)
- luminale Ca2+-Sensorstellen (1)
- luminescence (1)
- lunar rover (1)
- lung cancer (1)
- macrocycles (1)
- magnetic resonance imaging (1)
- mapping (1)
- mast cells (1)
- materials (1)
- mechanism (1)
- mechanosensation (1)
- medical students (1)
- megakaryocytes (1)
- melanoma (1)
- menschliches Darmepithel (1)
- messenger RNA (1)
- messenger RNA regulation (1)
- metabolism (1)
- metacognition (1)
- metacognitive activation (1)
- miRNS (1)
- microRNA (1)
- microRNA biogenesis (1)
- microbes (1)
- microbiology (1)
- micromorphology (1)
- microphysiologic 3D tumour model (1)
- midwife (1)
- midwifery (1)
- midwifery education (1)
- midwifery training (1)
- minimum leaf conductance (1)
- mite non-reproduction (1)
- mitochondria (1)
- modified inflation (1)
- modified nucleosides (1)
- molecular biology (1)
- molecular biopharmaceutics (1)
- molecular pathways (1)
- monogenetic cardiomyopathies (1)
- motivated beliefs (1)
- movement disorders (1)
- mucin (1)
- myocardial infarction (1)
- navigation (1)
- neutrophils (1)
- new institutional economics (1)
- nociceptive Schwann cells (1)
- nonsuicidal self-injury (NSSI) (1)
- nuclear magnetic resonance spectroscopy (1)
- obstetrics (1)
- oculomotor control (1)
- offshoring (1)
- older adults (1)
- organic compounds (1)
- outcome reporting (1)
- pain pattern (1)
- paleopedology (1)
- pancreas (1)
- patient and caregiver education (1)
- perception and action (1)
- perioperative setting (1)
- peripheral nerve trauma (1)
- permeability (1)
- permeance (1)
- person perception (1)
- photophysics (1)
- pig (1)
- piperacillin (1)
- piperacillin/tazobactam (1)
- plant-herbivore-interactions (1)
- platelet (1)
- platelets (1)
- polylines (1)
- poor water-soluble drugs (1)
- practice testing (1)
- preoperative setting (1)
- preschool (1)
- programmed ribosomal frameshifting (1)
- progressive encephalitis with rigidity and myoclonus (PERM) (1)
- prosocial (1)
- prosocial behavior (1)
- prosociality (1)
- protein binding (1)
- protein folding (1)
- protein localization (1)
- psychological interventions (1)
- psychology (1)
- psychotherapy (1)
- pyridoxal phosphatase (PDXP) (1)
- qubit (1)
- qubit interaction (1)
- rRNA processing (1)
- recapping (1)
- relaxation method (1)
- renew-able fuels (1)
- repair and replication (1)
- resolution (1)
- retrieval practice (1)
- ribosome profiling (1)
- rotation (1)
- ruthenium (1)
- ruthenium bda complexes (1)
- saccades (1)
- scanning tunneling microscopy (1)
- schistosmiasis (1)
- school (1)
- sedimentology (1)
- selection (1)
- semantics of gaze (1)
- semi-natural habitat (1)
- sense of agency (1)
- sensory neurons (1)
- sex differences (1)
- simulation (1)
- skin punch biopsy (1)
- small fiber neuropathy (1)
- social interaction (1)
- soil (1)
- soil-transmitted helminthiases (1)
- solid tumour (1)
- solid-state electrolyte (1)
- spin chemistry (1)
- stability (1)
- stiff-person syndrome (SPS) (1)
- straight-line segments (1)
- strategic management (1)
- stress management (1)
- stress response (1)
- striatum (1)
- stroke (1)
- succession (1)
- suicidality (1)
- surgery (1)
- systematic review (1)
- tazobactam (1)
- telomere-associated protein (1)
- temporal binding (1)
- testing effect (1)
- theoretical chemistry (1)
- thiol starvation (1)
- thrombo-inflammation (1)
- tissue model (1)
- tissue resident T cells (1)
- topological insulator (1)
- touch (1)
- transcription elongation factor A (SII)-like 1 (TCEAL1) (1)
- transcription factor SPT5 (1)
- transcriptomics (1)
- transfer (1)
- transition (1)
- transitional shrubland (1)
- trap closure (1)
- true bug (1)
- tumor growth (1)
- tumour microenvironment (1)
- tumour stroma (1)
- ultra high vacuum (1)
- ultrafiltration (1)
- vacuole (1)
- variants of unknown significance (1)
- variational network (1)
- vitamin B6 (1)
- v’Td (1)
- water loss (1)
- water oxidation (1)
- water oxidation catalysis (1)
- water splitting (1)
- well-balanced (1)
- wounding (1)
- Ätiologie (1)
- α-Galactosidase A (1)
- β cell (1)
Institute
- Graduate School of Life Sciences (59)
- Theodor-Boveri-Institut für Biowissenschaften (21)
- Institut für Psychologie (10)
- Institut für Organische Chemie (9)
- Neurologische Klinik und Poliklinik (9)
- Institut für Pharmazie und Lebensmittelchemie (7)
- Institut für Informatik (6)
- Rudolf-Virchow-Zentrum (6)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (5)
- Institut für Mathematik (5)
Sonstige beteiligte Institutionen
- Helmholtz Institute for RNA-based Infection Research (HIRI) (3)
- California Institute of Technology (1)
- Department of Mathematical Analysis, Faculty of Mathematics and Physics, Charles University in Prague (1)
- Department of Molecular Biology, University Medical Centre Göttingen, Göttingen 37073, Germany (1)
- Deutsches Krebsforschungszentrum Heidelberg (1)
- Deutsches Zentrum für Luft- und Raumfahrt e.V. (1)
- Eberhard Karls Universität Tübingen (1)
- European Space Agency (1)
- Experimental Physics V, University of Wuerzburg (1)
- Fraunhofer Insitut für Silicatforschung ISC (1)
Colon carcinomas (CRC) are statistically among the most fatal cancer types and hence one of the top reasons for premature mortality in the developed world. CRC cells are characterized by high proliferation rates caused by deregulation of gene transcription of proto-oncogenes and general chromosomal instability. On macroscopic level, CRC cells show a strongly altered nutrient and energy metabolism.
This work presents research to understand general links between the metabolism and transcription alteration. Mainly focussing on glutamine dependency, shown in colon carcinoma cells and expression pathways of the pro-proliferation protein c-MYC.
Previous studies showed that a depletion of glutamine in the cultivation medium of colon carcinoma cell lines caused a proliferation arrest and a strong decrease of overall c-MYC levels. Re-addition of glutamine quickly replenished c-MYC levels through an unknown mechanism. Several proteins altering this regulation mechanism were identified and proposed as possible starting point for further in detail studies to unveil the precise biochemical pathway controlling c-MYC translation repression and reactivation in a rapid manner.
On a transcriptional level the formation of RNA:DNA hybrids, so called R-loops, was observed under glutamine depleted conditions. The introduction and overexpression of RNaseH1, a R-loop degrading enzyme, in combination with an ectopically expressed c-MYC variant, independent of cellular regulation mechanisms by deleting the regulatory 3’-UTR of the c-MYC gene, lead to a high rate of apoptotic cells in culture. Expression of a functionally inactive variant of RNaseH1 abolished this effect. This indicates a regulatory function of R-loops formed during glutamine starvation in the presence of c-MYC protein in a cell. Degradation of R-loops and high c-MYC levels in this stress condition had no imminent effect on the cell cycle progression is CRC cells but disturbed the nucleotide metabolism. Nucleotide triphosphates were strongly reduced in comparison to starving cells without R-loop degradation and proliferating cells.
This study proposes a model of a terminal cycle of transcription termination, unregulated initiation and elongation of transcription leading to a depletion of energy resources of cells. This could finally lead to high apoptosis of the cells. Sequencing experiments to determine a coinciding of termination sites and R-loop formation sides failed so far but show a starting point for further studies in this essential survival mechanism involving R-loop formation and c-MYC downregulation.
Over the years, hydrogels have been developed and used for a huge variety of different applications ranging from drug delivery devices to medical products. In this thesis, a poly(2-methyl-2-oxazoline) (POx) / poly(2-n-propyl-2-oxazine) (POzi) bioink was modified and analyzed for the use in biofabrication and targeted drug delivery. In addition, the protein fibrinogen (Fbg) was genetically modified for an increased stability towards plasmin degradation for its use as wound sealant.
In Chapter 1, a thermogelling, printable POx/POzi-based hydrogel was modified with furan and maleimide moieties in the hydrophilic polymer backbone facilitating post-printing maturation of the constructs via Diels-Alder chemistry. The modification enabled long-term stability of the hydrogel scaffolds in aqueous solutions which is necessary for applications in biofabrication or tissue engineering. Furthermore, we incorporated RGD-peptides into the hydrogel which led to cell adhesion and elongated morphology of fibroblast cells seeded on top of the scaffolds. Additional printing experiments demonstrate that the presented POx/POzi system is a promising platform for the use as a bioink in biofabrication.
Chapter 2 highlights the versatility of the POx/POzi hydrogels by adapting the system to a use in targeted drug delivery. We used a bioinspired approach for a bioorthogonal conjugation of insulin-like growth factor I (IGF-I) to the polymer using an omega-chain-end dibenzocyclooctyne (DBCO) modification and a matrix metalloprotease-sensitive peptide linker. This approach enabled a bioresponsive release of IGF-I from hydrogels as well as spatial control over the protein distribution in 3D printed constructs which makes the system a candidate for the use in personalized medicine.
Chapter 3 gives a general overview over the necessity of wound sealants and the current generations of fibrin sealants on the market including advantages and challenges. Furthermore, it highlights trends and potential new strategies to tackle current problems and broadens the toolbox for future generations of fibrin sealants.
Chapter 4 applies the concepts of recombinant protein expression and molecular engineering to a novel generation of fibrin sealants. In a proof-of-concept study, we developed a new recombinant fibrinogen (rFbg) expression protocol and a Fbg mutant that is less susceptible to plasmin degradation. Targeted lysine of plasmin cleavage sites in Fbg were exchanged with alanine or histidine in different parts of the molecule. The protein was recombinantly produced and restricted plasmin digest was analyzed using high resolution mass spectrometry. In addition to that, we developed a novel time resolved screening protocol for the detection of new potential plasmin cleavage sites for further amino acid exchanges in the fibrin sealant.
This thesis investigates the charged moments and the symmetry-resolved
entanglement entropy in the context of the AdS3/CFT2 duality. In the
first part, I focus on the holographic U(1) Chern-Simons-Einstein gravity,
a toy model of AdS3/CFT2 with U(1) Kac-Moody symmetry. I
start with the vacuum background with a single entangling interval. I
show that, apart from a partition function in the grand canonical ensemble,
the charged moments can also be interpreted as the two-point
function of vertex operators on the replica surface. For the holographic
description, I propose a duality between the bulk U(1) Wilson line and
the boundary vertex operators. I verify this duality by deriving the
effective action for the Chern-Simons fields and comparing the result
with the vertex correlator. In the twist field approach, I show that the
charged moments are given by the correlation function of the charged
twist operators and the additional background operators. To solve the
correlation functions involved, I prove the factorization of the U(1) extended
conformal block into a U(1) block and a Virasoro block. The
general expression for the U(1) block is derived by directly summing
over the current descendant states, and the result shows that it takes
an identical form as the vertex correlators. This leads to the conclusion
that the disjoint Wilson lines compute the neutral U(1) block. The final
result for the symmetry-resolved entanglement entropy shows that
it is always charge-independent in this model. In the second part, I
study charged moments in higher spin holography, where the boundary
theory is a CFT with W3 symmetry. I define the notion of the
higher spin charged moments by introducing a spin-3 modular charge
operator. Restricting to the vacuum background with a single entangling
interval, I employ the grand canonical ensemble interpretation
and calculate the charged moments via the known higher spin black
hole solution. On the CFT side, I perform a perturbative expansion for
the higher spin charged moments in terms of the connected correlation
functions of the spin-3 modular charge operators. Using the recursion
relation for the correlation functions of the W3 currents, I evaluate the
charged moments up to the quartic order of the chemical potential. The
final expression matches with the holographic result. My results both
for U(1) Chern-Simons Einstein gravity and W3 higher spin gravity
constitute novel checks of the AdS3/CFT2 correspondence.
Interactions between host and pathogen determine the development, progression and outcomes
of disease. Medicine benefits from better descriptions of these interactions through increased
precision of prevention, diagnosis and treatment of diseases. Single-cell genomics is a
disruptive technology revolutionizing science by increasing the resolution with which we study
diseases. Cell type specific changes in abundance or gene expression are now routinely investigated
in diseases. Meanwhile, detecting cellular phenotypes across diseases can connect
scientific fields and fuel discovery. Insights acquired through systematic analysis of high resolution
data will soon be translated into clinical practice and improve decision making. Therefore,
the continued use of single-cell technologies and their application towards clinical samples will
improve molecular interpretation, patient stratification, and the prediction of outcomes.
In the past years, I was fortunate to participate in interdisciplinary research groups bridging
biology, clinical research and data science. I was able to contribute to diverse projects through
computational analysis and biological interpretation of sequencing data. Together, we were
able to discover cellular phenotypes that influence disease progression and outcomes as well
as the response to treatment. Here, I will present four studies that I have conducted in my PhD.
First, we performed a case study of relapse from cell-based immunotherapy in Multiple Myeloma.
We identified genomic deletion of the epitope as mechanism of immune escape and implicate
heterozygosity or monosomy of the genomic locus at baseline as a potential risk factor. Second,
we investigated the pathomechanisms of severe COVID-19 at the earliest stage of the COVID-
19 pandemic in Germany in March 2020. We discovered that profibrotic macrophages and
lung fibrosis can be caused by SARS-CoV-2 infection. Third, we used a mouse model of chronic
infection with Staphylococcus aureus that causes Osteomyelitis similar to the human disease.
We were able to identify dysregulated immunometabolism associated with the generation of
myeloid-derived suppressor cells (MDSC). Fourth, we investigated Salmonella infection of the
human small intestine in an in vitro model and describe features of pathogen invasion and host
response.
Overall, I have been able to successfully employ single-cell sequencing to discover important
aspects of diseases ranging from development to treatment and outcome. I analyzed samples
from the clinics, human donors, mouse models and organoid models to investigate different
aspects of diseases and managed to integrate data across sample types, technologies and
diseases. Based on successful studies, we increased our efforts to combine data from multiple
sources to build comprehensive references for the integration of large collections of clinical
samples. Our findings exemplify how single-cell sequencing can improve clinical research and
highlights the potential of mechanistic discoveries to drive precision medicine.
African trypanosomes are unicellular parasites that cause nagana and sleeping sickness in livestock and man, respectively. The major pathogens for the animal disease include Trypanosoma vivax, T. congolense, and T. brucei brucei, whereas T. b. gambiense and T. b. rhodesiense are responsible for human infections. Given that the bloodstream form (BSF) of African trypanosomes is exclusively extracellular, its cell surface forms a critical boundary with the host environment. The cell surface of the BSF African trypanosomes is covered by a dense coat of immunogenic variant surface glycoproteins (VSGs). This surface protein acts as an impenetrable shield that protects the cells from host immune factors and is also involved in antibody clearance and antigenic variation, which collectively ensure that the parasite stays ahead of the host immune system. Gene expression in T. brucei is markedly different from other eukaryotes: most genes are transcribed as long polycistronic units, processed by trans-splicing a 39-nucleotide mini exon at the 5′ and polyadenylation at the 3′ ends of individual genes to generate the mature mRNA.
Therefore, gene expression in T. brucei is regulated post-transcriptionally, mainly by the action of RNA binding proteins (RBPs) and conserved elements in the 3′ untranslated regions (UTR) of transcripts. The expression of VSGs is highly regulated, and only a single VSG gene is expressed at a time from one of the ~15 subtelomeric domains termed bloodstream expression sites (BES). When cells are engineered to simultaneously express two VSGs, the total VSG mRNA do not exceed the wild type amounts. This suggests that a robust VSG mRNA balancing mechanism exists in T. brucei. The present study uses inducible and constitutive expression of ectopic VSG genes to show that the endogenous VSG mRNA is regulated only if the second VSG is properly targeted to the ER. Additionally, the endogenous VSG mRNA response is triggered when high amounts of the GFP reporter with a VSG 3′UTR is targeted to the ER. Further evidence that non-VSG ER import signals can efficiently target VSGs to the ER is presented. This study suggests that a robust trans-regulation of the VSG mRNA is elicited at the ER through a feedback loop to keep the VSG transcripts in check and avoid overshooting the secretory pathway capacity.
Further, it was shown that induction of expression of the T. vivax VSG ILDat1.2 in T. brucei causes a dual cell cycle arrest, with concomitant upregulation of the protein associated with differentiation (PAD1) expression. It could be shown that T. vivax VSG ILDat1.2 can only be sufficiently expressed in T. brucei after replacing its native GPI signal peptide with that of a T. brucei VSG. Taken together, these data indicate that inefficient VSG GPI anchoring and expression of low levels of the VSG protein can trigger differentiation from slender BSF to stumpy forms. However, a second T. vivax VSG, ILDat2.1, is not expressed in T. brucei even after similar modifications to its GPI signals. An X-ray crystallography approach was utilized to solve the N-terminal domain (NTD) structure of VSG ILDat1.2. This is first structure of a non-T. brucei VSG, and the first of a surface protein of T. vivax to be solved. VSG ILDat1.2 NTD maintains the three-helical bundle scaffold conserved in T. brucei surface proteins. However, it is likely that there are variations in the architecture of the membrane proximal region of the ILDat1.2 NTD and its CTD from T. brucei VSGs. The tractable T. brucei system is presented as a model that can be used to study surface proteins of related trypanosome species, thus creating avenues for further characterization of trypanosome surface coats.
Among the defense strategies developed in microbes over millions of years, the innate adaptive CRISPR-Cas immune systems have spread across most of bacteria and archaea. The flexibility, simplicity, and specificity of CRISPR-Cas systems have laid the foundation for CRISPR-based genetic tools. Yet, the efficient administration of CRISPR-based tools demands rational designs to maximize the on-target efficiency and off-target specificity. Specifically, the selection of guide RNAs (gRNAs), which play a crucial role in the target recognition of CRISPR-Cas systems, is non-trivial. Despite the fact that the emerging machine learning techniques provide a solution to aid in gRNA design with prediction algorithms, design rules for many CRISPR-Cas systems are ill-defined, hindering their broader applications.
CRISPR interference (CRISPRi), an alternative gene silencing technique using a catalytically dead Cas protein to interfere with transcription, is a leading technique in bacteria for functional interrogation, pathway manipulation, and genome-wide screens. Although the application is promising, it also is hindered by under-investigated design rules. Therefore, in this work, I develop a state-of-art predictive machine learning model for guide silencing efficiency in bacteria leveraging the advantages of feature engineering, data integration, interpretable AI, and automated machine learning. I first systematically investigate the influential factors that attribute to the extent of depletion in multiple CRISPRi genome-wide essentiality screens in Escherichia coli and demonstrate the surprising dominant contribution of gene-specific effects, such as gene expression level. These observations allowed me to segregate the confounding gene-specific effects using a mixed-effect random forest (MERF) model to provide a better estimate of guide efficiency, together with the improvement led by integrating multiple screens. The MERF model outperformed existing tools in an independent high-throughput saturating screen. I next interpret the predictive model to extract the design rules for robust gene silencing, such as the preference for cytosine and disfavoring for guanine and thymine within and around the protospacer adjacent motif (PAM) sequence. I further incorporated the MERF model in a web-based tool that is freely accessible at www.ciao.helmholtz-hiri.de.
When comparing the MERF model with existing tools, the performance of the alternative gRNA design tool optimized for CRISPRi in eukaryotes when applied to bacteria was far from satisfying, questioning the robustness of prediction algorithms across organisms. In addition, the CRISPR-Cas systems exhibit diverse mechanisms albeit with some similarities. The captured predictive patterns from one dataset thereby are at risk of poor generalization when applied across organisms and CRISPR-Cas techniques. To fill the gap, the machine learning approach I present here for CRISPRi could serve as a blueprint for the effective development of prediction algorithms for specific organisms or CRISPR-Cas systems of interest. The explicit workflow includes three principle steps: 1) accommodating the feature set for the CRISPR-Cas system or technique; 2) optimizing a machine learning model using automated machine learning; 3) explaining the model using interpretable AI. To illustrate the applicability of the workflow and diversity of results when applied across different bacteria and CRISPR-Cas systems, I have applied this workflow to analyze three distinct CRISPR-Cas genome-wide screens. From the CRISPR base editor essentiality screen in E. coli, I have determined the PAM preference and sequence context in the editing window for efficient editing, such as A at the 2nd position of PAM, A/TT/TG downstream of PAM, and TC at the 4th to 5th position of gRNAs. From the CRISPR-Cas13a screen in E. coli, in addition to the strong correlation with the guide depletion, the target expression level is the strongest predictor in the model, supporting it as a main determinant of the activation of Cas13-induced immunity and better characterizing the CRISPR-Cas13 system. From the CRISPR-Cas12a screen in Klebsiella pneumoniae, I have extracted the design rules for robust antimicrobial activity across K. pneumoniae strains and provided a predictive algorithm for gRNA design, facilitating CRISPR-Cas12a as an alternative technique to tackle antibiotic resistance.
Overall, this thesis presents an accurate prediction algorithm for CRISPRi guide efficiency in bacteria, providing insights into the determinants of efficient silencing and guide designs. The systematic exploration has led to a robust machine learning approach for effective model development in other bacteria and CRISPR-Cas systems. Applying the approach in the analysis of independent CRISPR-Cas screens not only sheds light on the design rules but also the mechanisms of the CRISPR-Cas systems. Together, I demonstrate that applied machine learning paves the way to a deeper understanding and a broader application of CRISPR-Cas systems.
Cognition refers to the ability to of animals to acquire, process, store and use vital information from the environment. Cognitive processes are necessary to predict the future and reduce the uncertainty of the ever-changing environment. Classically, research on animal cognition focuses on decisive cognitive tests to determine the capacity of a species by the testing the ability of a few individuals. This approach views variability between these tested key individuals as unwanted noise and is thus often neglected. However, inter-individual variability provides important insights to behavioral plasticity, cognitive specialization and brain modularity. Honey bees Apis mellifera are a robust and traditional model for the study of learning, memory and cognition due to their impressive capabilities and rich behavioral repertoire. In this thesis I have applied a novel view on the learning abilities of honey bees by looking explicitly at individual differences in a variety of learning tasks. Are some individual bees consistently smarter than some of her sisters? If so, will a smart individual always perform good independent of the time, the context and the cognitive requirements or do bees show distinct isolated ‘cognitive modules’?
My thesis presents the first comprehensive investigation of consistent individual differences in the cognitive abilities of honey bees. To speak of an individual as behaving consistently, a crucial step is to test the individual multiple times to examine the repeatability of a behavior. I show that free-flying bees remain consistent in a visual discrimination task for three consecutive days. Successively, I explored individual consistency in cognitive proficiency across tasks involving different sensory modalities, contexts and cognitive requirements. I found that free-flying bees show a cognitive specialization between visual and olfactory learning but remained consistent across a simple discrimination task and a complex concept learning task. I wished to further explore individual consistency with respect to tasks of different cognitive complexity, a question that has never been tackled before in an insect. I thus performed a series of four experiments using either visual or olfactory stimuli and a different training context (free-flying and restrained) and tested bees in a discrimination task, reversal learning and negative patterning. Intriguingly, across all these experiments I evidenced the same results: The bees’ performances were consistent across the discrimination task and reversal learning and negative patterning respectively. No association was evidenced between reversal learning and negative patterning. After establishing the existence of consistent individual differences in the cognitive proficiency of honey bees I wished to determine factors which could underlie these differences. Since genetic components are known to underlie inter-individual variability in learning abilities, I studied the effects of genetics on consistency in cognitive proficiency by contrasting bees originating from either from a hive with a single patriline (low genetic diversity) or with multiple patrilines (high genetic diversity). These two groups of bees showed differences in the patterns of individually correlated performances, indicating a genetic component accounts for consistent cognitive individuality. Another major factor underlying variability in learning performances is the individual responsiveness to sucrose solution and to visual stimuli, as evidenced by many studies on restrained bees showing a positive correlation between responsiveness to task relevant stimuli and learning performances. I thus tested whether these relationships between sucrose/visual responsiveness and learning performances are applicable for free-flying bees. Free-flying bees were again subjected to reversal learning and negative patterning and subsequently tested in the laboratory for their responsiveness to sucrose and to light. There was no evidence of a positive relationship between sucrose/visual responsiveness and neither performances of free-flying bees in an elemental discrimination, reversal learning and negative patterning. These findings indicate that relationships established between responsiveness to task relevant stimuli and learning proficiency established in the laboratory with restrained bees might not hold true for a completely different behavioral context i.e. for free-flying bees in their natural environment.
These results show that the honey bee is an excellent insect model to study consistency in cognitive proficiency and to identify the underlying factors. I mainly discuss the results with respect to the question of brain modularity in insects and the adaptive significance of individuality in cognitive abilities for honey bee colonies. I also provide a proposition of research questions which tie in this theme of consistent cognitive proficiency and could provide fruitful areas for future research.
Interpreting gaze behavior is essential in evaluating interaction partners, yet the ‘semantics of gaze’ in dynamic interactions are still poorly understood. We aimed to comprehensively investigate effects of gaze behavior patterns in different conversation contexts, using a two-step, qualitative-quantitative procedure. Participants watched video clips of single persons listening to autobiographic narrations by another (invisible) person. The listener’s gaze behavior was manipulated in terms of gaze direction, frequency and direction of gaze shifts, and blink frequency; emotional context was manipulated through the valence of the narration (neutral/negative). In Experiment 1 (qualitative-exploratory), participants freely described which states and traits they attributed to the listener in each condition, allowing us to identify relevant aspects of person perception and to construct distinct rating scales that were implemented in Experiment 2 (quantitative-confirmatory). Results revealed systematic and differential meanings ascribed to the listener’s gaze behavior. For example, rapid blinking and fast gaze shifts were rated more negatively (e.g., restless and unnatural) than slower gaze behavior; downward gaze was evaluated more favorably (e.g., empathetic) than other gaze aversion types, especially in the emotionally negative context. Overall, our study contributes to a more systematic understanding of flexible gaze semantics in social interaction.
In 2020, cancer was the leading cause of death worldwide, accounting for nearly 10 million deaths. Lung cancer was the most common cancer, with 2.21 million cases per year in both sexes. This non-homogeneous disease is further subdivided into small cell lung cancer (SCLC, 15%) and non-small cell lung cancer (NSCLC, 85%). By 2023, the American Cancer Society estimates that NSCLC will account for 13% of all new cancer cases and 21% of all estimated cancer deaths. In recent years, the treatment of patients with NSCLC has improved with the development of new therapeutic interventions and the advent of targeted and personalised therapies. However, these advances have only marginally improved the five-year survival rate, which remains alarmingly low for patients with NSCLC. This observation highlights the importance of having more appropriate experimental and preclinical models to recapitulate, identify and test novel susceptibilities in NSCLC. In recent years, the Trp53fl/fl KRaslsl-G12D/wt mouse model developed by Tuveson, Jacks and Berns has been the main in vivo model used to study NSCLC. This model mimics ADC and SCC to a certain extent. However, it is limited in its ability to reflect the genetic complexity of NSCLC. In this work, we use CRISPR/Cas9 genome editing with targeted mutagenesis and gene deletions to recapitulate the conditional model. By comparing the Trp53fl/fl KRaslsl- G12D/wt with the CRISPR-mediated Trp53mut KRasG12D, we demonstrated that both showed no differences in histopathological features, morphology, and marker expression. Furthermore, next-generation sequencing revealed a very high similarity in their transcriptional profile. Adeno-associated virus-mediated tumour induction and the modular design of the viral vector allow us to introduce additional mutations in a timely manner. CRISPR-mediated mutation of commonly mutated tumour suppressors in NSCLC reliably recapitulated the phenotypes described in patients in the animal model. Lastly, the dual viral approach could induce the formation of lung tumours not only in constitutive Cas9 expressing animals, but also in wildtype animals. Thus, the implementation of CRISPR genome editing can rapidly advance the repertoire of in vivo models for NSCLC research. Furthermore, it can reduce the necessity of extensive breeding.
Physical regimes characterized by low Mach numbers and steep stratifications pose severe challenges to standard finite volume methods. We present three new methods specifically designed to navigate these challenges by being both low Mach compliant and well-balanced. These properties are crucial for numerical methods to efficiently and accurately compute solutions in the regimes considered.
First, we concentrate on the construction of an approximate Riemann solver within Godunov-type finite volume methods. A new relaxation system gives rise to a two-speed relaxation solver for the Euler equations with gravity. Derived from fundamental mathematical principles, this solver reduces the artificial dissipation in the subsonic regime and preserves hydrostatic equilibria. The solver is particularly stable as it satisfies a discrete entropy inequality, preserves positivity of density and internal energy, and suppresses checkerboard modes.
The second scheme is designed to solve the equations of ideal MHD and combines different approaches. In order to deal with low Mach numbers, it makes use of a low-dissipation version of the HLLD solver and a partially implicit time discretization to relax the CFL time step constraint. A Deviation Well-Balancing method is employed to preserve a priori known magnetohydrostatic equilibria and thereby reduces the magnitude of spatial discretization errors in strongly stratified setups.
The third scheme relies on an IMEX approach based on a splitting of the MHD equations. The slow scale part of the system is discretized by a time-explicit Godunov-type method, whereas the fast scale part is discretized implicitly by central finite differences. Numerical dissipation terms and CFL time step restriction of the method depend solely on the slow waves of the explicit part, making the method particularly suited for subsonic regimes. Deviation Well-Balancing ensures the preservation of a priori known magnetohydrostatic equilibria.
The three schemes are applied to various numerical experiments for the compressible Euler and ideal MHD equations, demonstrating their ability to accurately simulate flows in regimes with low Mach numbers and strong stratification even on coarse grids.