Refine
Has Fulltext
- yes (533)
Is part of the Bibliography
- yes (533) (remove)
Year of publication
- 2018 (533) (remove)
Document Type
- Journal article (344)
- Doctoral Thesis (156)
- Preprint (22)
- Conference Proceeding (3)
- Other (2)
- Working Paper (2)
- Book (1)
- Book article / Book chapter (1)
- Habilitation (1)
- Master Thesis (1)
Language
- English (533) (remove)
Keywords
- Parton Distributions (23)
- Hadron-Hadron scattering (experiments) (16)
- Positronen-Emissions-Tomografie (16)
- Extension (14)
- PET (14)
- Decay (13)
- boron (12)
- Squark (11)
- ++ (10)
- positron emission tomography (9)
- Mass (7)
- Maus (7)
- Physics (7)
- Cross-Section (6)
- Gluino Production (6)
- LHC (6)
- Parton distributions (6)
- diborenes (6)
- Higgs bosons (5)
- MASS (5)
- Model (5)
- SPECT (5)
- carbenes (5)
- inflammation (5)
- neuroendocrine tumor (5)
- ADHD (4)
- Beyond Standard Model (4)
- Breaking (4)
- Distributions (4)
- Energy (4)
- Fluoreszenzmikroskopie (4)
- Hadron colliders (4)
- Hierarchy (4)
- Models (4)
- PRRT (4)
- Stress (4)
- Supersymmetry (4)
- Thrombozyt (4)
- Top quark (4)
- Topologischer Isolator (4)
- physical activity (4)
- 18F-DCFPyL (3)
- 18F-FDG (3)
- Aspergillus fumigatus (3)
- Biene (3)
- Biofilm (3)
- Boson (3)
- DaTscan (3)
- Events (3)
- Fluorescence (3)
- Fluoreszenz (3)
- G-Protein gekoppelte Rezeptoren (3)
- Hadron Colliders (3)
- Kernspintomografie (3)
- MRI (3)
- Makroökonomie (3)
- Measuring Masses (3)
- Microscopy (3)
- Monte-Carlo (3)
- PET/CT (3)
- Particle data analysis (3)
- Polymere (3)
- RADS (3)
- SSTR (3)
- Search (3)
- Stammzelle (3)
- Staphylococcus aureus (3)
- Supersymmetric models (3)
- T cells (3)
- Thrombose (3)
- Trypanosomen (3)
- Weak (3)
- ageing (3)
- apoptosis (3)
- breast cancer (3)
- cancer (3)
- children (3)
- diborynes (3)
- immune evasion (3)
- induced pluripotent stem cells (3)
- infection (3)
- machine learning (3)
- mitochondria (3)
- mouse model (3)
- obesity (3)
- prostate cancer (3)
- psychology (3)
- spectroscopy (3)
- stroke (3)
- theranostics (3)
- 11C-HED (2)
- 123I-mIBG (2)
- 123I-metaiodobenzylguanidine (2)
- 18F-LMI1195 (2)
- ABCG2 (2)
- Activation (2)
- Alzheimer’s disease (2)
- Ants (2)
- Apis mellifera (2)
- Arteriosklerose (2)
- Arzneimittelforschung (2)
- B cells (2)
- Biomarkers (2)
- Boron (2)
- Bosons (2)
- Cadherine (2)
- Camponotus floridanus (2)
- Cancer immunotherapy (2)
- Catalysis (2)
- China (2)
- Code examples (2)
- Coffin-Lowry syndrome (2)
- DFT calculations (2)
- Diabetes mellitus (2)
- Drosophila (2)
- Drosophila melanogaster (2)
- Emotion (2)
- Entwicklung (2)
- Epigenetik (2)
- Europäische Union (2)
- Extrazelluläre Matrix (2)
- Femtosekundenspektroskopie (2)
- Fernerkundung (2)
- GPCR (2)
- Genom (2)
- Gluino production (2)
- Hämostase (2)
- Innate immunity (2)
- Ioflupane (2)
- Jets (2)
- Leistungsbewertung (2)
- Mikroskopie (2)
- Muscarinrezeptor (2)
- Myc (2)
- Neisseria meningitidis (2)
- Netzwerk (2)
- Optische Spektroskopie (2)
- PSMA-PET (2)
- Pair production (2)
- Parkinson (2)
- Parkinson Disease (2)
- Parkinson-Krankheit (2)
- Patron Distributions (2)
- Performance Evaluation (2)
- Phänologie (2)
- Plasma (2)
- Plus plus (2)
- Positron Emission Tomography (2)
- Program (2)
- Prostate Cancer (2)
- Proton-Proton Collisions (2)
- QAHE (2)
- QCD (2)
- Quanten-Hall-Effekt (2)
- Quecksilbertellurid (2)
- RSK2 (2)
- Rhodium (2)
- Risk factors (2)
- SPECT/CT (2)
- SQH method (2)
- Signaltransduktion (2)
- Simulation (2)
- Sozialpsychologie (2)
- Squaraine (2)
- Supramolekulare Chemie (2)
- Survival (2)
- Symmetry (2)
- Symmetry-breaking (2)
- Tagesrhythmus (2)
- Taufliege (2)
- Textverstehen (2)
- Timing (2)
- Transcriptome (2)
- Trypanosoma brucei (2)
- Ultrakurzzeitspektroskopie (2)
- Umverteilung (2)
- Ungleichheit (2)
- Virchow Node (2)
- Virulenzfaktor (2)
- WZ (2)
- [177Lu]-DOTATATE/-DOTATOC (2)
- [68Ga] (2)
- adolescents (2)
- anxiety (2)
- bees (2)
- biological models (2)
- borylene (2)
- calcium (2)
- carbon dioxide (2)
- cardiomyocytes (2)
- chemokines (2)
- chronic kidney disease (2)
- circadian clock (2)
- circadian rhythm (2)
- classification (2)
- data mining (2)
- desirable difficulties (2)
- diet (2)
- diradicals (2)
- division of labor (2)
- emotion (2)
- epigenetics (2)
- evolution (2)
- fatty acid (2)
- ferroelectricity (2)
- fitness (2)
- fluorescence (2)
- foraging (2)
- forest health (2)
- gamma rays (2)
- glucose (2)
- glycine receptor (2)
- hemodialysis (2)
- hiPSC-CM (2)
- honeybee (2)
- immunology (2)
- insulin (2)
- interferon (2)
- knee arthroplasty (2)
- land use (2)
- load management (2)
- low-valent compounds (2)
- medullary thyroid carcinoma (2)
- melanoma (2)
- metabolomics (2)
- miRNS (2)
- molecular imaging (2)
- mothers (2)
- muscle degeneration (2)
- myocardial sympathetic innervation imaging (2)
- neuroblastoma (2)
- optimization (2)
- optogenetics (2)
- pancreas (2)
- pathogens (2)
- periprosthetic infection (2)
- personalized medicine (2)
- personalized treatment (2)
- platelets (2)
- polymer (2)
- pp Collisions (2)
- pp collisions (2)
- precision medicine (2)
- self (2)
- sensor fusion (2)
- somatostatin receptor (2)
- spontaneous symmetry breaking (2)
- startle disease (2)
- stem cell therapy (2)
- symbiosis (2)
- therapy (2)
- tissue engineering (2)
- tracer (2)
- tumor heterogeneity (2)
- two-stage exchange (2)
- tyrosine kinase inhibitor (2)
- vandetanib (2)
- virtual reality (2)
- *-algebra (1)
- 11C-Hydroxyephedrine (1)
- 11C-hydroxyephedrine (1)
- 123I-Ioflupane (1)
- 16S metabarcoding (1)
- 18F-FDS (1)
- 18F-flurpiridaz (1)
- 18FFBnTP (1)
- 2- deoxy-2-(18F)fluoro-D-glucose (1)
- 2-Aminoethylphosphonic acid (1)
- 2-deoxy-2-(18F)fluoro-D-glucose (1)
- 3D echocardiography (1)
- 3D modeling (1)
- 3D point cloud (1)
- 3D powder printing (1)
- 3D printing (1)
- 3D thermal mapping (1)
- 53BP1 (1)
- 68Ga-DOTATATE/-TOC (1)
- 8 TEV (1)
- 99mTc-DTPA (1)
- ACL (1)
- AChE inhibitor (1)
- ADHS (1)
- AI (1)
- AIME (1)
- AKI (1)
- AMP-activated protein kinase (AMPK) (1)
- APC (1)
- ARPES (1)
- ATLAS <Teilchendetektor> (1)
- ATLAS New Small Wheels (NSW) (1)
- ATLAS experiment (1)
- Accelerator modelling and simulations (multi-particle dynamics; single-particle dynamics) (1)
- Achillea Fragrantissima (1)
- Acid adaptation (1)
- Ackerschmalwand (1)
- Acoustic equations (1)
- Acoustics (1)
- Acute myeloid leukemia (1)
- Acyrthosiphon pisum (1)
- AdS-CFT Correspondence (1)
- Adhäsion (1)
- Adipositas (1)
- Adsorption (1)
- Affekt (1)
- African trypanosomes (1)
- Agonist (1)
- Ahmed (1)
- Alemtuzumab (1)
- Algorithm (1)
- Algorithmus (1)
- Aliphatics (1)
- Alkaloide (1)
- Alkamiden (1)
- Alkamides (1)
- Allogeneic stem cell transplantation (1)
- Allotransplantation (1)
- Ameise (1)
- Ameisen (1)
- American foulbrood (1)
- Analysis (1)
- Anderson-Lokalisation (1)
- Aneuploidy (1)
- Angeborene Immunität (1)
- Angst (1)
- Animal behavior IntelliCage system (1)
- Animal model (1)
- Ant (1)
- Antibiotic (1)
- Antibody clearance (1)
- Antidepressants (1)
- Antitrypanosomal (1)
- Antitrypanosomen (1)
- Anxiety (1)
- Aorta (1)
- Approximationsalgorithmus (1)
- Arbeitsgedächtnis (1)
- Arbeitsmarkt (1)
- ArsZ (1)
- Arterie (1)
- Artery (1)
- Articular-Cartilage (1)
- Arzneimittel (1)
- Arzneimitteldesign (1)
- Aspergillus (1)
- AstA (1)
- Asylpolitik (1)
- Asymptotic Preserving (1)
- Atherosclerosis (1)
- Atmosphäre (1)
- Atomic and molecular interactions with photons (1)
- Atomketten (1)
- Atta vollenweideri (1)
- Attitudes towards immigrants (1)
- Auditory pathway (1)
- Aurora-A (1)
- Auto-Scaling (1)
- Automation (1)
- Automatisiertes Fahren (1)
- Autonomes Fahrzeug (1)
- Axion (1)
- B-0 (1)
- B-Lymphozyt (1)
- BB bond activation (1)
- BB/BC Bond activation (1)
- BC bond activation (1)
- BCL6 (1)
- BRAF (1)
- BRCA1 (1)
- BRCA2 (1)
- BRIP1 gene (1)
- Bacillus subtilis (1)
- Bacteria (1)
- Bacterial infection (1)
- Baerveldt (1)
- Bakterien (1)
- Bakteriophagen (1)
- Banach-Raum (1)
- Bank Credit Market (1)
- Bankgeschäft (1)
- Bariumtitanat (1)
- Bayes analysis (1)
- Bayes-Verfahren (1)
- Bayesian methods (1)
- Bayesian model comparison (1)
- Beatty sequence (1)
- Beauveria bassiana (1)
- Beige adipocytes (1)
- Benchmarking (1)
- Benutzerinteraktion (1)
- Bewusstsein (1)
- Bi2Se3 (1)
- Bildgebendes Verfahren (1)
- Bildverarbeitung (1)
- Bioabbaubarkeit (1)
- Biochemical-Diagnosis (1)
- Biodegradability (1)
- Biodiversity Exploratories (1)
- Biodiversitätsexploratorien (1)
- Biofilm formation (1)
- Biofilms (1)
- Bioinformatics (1)
- Bioinformatik (1)
- Biokinetics (1)
- Biologie (1)
- Biologischer Abbau (1)
- Biomarker (1)
- Biomechanical Properties (1)
- Biomedical engineering (1)
- Bioverfügbarkeit (1)
- Bipolar Disorder (1)
- Bismutselenide (1)
- Bodipy (1)
- Body size (1)
- Body weight (1)
- Bone (1)
- Bootstrap (1)
- Bor (1)
- Borylierung (1)
- Breeding system (1)
- Bregman distance (1)
- Brushite (1)
- Bruton Tyrosine Kinase (1)
- Burgers-Gleichung (1)
- Burkina Faso (1)
- Butyrylcholinesterase (1)
- Bärtierchen (1)
- C-C coupling (1)
- C/EBP (1)
- C5aR1 (1)
- CAGSSS (1)
- CCHamide1 (1)
- CCL4 (1)
- CD28 costimulation (1)
- CD28 superagonists (1)
- CD3/19 depletion (1)
- CD34 selection (1)
- CD4\(^{+}\) T helper cells (1)
- CD52 (1)
- CD74 (1)
- CDH13 (1)
- CDR3 sequences (1)
- CIR aerial imagery (1)
- CLEC-2 (1)
- CML (1)
- CNG channel (1)
- CNS (1)
- CO2 fixation (1)
- COMT (1)
- COPD (1)
- CPAF activation (1)
- CRAC (1)
- CRHR1 (1)
- CRISPR/Cas9 (1)
- CXCL13 (1)
- Ca2+ (1)
- Cadherin 13 (1)
- Cadherin-13 (1)
- Caenorhabditis elegans (1)
- Calcium (1)
- Calcium Citrate (1)
- Calcium phosphate (1)
- Calciumphosphate (1)
- Calibration (1)
- Camponotus (1)
- Cancer (1)
- Cancer models (1)
- Cancer therapeutic resistance (1)
- Candida albicans (1)
- Cannabinoid Receptor (1)
- CarO (1)
- Carbenes (1)
- Cardiovascular biology (1)
- Cardiovascular diseases (1)
- Cartilage Regeneration (1)
- Catheter Lock Solution (1)
- Catheter-related Bloodstream Infections (CRBSI) (1)
- Cauchy-Born rule (1)
- Caudate nucleus (1)
- Cell differentiation (1)
- Cellular imaging (1)
- Central Spin (1)
- Ceramides (1)
- Cerebellar nuclei (1)
- Chain-length distribution (1)
- Chains (1)
- Charged-Particles (1)
- Charm quark (1)
- Charmonia (1)
- Chemische Reaktion (1)
- Chemische Synthese (1)
- Chemistry (1)
- Chemotherapeutic resistance (1)
- Cherenkov detectors (1)
- Chimeric antigen receptor (1)
- Chinolonderivate (1)
- Chlamydia (1)
- Chlamydienkrankheit (1)
- Cholinesterase (1)
- Chromatin (1)
- Chromatin and Epigenetics (1)
- Chromophor (1)
- Chronic heart-failure (1)
- Chronic myeloid leukaemia (1)
- Chronobiologie (1)
- Circadian Clock (1)
- Circadiane Uhr (1)
- Circadianer Rhythmus (1)
- Circular dichroism (1)
- Climate change (1)
- Clinical trial (1)
- Clonality (1)
- Cloud Computing (1)
- Coffin–Lowry syndrome (1)
- Coherent Multidimensional Spectroscopy (1)
- Coherent control (1)
- Cohesin complex (1)
- Collagen (1)
- Collicions (1)
- Colloidal Stability (1)
- Color (1)
- Combination (1)
- Comparative genomics (1)
- Complexity (1)
- Component selectivity (1)
- Compressive Properties (1)
- Computational drug design (1)
- Computersimulation (1)
- Concealed Information Test (1)
- Confidence interval (1)
- Conformal Field Theory (1)
- Conical Intersection (1)
- Consistent partial least squares (1)
- Copal\(^®\) spacem (1)
- Copeptin (1)
- Copper (1)
- Copper catalysis (1)
- Copy number changes (1)
- Corneal confocal microscopy (1)
- Corticoliberin (1)
- Corynebacterium urealyticum (1)
- Counterfeit Medicines (1)
- Coupled Electron-Nuclear Dynamics (1)
- Cross-section (1)
- Cuticle (1)
- Cuticular water permeabilities (1)
- Cuticular waxes (1)
- Cyclics (1)
- Cyclotrimerisation (1)
- Cyropaidia (1)
- D665 (1)
- DCGAN (1)
- DECAY (1)
- DFNB68 (1)
- DFT-LDA (1)
- DHAP (1)
- DLBCL (1)
- DM2 (1)
- DNA (1)
- DNA Breaks (1)
- DNA catalyst (1)
- DNA complex (1)
- DNA damage (1)
- DNA methylation (1)
- DNA transcription (1)
- DNMR-Spektroskopie (1)
- DRG (1)
- DT40 cells (1)
- Dark-Matter (1)
- Dark-matter production (1)
- Data Science (1)
- DecaWave (1)
- Decay sequence (1)
- Decays (1)
- Decoherence (1)
- Deep Georeferencing (1)
- Deformation (1)
- Deformationsquantisierung (1)
- Delta Repertoire (1)
- Democracy Matrix (1)
- Dendritic cells (1)
- Dendritische Zelle (1)
- Dependence (1)
- Depression (1)
- Design (1)
- Desynchronisation (1)
- Desynchronization (1)
- Diabetic nephropathies (1)
- Diagnose (1)
- Diagnosis (1)
- Dicarboximide (1)
- Dicarboximides (1)
- Dietary process-related contaminants (1)
- Differential Cross-Sections (1)
- Differentialgleichung (1)
- Dilatometrie (1)
- Diophantine approximation (1)
- Dipeptidyl-peptidase IV inhibitors (1)
- Discrete-to-continuum limits (1)
- Disney (1)
- Disorder (1)
- Dmrt1bY (1)
- Doppelquantenkohärenz (1)
- Drahtloses Sensornetz (1)
- Drosophila Myc transcription growth PAF1 (1)
- Drosophila melanogaster motoneuron (1)
- Drosophila model (1)
- Drug delivery (1)
- Dualstere Liganden (1)
- Dualsteric Ligands (1)
- Dyad (1)
- Dyade (1)
- Dynamic magnetic resonance imaging (1)
- Dynamical Supersymmetry Breaking (1)
- Dynamics (1)
- Dynamische MR Bildgebung (1)
- Dynamische Messung (1)
- E. coli Nissle 1917 (1)
- EAE (1)
- ECG (1)
- EDC-NHS chemistry (1)
- EEG (1)
- EHEC (1)
- EU Governance (1)
- EW (1)
- Eccentricities (1)
- Ecology (1)
- Economic Growth (1)
- Effizienter Algorithmus (1)
- Efflux pump (1)
- Egypt (1)
- Einkommensverteilung (1)
- Einstellung gegenüber Immigranten (1)
- Einwanderung (1)
- Elasticity (1)
- Elasticity tensor (1)
- Elastizitätstensor (1)
- Elderly (1)
- Electron Flux (1)
- Electroweak interaction (1)
- Elektroencephalogramm (1)
- Elektronenspektroskopie (1)
- Elektronentransfer (1)
- Elite Rowers (1)
- Elliptische Differentialgleichung (1)
- Empirical Economics (1)
- Empirische Wirtschaftsforschung (1)
- Employment (1)
- Endogenous clock (1)
- Endophytische Pilze (1)
- Energieaufnahme (1)
- Energies (1)
- Energy Transfer (1)
- Enoyl-acyl-carrier-protein-Reductase <Enoyl-[acyl-carrier-protein]-Reductase> (1)
- Enterohemorrhagic Escherichia coli (1)
- Entomology (1)
- Entropiebedingung (1)
- Entropielösung (1)
- Entropy admissibility condition (1)
- Entwicklung chimärer Antigenrezeptor T-Zellen (1)
- Entzündung (1)
- Entzündungsschmerz (1)
- Enzymes (1)
- Enzyminhibitor (1)
- Epichloe (1)
- Epichloë (1)
- Epistemic Competences (1)
- Epistemische Kompetenzen (1)
- Epitope (1)
- Erythrozyt (1)
- Erythrozytenadhärenz (1)
- Euclidean plane (1)
- Euklidische Ebene (1)
- Euler equations (1)
- European Asylum System (1)
- European Union (1)
- European foulbrood (1)
- Europäische Zentralbank (1)
- Event (1)
- Exacerbation (1)
- Exazerbation (1)
- Excited states (1)
- Exciton dynamics (1)
- Excitons (1)
- Executive Compensation (1)
- Existenz und Eindeutigkeit (1)
- Exotic mesons (1)
- Experiment / Sozialpsychologie (1)
- Expression (1)
- Extensions of Higgs sector (1)
- Extensions of gauge sector (1)
- External exposure assessment (1)
- Extracellular matrix proteins (1)
- Exziton (1)
- F-actin (1)
- FAIR (1)
- FGF (1)
- FGF-2 (1)
- FGF21 (1)
- FV45 (1)
- Fabry disease (1)
- Fabry-Krankheit (1)
- Factor messenger-RNA (1)
- Fagus sylvatica (1)
- Fahrerablenkung (1)
- Fahrerverhalten (1)
- Fanconi anaemia (1)
- Farbensehen (1)
- Feedforward loop (1)
- Feldeffekttransistor (1)
- Femtosekundenlaser (1)
- Ferroelektrikum (1)
- Fibroblast Growth Factor-21 (1)
- Fibroblastenwachstumsfaktor (1)
- Field effect transistor (1)
- Finanzkrise (1)
- Finite-Volumen-Methode (1)
- Fitness (1)
- Flavoniden (1)
- Flavonoinds (1)
- Fluconazole (1)
- Fluid-Partikel-Strömung (1)
- Fluorescence Microscopy (1)
- Fluorescence Resonance Energy Transfer (1)
- Fluorescence resonance energy transfer (1)
- Fluorescence spectroscopy (1)
- Flüchtlingskrise (1)
- Flüssigkristall (1)
- Foraging behaviour (1)
- Formulierungsentwicklung (1)
- Fortran code (1)
- Fourier-Spektroskopie (1)
- Fragmentation (1)
- Fremdscham (1)
- Fremdschämen (1)
- Frequency (1)
- Fruit (1)
- Fulleren-Netzwerk (1)
- Fullerene (1)
- Functional differential equations (1)
- Fungal cell-walls (1)
- Fusarium fujikuroi (1)
- Fälschung (1)
- Förderung (1)
- G Protein-Coupled Receptors (1)
- G protein-coupled receptors (1)
- G-Protein gekoppelte Rezeptor (1)
- GABAerge Nervenzelle (1)
- GAMMA (1)
- GAN (1)
- GI (1)
- GLP-1 (1)
- GPVI (1)
- GPX4 (1)
- Galactosidase <alpha-> (1)
- Galectin-1 (1)
- Gamma (1)
- Gamma-convergence (1)
- Gasgemisch (1)
- Gasionisationsdetektor (1)
- Gastrointestinal (1)
- Gauge-gravity correspondence (1)
- Gb3 accumulation (1)
- Gefühl (1)
- Gehirn (1)
- Gehirn-Computer-Schnittstelle (1)
- Geitonogamy (1)
- Geldpolitik (1)
- Gene Regulation (1)
- Gene-expression (1)
- Gene-prediction (1)
- Generalized Nash Equilibrium Problem (1)
- Genetics (1)
- Genexpression (1)
- Genome editing (1)
- Genomeditierung (1)
- Genregulation (1)
- Geo-spatial behavior (1)
- Geografie (1)
- Geometric Phase (1)
- Georeferenzierung (1)
- German healthcare system (1)
- Germanium telluride (1)
- Germination (1)
- Geruchssinn (1)
- Gland (1)
- Global Change (1)
- Globaler Wandel (1)
- Globalisierung (1)
- Glomerular filtration (1)
- Gluon (1)
- Gluon Fusion (1)
- Glutamin (1)
- Glycoprotein GPV (1)
- Glykoproteine (1)
- God in 3 Macc (1)
- Gold-Nanoparticles (1)
- Golgi-Apparat (1)
- Governance (1)
- Graph (1)
- Gräser (1)
- Guinier-Preston zones (1)
- HECT (1)
- HFmrEF (1)
- HIGGS (1)
- HIV (1)
- HLA class II (1)
- HLA peptidome (1)
- HP1432, Hpn2 (1)
- HPLC (1)
- HUWE1 (1)
- Hadron Collider (1)
- Halbleiter (1)
- Haploidentical (1)
- Hardware (1)
- Heavy-Particles (1)
- Hekate (1)
- Helicität <Chemie> (1)
- Helicobacter pylori (1)
- Helix- and Zick-Zack-Konformere (1)
- Helix- and Zig-Zag-Conformers (1)
- Hellenistic kingship (1)
- Hematopoietic Stem Cell (1)
- Hemostasis (1)
- Herzinfarkt (1)
- Herzkatheter (1)
- Herzkathetereingriff (1)
- Heubacillus (1)
- Hexaarylbenzene (1)
- HgTe (1)
- Hibernation (1)
- Hic-5 (1)
- Hierarchische Matrix (1)
- Hierarchy problem (1)
- Higgs (1)
- Higgs boson (1)
- Higgs boson decays (1)
- Higgs boson mass (1)
- Higgs physics (1)
- High-throughput screening (1)
- Higher Education (1)
- Hippocampus (1)
- Histatin 5 (1)
- Historical Maps (1)
- Historische Karte (1)
- Historische Landkarten (1)
- Hochauflösende Mikroskopie (1)
- Homöostase (1)
- Hospitalismus <Hygiene> (1)
- Host defense (1)
- Host-endosymbiont interactions (1)
- Host-pathogen interaction (1)
- Host-pathogen interactions (1)
- Housing Markets (1)
- Hsp90 (1)
- Human Knee (1)
- Human Medial Meniscus (1)
- Human Resource Management <Humanvermögen> <Personalentwicklung> (1)
- Human behavior (1)
- Human behaviour (1)
- Hurst Exponent (1)
- Hyaluronic acid (1)
- Hyaluronsäure (1)
- Hybrid (1)
- Hybrid GPCR Ligands (1)
- Hydrogel (1)
- Hymenoptera (1)
- Hyperbolic Partial Differential Equations (1)
- Hyperbolische Differentialgleichung (1)
- Hypothesis comparison (1)
- Hypothetical gauge bosons (1)
- Hypothetical particle physics models (1)
- IARS2 (1)
- ICD (1)
- IDO-1 (1)
- IFN-gamma (1)
- IGF-I (1)
- IL-23 (1)
- Ibrutinib (1)
- Identification (1)
- Image Processing (1)
- Imatinib (1)
- Immun-Transkriptom (1)
- Immune Thrombocytopenia (1)
- Immunosuppression (1)
- Immunreaktion (1)
- Immunsystem (1)
- Immuntherapie (1)
- Immunthrombozytopenie (1)
- Importwettbewerb (1)
- Impulsformung (1)
- Impurity Profiling (1)
- Inbreeding depression (1)
- Inequality (1)
- Influenza (1)
- Information Extraction (1)
- Informationsverarbeitung (1)
- Injuries (1)
- Innere Uhr (1)
- Innervation (1)
- Insect (1)
- Insekt (1)
- Instrumentelle Analytik (1)
- Insulin-like Growth Factor (1)
- Integrated circuit (1)
- Integriert-optisches Bauelement (1)
- Integrodifferentialgleichung (1)
- Interactome (1)
- Interaktion (1)
- Intergenerational income mobility (1)
- Intergenerative Einkommensmobilität (1)
- Interleukin 6 (1)
- Interleukine (1)
- Internet der Dinge (1)
- Intervention (1)
- Intestinal Intraepithelial Lymphocy (1)
- Intestinal stem cell (1)
- Intragenerational wage mobility (1)
- Intragenerative Lohnmobilität (1)
- Intrinsic charm (1)
- Invertebrate vision (1)
- IoT (1)
- Ion channel function (1)
- Ionenkanal (1)
- Iridium bis(phosphinite) pincer complexes (1)
- Iridiumkomplexe (1)
- Ischemic stroke (1)
- Isocrates (1)
- Itinerare (1)
- Itineraries (1)
- J- and H-Aggregate (1)
- J- and H-Aggregates (1)
- JNK (1)
- Jacobian matrix (1)
- Jmjd6 (1)
- Josephson junction (1)
- K* µ+μ− (1)
- KDIGO (1)
- Karte (1)
- Katalyse (1)
- Kation (1)
- Kirchhoff's law (1)
- Klima (1)
- Kloosterman sum (1)
- Klotho-related molecules (1)
- Knochenersatz (1)
- Knochenmark (1)
- Knochenzemente (1)
- Knockout (1)
- Knockout <Molekulargenetik> (1)
- Knorpel (1)
- Kohlendioxid (1)
- Kohlenstoff-Nanoröhre (1)
- Kohärente Kontrolle (1)
- Kohärente Multidimensionale Spektroskopie (1)
- Kommunikation (1)
- Kommunikationsprotokoll (1)
- Kompetenzen im Hochschulsektor (1)
- Komplexauge (1)
- Komplexität (1)
- Kontrollierte Wirkstofffreisetzung (1)
- Korrekt gestelltes Problem (1)
- Korrelative Mikroskopie (1)
- Krebs <Medizin> (1)
- Krebsimmuntherapie (1)
- Kritische Infrastruktur (1)
- Kultur (1)
- Kupfer katalyse (1)
- Kupplungsreaktion (1)
- LAD (1)
- LHS (1)
- Labor Mobility (1)
- Laguerre-Gauss (1)
- Lambdoide Prophagen (1)
- Landnutzung (1)
- Landsat (1)
- Landwirtschaft (1)
- Large detector systems for particle and astroparticle physics (1)
- Laser Pulse Shaping (1)
- Laser scanning (1)
- Laserimpulsformung (1)
- Lasermode (1)
- Latimeria menadoensis (1)
- Leaf (1)
- Leaf cutting ants (1)
- Leishmania (1)
- Lepton (1)
- Leptons (1)
- Lewis acids (1)
- Lgr5 (1)
- Lidar (1)
- Ligand (1)
- Ligand <Biochemie> (1)
- Light (1)
- Linagliptin (1)
- Linked Data (1)
- Lithography (1)
- Localization (1)
- Locked-in-Syndrom (1)
- Logik (1)
- Lolium perenne (1)
- Long-term follow-up (1)
- Lower Reference Value (1)
- Lu-177 (1)
- Lumineszenz (1)
- Lutetium (1)
- Lymphoma (1)
- Löslichkeit (1)
- MAC Protocol (1)
- MDD (1)
- MDR1 (1)
- ME/CFS (1)
- MIP-1β (1)
- MIPs (1)
- MPI (1)
- MRR1 (1)
- MRT (1)
- MS (1)
- MUD (1)
- MYC (1)
- Maccabees (1)
- Machine Learning (1)
- Machzahl (1)
- Macroscopic transport (1)
- Magnetfeldeffekt (1)
- Magnetic Resonance Spectroscopy Imaging (1)
- Magnetic Topological Insulator (1)
- Magnetic resonance (1)
- Magnetic resonance imaging (1)
- Magnetische Resonanz (1)
- Magnetresonanztomografie (1)
- Majorana bound state (1)
- Malaria (1)
- Malignancies (1)
- Malvaviscus arboreus (1)
- Manisch-depressive Krankheit (1)
- Marine sponge-derived actinomycetes (1)
- Marine sponges (1)
- Markarian 501 (1)
- Marrow (1)
- Maschinelles Lernen (1)
- Mass Spectrum (1)
- Masse (1)
- Materials chemistry (1)
- Mathematisches Modell (1)
- Measuring masses (1)
- Mechanisms (1)
- Mechanistic model (1)
- Medicago truncatula (1)
- Medullärer Schilddrüsenkrebs (1)
- Megakaryocyte (1)
- Megakaryocytes (1)
- Megakaryozyt (1)
- Mehrgitterverfahren (1)
- Meiose (1)
- Meiosis (1)
- Melanom (1)
- Melanoma (1)
- Melt electrospinning (1)
- Membranlipide (1)
- Men (1)
- Mensch (1)
- Mensch-Maschine-Interaktion (1)
- Mensch-Maschine-Kommunikation (1)
- Merkel cell carcinoma (1)
- Merkelzellkarzinom (1)
- Merogone experiments (1)
- Mesenchymal Stem Cell (1)
- Mesenchymal Stromal Cells (1)
- Mesogen (1)
- Metabolismus (1)
- Metabolomic Imaging (1)
- Metabolomics (1)
- Metallorganische Chemie (1)
- Metallosupramolekulare Chemie (1)
- Metanephrine (1)
- Metapleural gland (1)
- Metarhizium anisopliae (1)
- Methotrexate (1)
- Metrics (1)
- MicroRNAs (1)
- Minimally invasive vascular intervention (1)
- Mitgliedsstaaten (1)
- Mitochondria (1)
- Mitochondrium (1)
- MitraClip (1)
- Mobility (1)
- Mobilität (1)
- Mode propagation (1)
- Model comparison (1)
- Model simulation (1)
- Modellierung (1)
- Modenpropagation (1)
- Molecular biology (1)
- Molecular biophysics (1)
- Molecular neuroscience (1)
- Molecularly targeted therapy (1)
- Molekülzustand (1)
- Monetary Policy (1)
- Monocytes and macrophages (1)
- Motiliät (1)
- Motion detection (1)
- Motivation (1)
- Motivationspsychologie (1)
- Mrr1 (1)
- Multi-Hop Topologie (1)
- Multi-Hop Topology (1)
- Multicellular aggregates (1)
- Multifunctionalisability (1)
- Multipolar mitosis (1)
- Multizellulären Bakteriengemeinschaften (1)
- Muscidifurax (1)
- Muskelatrophie (1)
- Muskelzelle (1)
- Mutagenese (1)
- Mycobacterium tuberculosis (1)
- Mycobacterium tuberculosis InhA (1)
- Myokarditis (1)
- Myositis (1)
- N-MYC (1)
- N-heterocyclic carbenes (1)
- N6-methyladenosine (1)
- ND10 complex (1)
- NFATc1 (1)
- NIR-Spektroskopie (1)
- NK cells (1)
- NNLO (1)
- NOS-I (1)
- NOS1AP (1)
- NOX-Inhibitoren (1)
- NP-schweres Problem (1)
- NRF2 (1)
- NT-proBNP (1)
- NTHi (1)
- NaV1.9. oxidized phospholipids (1)
- Nahrungsaufnahme (1)
- Nanooptik (1)
- Nanopartikel (1)
- Nanoporöser Stoff (1)
- Nanosegregation (1)
- Nanostruktur (1)
- Nash-Gleichgewicht (1)
- Nasonia (1)
- Naturgefahr (1)
- Naturkatastrophe (1)
- Navigation analysis (1)
- Neostriatum (1)
- Nerve fibers (1)
- Nerve growth-factorcopy (1)
- Nestbau (1)
- Network Function Virtualization (1)
- Netzhaut (1)
- Netzwerktopologie (1)
- Neuroanatomie (1)
- Neurobiologie (1)
- Neurobiology (1)
- Neurodevelopment (1)
- Neuroendocrine (1)
- Neuroendocrine Tumor (1)
- Neurogenese (1)
- Neuronale Plastizität (1)
- Neutrino (1)
- Neutrino Telescope (1)
- Neutrino detectors (1)
- Neutrophils (1)
- Nichtlineares System (1)
- Nickelkomplexe (1)
- Niederdimensionales Elektronengas (1)
- Nierenfunktionsstörung (1)
- Non-coding RNA (1)
- Non-viral genome engineering (1)
- Nonlinear systems (1)
- Normetanephrine (1)
- Nosocomial Infections (1)
- Nosokomiale Infektionen (1)
- Notch1 (1)
- Notenbank (1)
- Nuclear (1)
- Nucleus accumbens (1)
- Numerical Methods (1)
- Numerical analysis (1)
- OCT1 (1)
- OPT (1)
- OSM (1)
- OSMR (1)
- Oberflächenplasmon (1)
- Oberflächenzustand (1)
- Obstruktive Ventilationsstörung (1)
- Olfaction (1)
- Oligomere (1)
- Oligomers and Polymers (1)
- Omega-3-Fettsäuren (1)
- Oncology (1)
- Oncostatin M (1)
- OncotypeDX\(^{®}\) (1)
- Onkogen (1)
- OpenFlow (1)
- OpsA (1)
- Optical spectroscopy (1)
- Optimale Steuerung (1)
- Optimierung (1)
- Optimierungsproblem (1)
- Optische Eigenschaft (1)
- Organische Synthese (1)
- Organometallic chemistry (1)
- Oryza sativa (1)
- Osmia (1)
- Osteoarthritis (1)
- P(P)over-bar collicions (1)
- P300 (1)
- PABPs (1)
- PAI-1 (1)
- PB-PB Collisions (1)
- PCI-32765 (1)
- PDE (1)
- PEST (1)
- PF-05231023 (1)
- PKCζ, (1)
- PML (1)
- PML nuclear-bodies (1)
- PMMA bone cement (1)
- PMNs (1)
- PP Collicions (1)
- PSMA (1)
- PSMA-RADS (1)
- PSMA-RADS-3A (1)
- PSMA-RADS-3B (1)
- PSMA-targeted PET (1)
- Paenibacterin (1)
- Pain (1)
- Pair Production (1)
- Pair Prodution (1)
- Pair-Production (1)
- Pan1 (1)
- Pancreas (1)
- Panel-Data Econometrics (1)
- Panelanalyse (1)
- Panic Disorder (1)
- Paniksyndrom (1)
- Paraganglioma (1)
- Parasite development (1)
- Parkinsonism (1)
- Parkinson’s disease (1)
- Partial Agonists (1)
- Partialagonismus (1)
- Particle dark matter (1)
- Particle production (1)
- Particle properties (1)
- Parton Ditributions (1)
- Pathogenität (1)
- Pathway (1)
- Peinlichkeit (1)
- Peptide (1)
- Period (1)
- Permeability (1)
- Permeabilität (1)
- Perturbative QCD (1)
- Pflanzen (1)
- Pflanzenbildgebung (1)
- Pharmaceutical Analysis (1)
- Phase Transition (1)
- Phospholipase D (1)
- Phospholipide (1)
- Phosphorescence (1)
- Photochemie (1)
- Photochemistry (1)
- Photoelektronenspektroskopie (1)
- Photon detectors for UV, visible and IR photons (vacuum) (1)
- Photons (1)
- Physiologically based kinetic models (1)
- Phänomenologische Soziologie (1)
- Plasmon (1)
- Plasmonic (1)
- Platelet (1)
- Plus (1)
- Plus Plus (1)
- Pollen (1)
- Pollinators (1)
- Poly(2-oxazolin)e (1)
- Poly(2-oxazoline)s (1)
- Poly(glycidol) (1)
- Polyatomare Verbindungen (1)
- Polycyclic aromatic hydrocarbons (1)
- Polycyclische Aromaten (1)
- Polyethylene glycol (1)
- Polyethylenglycol (1)
- Polypeptoide (1)
- Polypeptoids (1)
- Polysaccharide intercellular adhesin (PIA) (1)
- Polyspermy (1)
- Porphyrin (1)
- Positronenemissionstomografie (1)
- Post-transcriptional regulation (1)
- Postmarketing Experience (1)
- Practitioner's guide (1)
- Praktische Theologie (1)
- Preclinical (1)
- Prediction (1)
- Predictions (1)
- Preference for redistribution (1)
- Prevalence (1)
- Probiotikum (1)
- Production Cross-Section (1)
- Production cross-section (1)
- Prognostic impact (1)
- Programm (1)
- Progressive Relaxation (1)
- Proliferation (1)
- Propositional processing (1)
- Propositionale Verarbeitung (1)
- Prostatakrebs (1)
- Prostate cancer diagnostics (1)
- Protein (1)
- Protein folding (1)
- Protein kinase D1 (PKD1) (1)
- Proteinkinasen (1)
- Proteom (1)
- Proton-Proton- Collisions (1)
- Protonen-NMR-Spektroskopie (1)
- Protopterus annectens (1)
- Prototype (1)
- Pseudorapidity (1)
- Psychiatric disorders (1)
- Psychische Störung (1)
- Psychologie (1)
- Pteromalidae (1)
- Pump-Probe Technik (1)
- Pump-Probe-Technik (1)
- Punktwolke (1)
- Pyrenderivate (1)
- Pyrene (1)
- Pyrrolidinderivate (1)
- Pyrrolidine carboxamides (1)
- QCD Corrections (1)
- QoE Monitoring (1)
- Quality of Experience (1)
- Quanteninformatik (1)
- Quantentheorie (1)
- Quantum Spin Hall Effect (1)
- Quantum chromodynamics (1)
- Quark (1)
- Quark & gluon jets (1)
- Quark pair procuction (1)
- Quarkonium Production (1)
- Quarks (1)
- Quasi-1D Elektronensysteme (1)
- Quasi-Variational Inequality (1)
- Quasi-Variationsungleichung (1)
- RCT (1)
- REELS (1)
- REST-Complex (1)
- RGB-D (1)
- RNA Aptamer (1)
- RNA modification (1)
- RNA polymerase II (1)
- RNA sequencing (1)
- RNA-binding proteins (1)
- RNA-seq (1)
- RNS (1)
- RNase E (1)
- RSK (1)
- Ra-224 (1)
- Radiation calculations (1)
- Radionuclide Therapy (1)
- Radiotherapy (1)
- Raphe Kerne (1)
- Rapidity (1)
- Rashba effect (1)
- Rastertunnelmikroskopie (1)
- Raumdaten (1)
- Raumfüllung (1)
- Raumverhalten (1)
- Re-Annotation (1)
- Re-annotation (1)
- Reaction kinetics and dynamics (1)
- Receptors (1)
- Refugee Crisis (1)
- Registration (1)
- Regularisierung (1)
- Regulator of G protein signaling 2 (1)
- Regulatorischer Fokus (1)
- Regulatory T cells (1)
- Regulatory focus (1)
- Rekonstruktion (1)
- Relative Entropy (1)
- Release system (1)
- Remote Sensing (1)
- Renal abnormalities (1)
- Repair (1)
- Research design (1)
- Reservoir Strain (1)
- Resiliente Stadt (1)
- Resilienz (1)
- Resistance (1)
- Rezeptor (1)
- Rgs2 (1)
- Rho-Proteine (1)
- RhoGTPase (1)
- Rhodacyclopentadiene (1)
- Rhodobacter sphaeroides (1)
- Risikoanalyse (1)
- Risikomanagement (1)
- Risk assessment (1)
- Risk-factors (1)
- Ritual (1)
- River Basins (1)
- Robotics (1)
- Robotik (1)
- Root s=7 (1)
- Root-S=13 TEV (1)
- Rowing Ergometer (1)
- Ruthenium Komplexe (1)
- Räumliches Verhalten (1)
- Röntgen-Kleinwinkelstreuung (1)
- Röntgenstrukturanalyse (1)
- S1PR2 (1)
- SDN (1)
- SDN Controllers (1)
- SDN Switches (1)
- SIM (1)
- SLC2A3 (1)
- SNP (1)
- SNP-microarray (1)
- SOCE (1)
- SSTR-PET (1)
- STIM1 (1)
- STIM2 (1)
- SWOT (1)
- Scale (1)
- Schafgarbe <Gattung> (1)
- Schilddrüse (1)
- Schlaf (1)
- Schlaganfall (1)
- Schleuderguss (1)
- Schmerz (1)
- Schwann-cells (1)
- Science history (1)
- Sea urchin development (1)
- Selbst (1)
- Selbstorganisation (1)
- Semantic Search (1)
- Semantic Technologies (1)
- Semantic cognition (1)
- Semantische Analyse (1)
- Semantische Verarbeitung (1)
- Sensorimotor Rhythms (1)
- Sequenzanalyse <Chemie> (1)
- Serotonerge Nervenzelle (1)
- Serotonin (1)
- Sesquiterpene lactones (1)
- Sesquiterpenlactonen (1)
- Sglt1 (1)
- Shaggy kinase (1)
- Shigella flexneri (1)
- Shin-Metiu Model (1)
- Showers (1)
- Siberian spurge (1)
- Silibinin (1)
- Silibinin ester (1)
- Simulation methods and programs (1)
- Simulator (1)
- Single-Photon Detectors (1)
- Single-Photon-Emissions-Computertomographie (1)
- Single-molecule fluorescence microscopy (1)
- Sleeping Beauty transposon (1)
- Small RNA (1)
- Smart User Interaction (1)
- SnRK1 (1)
- Social Media (1)
- Social neuroscience (1)
- Society (1)
- Software (1)
- Software Defined Networking (1)
- Sonogashira (1)
- Sonogashira coupling (1)
- Sonogashira-Hagihara-Reaktion (1)
- Sox5 (1)
- Soziale Insekten (1)
- Soziale Mobilität (1)
- Sozialstaat (1)
- Soziologie (1)
- Sozioökonomisches System (1)
- Space filling (1)
- Sparse Sampling (1)
- Spatial behavior (1)
- Spatiotemporal analysis (1)
- Sphingomyelinase (1)
- Spinal nerves (1)
- Spinkette (1)
- Spintronik (1)
- Spleen tyrosine kinase (1)
- Spontaneous symmetry breaking (1)
- Sprue (1)
- Squarain Farbstoffe (1)
- Squaraine Dyes (1)
- Stability (1)
- Stabilität (1)
- Standardisierung (1)
- Staphylococci (1)
- Staphylococcus epidermidis (1)
- Star-shaped poly(ethylene glycol) (1)
- States (1)
- Statistical misconception (1)
- Statistische Hypothese (1)
- Stickstoffmonoxid-Synthase (1)
- Stiffness (1)
- Stimulating factor (1)
- Stofftransport <Biologie> (1)
- Strain Assessment (1)
- Streptomyces (1)
- Stress-Syndrom (1)
- Stressresistenz (1)
- Strong interaction (1)
- Structure-based (1)
- Strömung (1)
- Student (1)
- Super-resolution microscopy (1)
- Superpartners (1)
- Supraleitung (1)
- Supramolecular Chemistry (1)
- Surface plasmon (1)
- Surgery (1)
- Sustainability (1)
- Symmetries (1)
- Synaptische Proteine (1)
- Synaptonemal complex (1)
- Synovial Fluid Aspiration (1)
- Synthese (1)
- System (1)
- T cell acute lymphoblastic leukemia (1)
- T helper 1 cells (1)
- T-ALL (1)
- T-Lymphozyt (1)
- T-cell engineering (1)
- T-cell responses (1)
- T-cell therapy (1)
- T-lymphocytes (1)
- T. brucei (1)
- TAB08 (1)
- TFIIIC (1)
- TGF-β3 (1)
- TGN1412 (1)
- TK6 cells (1)
- TKI (1)
- TMJ (1)
- TRDV2 (1)
- TRGV9 (1)
- TRPA1 (1)
- TRPV1 (1)
- Tagesrhythmik (1)
- Talbot–Lau interferometer (1)
- Targeted Therapies (1)
- Targeted drug delivery (1)
- Targeted therapies (1)
- Tau leptons (1)
- Tauola (1)
- Taurolidine (1)
- Technical Documentation (1)
- Technische Unterlage (1)
- Testing parameter difference (1)
- Tetrazoliumsalze (1)
- Thalamic nuclei (1)
- Themenpark (1)
- Theologie (1)
- Theoretical Chemistry (1)
- Theoretische Chemie (1)
- Therapy (1)
- Thermografie (1)
- Thioether-Poly(glycidol) (1)
- Thrombopoese (1)
- Thrombopoiesis (1)
- Thrombosis (1)
- Thrombozytenaggregation (1)
- Tian Shan (1)
- Tiermodell (1)
- Time Series Analyses (1)
- Time-Resolved Spectroscopy (1)
- Timeless (1)
- Tiotropium (1)
- Tissue Engineering (1)
- Tissue engineering (1)
- Tn1549 transposon (1)
- Tn916-like transposon family (1)
- To-leading order (1)
- Tool (1)
- Top physics (1)
- Topological insulators (1)
- Training (1)
- Transkription (1)
- Transkription <Genetik> (1)
- Transkriptionsfaktor (1)
- Transkriptom (1)
- Translational research (1)
- Transparent motion (1)
- Transpiration barrier (1)
- Transporters (1)
- Transportkoeffizient (1)
- Transportprozess (1)
- Transposon (1)
- Transverse-momentum (1)
- Treatment (1)
- Treatment outcome (1)
- Trichomalopsis (1)
- TrkB (1)
- Tropomyosin receptor kinase B (1)
- Trypanosoma (1)
- Trypanosoma brucei brucei (1)
- Trypanosomes (1)
- Tuberkelbakterium (1)
- Tumor Microenvironment (1)
- Tumour angiogenesis (1)
- Tunnelspektroskopie (1)
- Two-dimensional Spectroscopy (1)
- UAV (1)
- UV-VIS-Spektroskopie (1)
- UV/Vis spectroscopy (1)
- UWB (1)
- Ultrafast information processing (1)
- Ultrakurzer Lichtpuls (1)
- Ultraschnelle Informationsverarbeitung (1)
- Ultraschnelle Photochemie (1)
- Umverteilungspräferenz (1)
- Universität Würzburg. Lehrstuhl für Pharmazeutische Technologie und Biopharmazie (1)
- Urbane Resilienz (1)
- Ureaplasma species (1)
- Usage (1)
- Utility (1)
- V800 (1)
- VEMP (1)
- VSG (1)
- VSMC (1)
- Valvular heart-desease (1)
- Variables Oberflächen Glycoprotein (1)
- Variant surface glycoprotein (1)
- Variationsungleichung (1)
- Varieties of Democracy (1)
- Venusfliegenfalle (1)
- Verallgemeinertes Nash-Gleichgewichtsproblem (1)
- Vergütung (1)
- Verhalten (1)
- Verkehrspsychologie (1)
- Verteilungspolitik (1)
- Viral infections (1)
- Virtualisierung (1)
- Viscosity (1)
- Voltage-Clamp-Methode (1)
- Vγ9Vδ2 (1)
- WTAP (1)
- Wasser Fett Trennung (1)
- Wasseroxidation (1)
- Weakly interacting massive particles (1)
- Web navigation (1)
- Well-Balanced (1)
- Well-posedness (1)
- Wellenleiter (1)
- Westafrika (1)
- Wild bees (1)
- Wire relaxation (1)
- Wirkstofffreisetzung (1)
- Wirtschaftsentwicklung (1)
- Wirtschaftsstruktur (1)
- Wirtschaftswachstum (1)
- Wissenschaftliche Literatur (1)
- Währungsunion (1)
- X-ray crystallography (1)
- X-ray imaging (1)
- XPS (1)
- Xenophon (1)
- Xenopus laevis oocytes (1)
- Z Boson (1)
- ZDF rats (1)
- ZO-1 (1)
- Zahlentheorie (1)
- Zeitaufgelöste Spektroskopie (1)
- Zeitauflösung (1)
- Zellbiologie (1)
- Zelldifferenzierung (1)
- Zelloberfläche (1)
- Zellteilung (1)
- Zika virus (1)
- Zinsänderungsrisiko (1)
- Zwei-Prozess-Modell (1)
- Zweidimensionale Spektroskopie (1)
- [68Ga]DOTATOC (1)
- \(^{18}\)F-FDG (1)
- \(^{18}\)F-fluorodeoxyglucose (1)
- \(^{99m}\)Tc-MAG3 (1)
- ab initio calculations (1)
- absorbed dose (1)
- absorbed dose to the blood (1)
- acetone (1)
- acquisition of host regulators (1)
- acrophobia (1)
- action potentials (1)
- active galactic nuclei (1)
- activity rhythms (1)
- activity tracker (1)
- acute myeloid leukemia (1)
- adaptive role (1)
- additive manufacturing (1)
- adrenal insufficiency (1)
- adsorption (1)
- adsorption-induced deformation (1)
- adult (1)
- adult treatment (1)
- advanced drug delivery system (1)
- aerobic fitness (1)
- aerobic training (1)
- affect (1)
- age-related macular degeneration (1)
- agricultural intensity (1)
- agricultural productivity (1)
- agroecology (1)
- airborne laser scanning (ALS) (1)
- airflow (1)
- alcohol (1)
- alkaloids (1)
- allogeneic stem cell transplantation (1)
- allosterism (1)
- allotype (1)
- alpha particles (1)
- altruism (1)
- altruistic compensation (1)
- altruistic punishment (1)
- aluminum copper alloys (1)
- amino acid analysis (1)
- amount of invested mental effort (1)
- amygdala (1)
- anaphylatoxins (1)
- anemia (1)
- aneurysm (1)
- anger (1)
- angiotensin II type 1 receptor (1)
- animal behaviour (1)
- anti-hiv agents (1)
- anti-infective vaccination (1)
- anti-inflammatory (1)
- anti-microbial activit (1)
- anti-retroviral agents (1)
- antibacterial activity (1)
- antibiotic resistance (1)
- anticoagulants (1)
- anticoagulation (1)
- antidepressant (1)
- antigenic recall (1)
- antioxidants (1)
- anuria (1)
- aphasia (1)
- approximation algorithm (1)
- aqua material (1)
- arachidonic acid metabolic network (1)
- arial fibrillation (1)
- arousal (1)
- arrhythmia (1)
- arterial hypotension (1)
- artificial diet (1)
- artificial intelligence (1)
- aspergillosis (1)
- assay (1)
- assessment of cognitive disorders/dementia (1)
- assortative mating (1)
- asymmetry (1)
- athletes (1)
- atomistic models (1)
- atrial fibrillation (1)
- attention bias (1)
- attention-deficit/hyperactivity disorder (1)
- atypical chemokine receptor 3 (1)
- autoantibodies (1)
- autoimmune antibodies (1)
- autoimmunity (1)
- autologous stem cell transplantation (1)
- automated driving (1)
- autosomal recessive non-synstromic hearing loss (1)
- axonal degeneration (1)
- bPAC (1)
- bSSFP (1)
- bZIPs (1)
- bacteria (1)
- bacterial genomics (1)
- bacterial transcription (1)
- bakanae (1)
- balanced steady state free precession (1)
- bank credit market (1)
- banking (1)
- bariatric surgery (1)
- barium titanate (1)
- basal ganglia (1)
- bee disease (1)
- beech forests (1)
- behavior (1)
- behavioral conditioning (1)
- behavioral rhythms (1)
- behavioral transition (1)
- behaviour (1)
- behaviour therapy (1)
- bi-compartmental (1)
- bi-compartmental knee arthoplasty (1)
- big data (1)
- bile (1)
- bioactive peptide (1)
- bioassays (1)
- bioconjugation (1)
- biodegradable implant (1)
- biodiversity (1)
- biodiversity estimation (1)
- biofabrication (1)
- biofeedback (1)
- bioinformatics (1)
- biokinetics (1)
- biological dosimetry (1)
- biological pest control (1)
- biologics (1)
- biomarker (1)
- biomedical applications (1)
- biomedical materials (1)
- biomedicine (1)
- bioprinting (1)
- bioreactor (1)
- bioresponsive (1)
- bipolar disorder (1)
- bird diversity (1)
- bitopic ligand (1)
- black woodpecker (1)
- blocking opsonization (1)
- blood (1)
- blood glucose regulation (1)
- blood-nerve barrier (1)
- body composition (1)
- bond activation (1)
- bond market (1)
- bone marrow niche (1)
- bone morphogenetic protein (1)
- boron chains (1)
- boronium cations (1)
- borylation (1)
- borylenes (1)
- brain metastasis (1)
- brain stimulation (1)
- brood rearing (1)
- building behavior (1)
- butyrophilin 3 (1)
- butyrophilins (1)
- cAMP (1)
- caffeine (1)
- calcium phosphate (1)
- calcium phosphate cement (1)
- cancer models (1)
- cancer risk (1)
- canonical microcircuits (1)
- capecitabine (1)
- capsaicin (1)
- carabid beetles (1)
- carbanion (1)
- carbene-stabilized nickel complexes (1)
- carbohydrates (1)
- carbon fiber reinforcement (1)
- cardiac device therapy (1)
- cardiac innervation imaging (1)
- cardiac nerve (1)
- cardiac surgery (1)
- cardiac sympathetic nerve system (1)
- cardiac sympathetic nervous system (1)
- cardiomyopathy (1)
- cardiovascular disease (1)
- cardiovascular morbidity (1)
- cardiovascular mortality (1)
- career self-management (1)
- careers (1)
- carmine (1)
- cartilage tissue engineering (1)
- catalysis (1)
- cataracts (1)
- ceftriaxone (1)
- cell membranes (1)
- cell wall channel (1)
- cell wall synthesis (1)
- cellular stress responses (1)
- cellular waveform (1)
- center of pressure (1)
- centrifugally casting (1)
- ceramides (1)
- chain structures (1)
- chalcogens (1)
- channel (1)
- chelates (1)
- chemical bonding (1)
- chemical communication (1)
- chemical ecology (1)
- chemotherapy (1)
- child (1)
- children/adults (1)
- chlamydia (1)
- chlamydia serine proteases (1)
- chlamydial inclusion (1)
- chlamydomonas reinhardtii (1)
- chlamyopsin (1)
- cholinergic system (1)
- chromatin (1)
- chronic constriction injury (1)
- chronophin (1)
- cicatricial pemphigoid (1)
- circadian clocks (1)
- cirrhosis (1)
- claudin-1 (1)
- click chemistry (1)
- climate change (1)
- climate control (1)
- climate scenarios (1)
- climate-change (1)
- co-delivery (1)
- coaptation line (1)
- cochlear nucleus (1)
- coevolution (1)
- cofilin (1)
- cognition (1)
- cognitive balance (1)
- cognitive dissonance (1)
- cognitive neuropsychology in dementia (1)
- coherence (1)
- cohesin (1)
- collagen-glycosaminoglycane matrix (CGM) (1)
- colon cancer (1)
- color vision (1)
- coloration (1)
- comparison (1)
- complement (1)
- complement system (1)
- complex (1)
- complexity (1)
- complications (1)
- compound eyes (1)
- compressive strength (1)
- computational modelling (1)
- conditional sex allocation (1)
- conditioned response (1)
- condyle pathomorphology (1)
- conical intersections (1)
- conjugated polymers (1)
- conjugative transposition (1)
- conjunctival defect (1)
- conjunctival hole (1)
- conjunctival repair (1)
- consciousness (1)
- content cluster (1)
- content-analysis (1)
- control-focused democracy (1)
- convergent star product (1)
- copeptin (1)
- copy number variation (1)
- corneal endothelium (1)
- corneal epithelium (1)
- corneal storage (1)
- coronary artery disease (1)
- correlative methods (1)
- costs (1)
- crop (1)
- crop diversity (1)
- cross-talk (1)
- cryostructuring (1)
- cryptochrome (1)
- crystal structure (1)
- crystallography (1)
- culturable command area (1)
- cyclic (alkyl)(amino) carbenes (1)
- cycloaddition (1)
- cylic GMP (1)
- cystic fibrosis (1)
- cytarabine dose (1)
- cytokine (1)
- cytokine secretion (1)
- cytotoxic T cells (1)
- dMyc (1)
- dSTORM (1)
- damage tolerant cement (1)
- darkfield imaging (1)
- data science (1)
- dead spot (1)
- dead tree (1)
- deadwood (1)
- debris-covered glaciers (1)
- decay (1)
- decision making (1)
- defense (1)
- deformation (1)
- deformation quantization (1)
- delayed cerebral infarction (1)
- democracy (1)
- density functional theory (1)
- deoxyribozymes (1)
- depolarization (1)
- depression (1)
- derivatives (1)
- dermatology (1)
- desymmetrization (1)
- diabetes (1)
- diabetes insipidus (1)
- diabetes mellitus (1)
- diabetic cardiomyopathy (1)
- diagnosis (1)
- diboranes (1)
- diboration (1)
- diboron (1)
- diboryne (1)
- dietary approaches to stop hypertension (1)
- differentiation (1)
- digitalization (1)
- dilatometer (1)
- direct anterior approach (1)
- disfluency (1)
- dispersal (1)
- distal radio-ulnar joint (1)
- distance measurement (1)
- distributary (1)
- distribution modulo one (1)
- dmP53 (1)
- dog microbiome (1)
- dogs (1)
- dorsal instrumentation (1)
- dosimetry (1)
- double-stranded (1)
- drainage tube (1)
- driver behavior (1)
- driver distraction (1)
- drug design (1)
- drug discovery (1)
- drug regulation (1)
- drug-induced immune hemolytic anemia (1)
- dry lung syndrome (1)
- dualsteric ligand (1)
- dyes (1)
- dynamic (1)
- eHealth (1)
- early neural precursors (1)
- early-life stress (1)
- eco-metabolomics (1)
- ecological intensification (1)
- ecology (1)
- economics (1)
- ecosystem services (1)
- educational psychology (1)
- educational tool (1)
- efficacy (1)
- egalitarian democracy (1)
- elderly (1)
- electrical and electronic engineering (1)
- electroencephalogram (1)
- electrometer (1)
- electrophiles (1)
- elektronisch angeregte Zustände (1)
- elution (1)
- emergence (1)
- emotion processing (1)
- emotion regulation (1)
- endocytosis (1)
- endometriosis (1)
- endophytic fungi (1)
- endophytische Pilze (1)
- endoreplication (1)
- endothelial cells (1)
- endovascular repair (1)
- energy metabolism (1)
- enoyl ACP reductase (1)
- entrepreneurship (1)
- entropy inequality (1)
- environmental degradation (1)
- enzyme activator (1)
- episcleral drainage device (1)
- erovalent diboron compounds (1)
- error estimate (1)
- erythrocyte adherence (1)
- evaluation (1)
- event (1)
- exaptation (1)
- exclusion criteria (1)
- exercise intervention (1)
- expansion (1)
- experience taking (1)
- expression (1)
- extended Kalman filter (1)
- extinction (1)
- extra cellular matrix (1)
- extremity trauma (1)
- eye tracking (1)
- eyetracking (1)
- fMRI (1)
- failure (1)
- fast decay (1)
- fatigue (1)
- fear behavior (1)
- fear conditioning (1)
- feral honey bees (1)
- fermentation (1)
- ferroptosis (1)
- fiber–matrix interaction (1)
- fibroblast growth factor (1)
- field testing (1)
- finite volume method (1)
- flagellate (1)
- flame test (1)
- fluorescent protein (1)
- fluorescent resonance energy transfer (1)
- flupyradifurone (1)
- flux distributions (1)
- flytrap (1)
- foliar fungal community (1)
- food security (1)
- foreign companies (1)
- fracture (1)
- fracture-associated vascular damage (1)
- free energy (1)
- frequency modulation (1)
- frontal cortex (1)
- frontotemporal dementia (1)
- frühe neurale Vorläufer (1)
- fullerene network (1)
- functional genetics (1)
- functional genomics (1)
- functional mitral regurgitation (1)
- functional near-infrared spectroscopy (1)
- functional regurgitation (1)
- functional training (1)
- fungal endophytes (1)
- fungal rhodopsins (1)
- fungicidal activity (1)
- fungus-farming insects (1)
- fungus-plant interaction (1)
- gametogenesis (1)
- gamma gamma channel (1)
- gender gap (1)
- gene expression (1)
- gene transfer (1)
- gene-expression (1)
- genome annotation (1)
- genomics (1)
- genotype (1)
- genotype-phenotype patterns (1)
- genotyping arrays (1)
- germinal center (1)
- germline mutations (1)
- glaciers (1)
- glaucoma drainage device (1)
- glioblastoma multiforme (1)
- glioma (1)
- glucose transporter (1)
- glycoprotein GPV (1)
- gp130 (1)
- granulocytes (1)
- graphs (1)
- grating interferometer (1)
- green light perception (1)
- green systems biology (1)
- ground dwelling predators (1)
- groundwater (1)
- group change (1)
- growth hormone deficiency (1)
- growth pattern (1)
- guanylyl cyclase-A (1)
- guidelines (1)
- gut microbiome (1)
- habitat requirements (1)
- habitat suitability model (HSM) (1)
- haematopoietic stem cells (1)
- half-life (1)
- half-sandwich complexes (1)
- halothane (1)
- hardness (1)
- health care payers (1)
- health promotion (1)
- healthy volunteers (1)
- heart failure (1)
- heart failure with mid-range ejection fraction (1)
- helminths (1)
- hemolysis (1)
- hemorrhagic stroke (1)
- hepatitis C virus (1)
- hereditary breast and ovarian cancer (1)
- hereditary hearing loss (1)
- hibernation (1)
- hierarchical matrix (1)
- high performance liquid chromatography (1)
- high-intensity interval training (1)
- hip (1)
- hippocampus (1)
- histones (1)
- history (1)
- hollow tree (1)
- homogeneous catalysis (1)
- honey bees (1)
- host screening (1)
- hub genes (1)
- human (1)
- human behaviour (1)
- human body weight (1)
- human brain microvascular endothelial cells (1)
- human herpesvirus 6 (1)
- human learning (1)
- human microbiome (1)
- human primary cells (1)
- human-automation interaction (1)
- human-computer interaction (1)
- humans (1)
- hyaluronic acid (1)
- hybrid molecules (1)
- hybrid pacemaker (1)
- hydrodynamic limits (1)
- hydrogel (1)
- hydrogenation (1)
- hydrological modelling (1)
- hydroxyephedrine (1)
- hypertension (1)
- hyphae (1)
- hypothalamus (1)
- icaADBC (1)
- identification (1)
- identity integration (1)
- illumina (1)
- image processing (1)
- imaginary quadratic field (1)
- imaging (1)
- iminoboranes (1)
- immersion (1)
- immune cells (1)
- immune reconstitution (1)
- immunoglobulin superfamily (1)
- immunosuppression (1)
- impact force (1)
- impervious surface areas (1)
- implant fit (1)
- implant positioning (1)
- implicit motives (1)
- impulse control disorders (1)
- in situ analysis (1)
- in situ forest monitoring (1)
- in vitro contracture test (1)
- in vitro selection (1)
- in-vitro (1)
- inactivity (1)
- index analysis (1)
- individualised modular treatment programme (1)
- individualized training (1)
- indole-3-acetic acid (IAA) (1)
- indoxyl sulfate (1)
- infinium HumanOmni1-Quad (1)
- inflammation mediators (1)
- inflammatory pain (1)
- information technology (1)
- injectable protein formulation (1)
- injury prevention (1)
- innate immune response (1)
- insect vision (1)
- insect-fungus mutualism (1)
- insecticides (1)
- insertion-site deep sequencing (1)
- insulin receptor (1)
- insulin-like growth factor 1 receptor (1)
- integrated optics (1)
- inter-rater reliability (1)
- interest rate risk (1)
- interface control (1)
- intergenerational contraction (1)
- intergroup bias (1)
- internet of things (1)
- interobserver (1)
- interreader (1)
- intervalence charge transfer (1)
- intervention (1)
- invasive disease (1)
- inventory (1)
- inverse parameterization (1)
- ionizing radiation (1)
- irrigation pricing (1)
- ischemia-reperfusion injury (1)
- ischemic (1)
- ischemic stroke (1)
- islets of Langerhans (1)
- isomers (1)
- jasmonate (1)
- joint aspiration (1)
- juvenile idiopathic arthritis (1)
- ketogenic diet (1)
- ketone bodies (1)
- killing (1)
- kinect (1)
- kinetic description of gases (1)
- knee (1)
- knee alignment (1)
- knee osteoarthritis (1)
- laboratory measurements (1)
- lambdoid prophage (1)
- laminin 332 (1)
- land surface temperature (1)
- landscape heterogeneity (1)
- laparoscopic right colectomy (1)
- large Stokes shift (1)
- laser scanner (1)
- laserscanner (1)
- latency (1)
- leaf-cutting ants (1)
- leaflet (1)
- learning (1)
- leukocytes (1)
- level of evidence: IV (1)
- levosimendan (1)
- libertarian democracy (1)
- lifetime spectroscopy (1)
- limbic system (1)
- linked open data (1)
- lipid bilayer membrane (1)
- lipid rafts (1)
- lipochitinoligosaccharides (1)
- literature review (1)
- liver diseases (1)
- liver oligometastases (1)
- loanable funds theory (1)
- localization microscopy (1)
- locus coeruleus (1)
- locus coerulus (1)
- low Mach number (1)
- low-cost spectrometer (1)
- low-valent main group chemistry (1)
- lymph nodes (1)
- lysosomal storage disorder (1)
- lytic replication (1)
- mHealth (1)
- mRNA (1)
- macrophages (1)
- macrophages immunobiology (1)
- magnesium (1)
- magnetic resonance imaging (1)
- main-group chemistry (1)
- major depression (1)
- major depressive disorder (1)
- malignant hyperthermia (1)
- mapping (1)
- market entry decisions (1)
- mass (1)
- mass casualties (1)
- mass spectrometry (1)
- master sex-determining gene (1)
- mate recognition (1)
- matrix metalloproteases (1)
- measurement of democracy (1)
- medaka (1)
- medical (1)
- medical research (1)
- medicinal plants (1)
- medicine authentication tools (1)
- melt electrospinning (1)
- melt electrowriting (1)
- membrane potential (1)
- membrane proteins (1)
- meningitis (1)
- mental disorders (1)
- mental representation (1)
- metabolic modeling (1)
- metabolic pathways (1)
- metabolic profile (1)
- metabolism (1)
- metacognitive control (1)
- metacognitive judgments (1)
- metacognitive monitoring (1)
- metacomprehension (1)
- metagenomics (1)
- metallosupramolecular chemistry (1)
- mevalonate pathway (1)
- miR-146a (1)
- miR-193a (1)
- miR-26 (1)
- miRNA Biogenesis (1)
- micro pattern gaseous detectors (1)
- micro-ionization chambers (1)
- microRNA (1)
- microbiome (1)
- microbot (1)
- microdialysis (1)
- microenvironment (1)
- micromegas detectors (1)
- micronuclei (1)
- microrna (1)
- microswimmer (1)
- mild (1)
- milk proteins (1)
- mineralization (1)
- minimal invasive surgery (1)
- minimally invasive (1)
- mitigation strategies (1)
- mitochondrial morphology (1)
- mitral valve (1)
- mixed hearing loss (1)
- mobile apps (1)
- model (1)
- model organism (1)
- modeling (1)
- moderate sedation (1)
- module (1)
- molecular docking (1)
- molecular dynamics (1)
- molecular radiotherapy (1)
- monetary economy (1)
- monitoring (1)
- monoamine oxidase A (1)
- monocyte-platelet aggregates (1)
- mood (1)
- mood induction (1)
- mortality (1)
- motility (1)
- mouse (1)
- mouse microbiome (1)
- mouse platelets (1)
- movement ecology (1)
- moycardial sympathetic innervation (1)
- mucous membrane pemphigoid (1)
- multi-fluid mixture (1)
- multi-source forest health monitoring network (1)
- multidrug-resistant bacteria (1)
- multigene-array (1)
- multigrid (1)
- multimodal fusion (1)
- multimodal interface (1)
- multiple bonds (1)
- multiplicity of infection (1)
- muon spectrometer (1)
- muscarinic receptors (1)
- muscle (1)
- mutualism (1)
- mycobacteria (1)
- mycolic acid (1)
- myocardial nerve (1)
- myocardial perfusion imaging (1)
- myocarditis (1)
- nanostructured (1)
- nanowires (1)
- narratives (1)
- natriuretic peptides (1)
- natural interfaces (1)
- natural variation (1)
- navigation (1)
- ncRNA (1)
- near-infrared spectroscopy (1)
- neoepitope-derived peptides (1)
- neonatal renal failure (1)
- nest climate (1)
- net testing effect (1)
- network (1)
- networking (1)
- neural circuits (1)
- neural stem cells (1)
- neuroepithelial progenitors (1)
- neuroepitheliale Vorläufer (1)
- neurogenesis (1)
- neuroinflammation (1)
- neuronal dysfunction (1)
- neuronal nitric oxide synthase (1)
- neuronale Stickstoffmonoxidsynthase (1)
- neuropathic pain (1)
- neuropeptide (1)
- neuroprotection (1)
- neuroprotective (1)
- neuropsychiatric disorders (1)
- neuropsychiatrische Störungen (1)
- neutral sphingomyelinase 2 (1)
- neutrophils (1)
- nicht-viraler Gentransfer (1)
- nicotinic receptors (1)
- nine-banded armadillo (1)
- non-coding RNA (1)
- non-nucleoside reverse transcriptase inhibitors (1)
- non-responder (1)
- nonadiabatic dynamics (1)
- norepinephrine (1)
- nucleosides (1)
- nuclesosome positioning (1)
- nucleus accumbens (1)
- null hypothesis testing (1)
- nutrients (1)
- object-based image analysis (1)
- objective assessment (1)
- oesophagogastroduodenoscopy (1)
- olfaction (1)
- oligo-recurrence (1)
- oligohydramnios sequence (1)
- oligometastases (1)
- ologen implant (1)
- omega-3 fatty acids (1)
- optical remote sensing (1)
- optical spectroscopy (1)
- optimal control (1)
- optimal control problem (1)
- oral anticancer drugs (1)
- organic electronics (1)
- organometallic chemistry (1)
- osmotic stimulation (1)
- osteochondral implant (1)
- outcome (1)
- outpatients (1)
- ovarian cancer (1)
- ovary (1)
- oxidierte Phospholipide (1)
- p-cresyl sulfate (1)
- p-value (1)
- pacemaker neuron (1)
- pancreatic carcinoma (1)
- paraganglioma (1)
- parasite (1)
- parent training (1)
- partial differential equation (1)
- partial integro-differential equations (1)
- partially-supervised (1)
- patch-clamp (1)
- pathogen vector (1)
- patient-doctor-relationship (1)
- patient-specific (1)
- pea aphid (1)
- peak oxygen uptake (1)
- pediatric patients (1)
- peer review (1)
- pelvic trauma (1)
- pemphigoid (1)
- pemphigus (1)
- penetrance (1)
- peptidase inhibitor PI15 (1)
- peptide receptor (1)
- peptide receptor radionuclide therapy (1)
- peptide synthesis (1)
- perception (1)
- percutaneous mitral valve repair (1)
- periodization (1)
- peripheral nervous system (1)
- pesticide (1)
- phaeochromocytoma (1)
- phagocytosis (1)
- pharmacology (1)
- phase IV (1)
- phase contrast imaging (1)
- phase stepping (1)
- phenological response (1)
- phenological shift (1)
- phenols (1)
- phenotype (1)
- pheochromocytoma (1)
- phosphine ligands (1)
- phosphoantigens (1)
- phospholipase D (1)
- photodynamics (1)
- photoelectron spectroscopy (1)
- photoreceptor (1)
- phototransduction (1)
- phototrophic growth (1)
- phylogenomics (1)
- physical fitness (1)
- phytochemicals (1)
- pi-conjugation (1)
- picture comprehension (1)
- pig microbiome (1)
- pigment epithelium derived factor (1)
- pigment pattern (1)
- pigment-dispersing factor (1)
- pigs (1)
- pilot-point-approach (1)
- placental mammals (1)
- plant-insect-microbe interactions (1)
- plasma cells (1)
- plasma modelling (1)
- plasmablasts (1)
- plasmonics (1)
- platelet (1)
- platelet biogenesis (1)
- polarity (1)
- polarization (1)
- policy (1)
- politics (1)
- polity (1)
- pollen (1)
- pollination (1)
- pollinator interactions (1)
- polyatomic molecules (1)
- polymer processing (1)
- polymorphonuclear neutrophils (1)
- population density (1)
- porin (1)
- pose estimation (1)
- potassium (1)
- potter sequence (1)
- power training (1)
- precipitates (1)
- predictor analysis (1)
- prejudice (1)
- premutation (1)
- presence (1)
- pressure sensor (1)
- preterm (1)
- prevalence (1)
- prevention (1)
- prezygotic reproductive isolation (1)
- primary polydipsia (1)
- prime number (1)
- probability of scoring a goal (1)
- probiotica (1)
- procedural fusion methods (1)
- processing speed (1)
- profile of democracy (1)
- progenitors (1)
- prognosis (1)
- program (1)
- proliferation (1)
- propionic acid (1)
- prospective (1)
- prospective study (1)
- prostate-specific membrane antigen (1)
- prostate-specific membrane antigen (PSMA) (1)
- protease-sensitive release (1)
- protein and mRNA expression (1)
- protein hydrolysis (1)
- protein maturation (1)
- protein modification (1)
- protein therapeutics (1)
- proteins (1)
- proteolipid protein (1)
- proton-proton collision (1)
- proton-proton collisions (1)
- psychologists (1)
- psychometrics (1)
- public health medicine (1)
- pulse simulation (1)
- pyrrolidine carboxamides (1)
- quality assurance (1)
- quality evaluation (1)
- quality indicators (1)
- quality of democracy (1)
- quantification (1)
- quantitative analysis (1)
- quantitative imaging (1)
- question format (1)
- questionnaire (1)
- rac1 inhibitors (1)
- radiation effects (1)
- radiation response (1)
- radionuclide therapy (1)
- radium (1)
- random forest (1)
- randomised controlled trial (1)
- ras (1)
- rat hippocampal neurons (1)
- reaction time (1)
- rearrangement (1)
- recategorization (1)
- recombinant DNA (1)
- reconstruction (1)
- recurrence (1)
- redox reactions (1)
- regenerative medicine (1)
- regression analysis (1)
- regularization (1)
- regulatory T cells (1)
- relative dosimetry (1)
- remote sensing (1)
- renal failure (1)
- renal tubular dysgenesis (1)
- renin-angiotensin system (1)
- repeated exercise (1)
- repeated sprint running (1)
- reporting and data system (1)
- reporting and data systems (1)
- rescue mission (1)
- research software (1)
- resistive micromegas (1)
- resource mapping (1)
- resource suitability (1)
- respiratory distress (1)
- retinal development (1)
- retinal pigment epithelium (1)
- retrieval practice (1)
- reverse transcriptase inhibitors (1)
- revision (1)
- rice–plant infection (1)
- ring-barking (1)
- risk assessment (1)
- robotic (1)
- rodent model (1)
- rotator cuff (1)
- rule discovery (1)
- ruthenium complexes (1)
- salivary alpha-amylase (1)
- salivary gland (1)
- sampling method (1)
- sarcoidosis (1)
- scaffold (1)
- scapula (1)
- scatter radiation (1)
- scientists (1)
- seahorse (1)
- search (1)
- second-tier cities (1)
- secretion (1)
- sedentary lifestyle (1)
- segmentation (1)
- selective retina therapy (1)
- selectivity (1)
- self-assembly (1)
- self-concept (1)
- self-reactivity (1)
- semantic fusion (1)
- semantic web (1)
- semiconductor devices (1)
- senescence (1)
- sensitivity analysis (1)
- sensorineural hearing loss (1)
- sensory cues (1)
- sensory neuropathy (1)
- sepsis (1)
- sex chromosomes (1)
- sex differentiation (1)
- sexual conflict (1)
- sexually antagonistic genes (1)
- signal integration (1)
- signal processing (1)
- signal transduction (1)
- significance testing (1)
- signs and symptoms (1)
- silk fibroin scaffolds (1)
- simulation (1)
- single photon emission computed tomography: sympathetic nerve (1)
- single top quark (1)
- single-wall carbon nanotubes (1)
- six-minute walk test (1)
- skeletal dysplasia (1)
- skeletal muscle (1)
- skin conduction response (1)
- small-molecule activation (1)
- smart soccer boot (1)
- smartwatch (1)
- snags (1)
- social bees (1)
- social capital (1)
- social comparison (1)
- social identification (1)
- social interaction (1)
- soil and water conservation (1)
- soil erosion (1)
- somatostatin receptor (SSTR) (1)
- somatostatin receptors (1)
- spacer (1)
- speciation (1)
- species interactions (1)
- species richness (1)
- spectral sensitivity (1)
- specular reflective (1)
- spiders (1)
- spin-orbitronics (1)
- spine trauma (1)
- spintronic (1)
- splicing (1)
- standardization (1)
- standing deadwood (1)
- staphylinid beetles (1)
- state-based model (1)
- statins (1)
- statistical significance (1)
- steady-state dendritic cells (1)
- stem cells (1)
- stereotactic body radiotherapy (1)
- storage vesicle turnover (1)
- store-operated calcium entry (1)
- streptozotocin (1)
- structure elucidation (1)
- structure-activity relationship (1)
- students (1)
- study system (1)
- stx-Phagen (1)
- stx-phages (1)
- subarachnoid hemorrhage (1)
- subphenotypes (1)
- substandard and falsified medicines (1)
- substantia nigra (1)
- super-resolution microscopy (1)
- supervisors (1)
- support vector machines (1)
- supramolecular chemistry (1)
- surface reflectances (1)
- surgical trauma room (1)
- surveillance (1)
- survey (1)
- sustainability (1)
- sustainable irrigation system (1)
- swarming (1)
- sweat osmolality (1)
- sweat secretion rate (1)
- sweet spot (1)
- symmetries (1)
- sympathetic nervous system (1)
- synapse (1)
- synaptic proteins (1)
- synaptic vesicles (1)
- sync-oligometastases (1)
- synthetic methodology (1)
- systemic micro-inflammation oxidative stress (1)
- tDCS (1)
- tVNS (1)
- tanzania (1)
- task complexity (1)
- taste (1)
- teleost fish (1)
- telephone-assisted self-help (1)
- temperate zones (1)
- temporal organization (1)
- tenting (1)
- teriflunomide (1)
- terror attack (1)
- testing effect (1)
- testis (1)
- text comprehension (1)
- the microtubule-organizing center (1)
- theme park (1)
- theoretical calculations (1)
- therapeutic approach (1)
- therapeutic vaccines (1)
- thermal camera (1)
- thermal stresses (1)
- thermoregulation (1)
- three-dimensional echocardiography (1)
- three-toed woodpecker (Picoides tridactylus) (1)
- thyroid stimulating hormone receptor (1)
- tight junction protein (1)
- tight junctions (1)
- tikhonov regularization (1)
- timing (1)
- tissue culture (1)
- tolerogenic dendritic cells (1)
- topological insulator (1)
- topological insulators (1)
- topological superconductor (1)
- total hip arthroplasty (1)
- toxicology (1)
- track and trace (1)
- trade-off (1)
- trafficking pathways (1)
- trail making test (1)
- training curriculum (1)
- training intensity (1)
- trans-Golgi network (1)
- transcriptional profiling (1)
- transcriptional rewiring (1)
- transcriptional termination (1)
- transcriptome (1)
- transcriptomics (1)
- transgluteal approach (1)
- transient absorption spectroscopy (1)
- transition metal complex (1)
- translational research (1)
- transparent (1)
- transport coefficients (1)
- transportation (1)
- treated metastases control (1)
- tree cavity (1)
- triple-negative breast cancer (1)
- trypanobot (1)
- trypanosoma (1)
- tsetse (1)
- tumor (1)
- tumor infiltrating lymphocytes (1)
- two-color microscopy (1)
- two-component system (1)
- two-dimensional electron gas (1)
- type 2 (1)
- type II esophageal achalasia (1)
- tyrosine recombinase (1)
- uPA (1)
- ubiquitin (1)
- ulnar-shortening osteotomy (1)
- ultrafast photochemistry (1)
- ultrasound strain elastography (1)
- unilateral ureteral obstruction (1)
- university teaching (1)
- valence (1)
- valsartan (1)
- value of water (1)
- vancomycin (1)
- variational fracture (1)
- varroa (1)
- vascular endothelial growth factor (1)
- vaskuläre glatte Muskelzelle (1)
- vasopressin (1)
- vector-like quarks (1)
- vena contracta area (1)
- ventromedial prefrontal cortex (1)
- venus (1)
- vertigo (1)
- very high energy (1)
- virus-infection (1)
- viruses (1)
- visual complexity (1)
- visual pigments (1)
- visuomotor coordination (1)
- vitamin metabolism (1)
- volumetric MRI (1)
- volvox carteri (1)
- vorticity preserving (1)
- waggle dance (1)
- water fat separation (1)
- water oxidation (1)
- wearable (1)
- wearable technology (1)
- web-based apps (1)
- weighted gene co-expression network (1)
- well posedness (1)
- whole exome sequencing (1)
- whole-blood infection assay (1)
- whole-blood model (1)
- wild bees (1)
- wild honey bees (1)
- work behavior (1)
- work capacity evaluation (1)
- working memory (1)
- workplace (1)
- world health organization (1)
- xenobiotic metabolism (1)
- ylides (1)
- zebrafish (1)
- zeitgeber (1)
- zeitliche Organisation (1)
- Ökonometrisches Modell (1)
- Übergangsmetall (1)
- Übergangsmetallkomplexe (1)
- α-emitter (1)
- β-Hydroxybutyrate (1)
- β-cells (1)
- β3 adrenergic receptor (ADRB3) (1)
- β8-β9 loop (1)
- γ-H2AX (1)
Institute
- Physikalisches Institut (82)
- Theodor-Boveri-Institut für Biowissenschaften (75)
- Graduate School of Life Sciences (64)
- Klinik und Poliklinik für Nuklearmedizin (34)
- Institut für Anorganische Chemie (22)
- Institut für Psychologie (20)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (17)
- Institut für Informatik (15)
- Medizinische Klinik und Poliklinik II (15)
- Institut für Mathematik (14)
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (15)
- Johns Hopkins University School of Medicine (5)
- Department of Biomedical Imaging, National Cerebral and Cardiovascular Research Center, Suita, Japan (2)
- Division of Medical Technology and Science, Department of Medical Physics and Engineering, Course of Health Science, Osaka University Graduate School of Medicine, Suita Japan (2)
- Institut for Molecular Biology and CMBI, Department of Genomics, Stem Cell Biology and Regenerative Medicine, Leopold-Franzens-University Innsbruck, Innsbruck, Austria (2)
- International Max Planck Research School Molecular Biology, University of Göttingen, Germany (2)
- Johns Hopkins School of Medicine, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD, USA (2)
- ACC GmbH Analytical Clinical Concepts (1)
- BMBF (1)
- Boehringer Ingelheim Pharma GmbH & Co. KG (1)
ResearcherID
- J-8841-2015 (1)
The aim of this thesis was the development of a multifunctional coating system for AuNPs based on thioether polymers, providing both excellent colloidal stability and a variable possibility to introduce functionalities for biological applications.
First, two thioether-polymer systems were synthesised as a systematic investigation into colloidal stabilisation efficacy. Besides commonly used monovalent poly(ethylene glycol) (PEG-SR), its structural analogue linear poly(glycidol) (PG-SR) bearing multiple statistically distributed thioether moieties along the backbone was synthesised. Additionally, respective thiol analogues (PEG-SH and PG-SH) were produced and applied as reference.
Successive modification of varyingly large AuNPs with aforementioned thiol- and thioether-polymers was performed via ligand exchange reaction on citrate stabilised AuNPs. An increased stabilisation efficacy of both thioether-polymers against biological and physiological conditions, as well as against freeze-drying compared to thiol analogues was determined.
Based on the excellent colloidal stabilisation efficacy and multi-functionalisability of thioether-PG, a plethora of functional groups, such as charged groups, hydrophilic/hydrophobic chains, as well as bio-active moieties namely diazirine and biotin was introduced to the AuNP surface. Moreover, the generic and covalent binding of diazirine-modified PG-SR with biomolecules including peptides and proteins was thoroughly demonstrated.
Lastly, diverse applicability and bioactivity of aforementioned modified particles in various studies was displayed, once more verifying the introduction of functionalities. On the one hand the electrostatic interaction of charged AuNPs with hydrogels based on hyaluronic acid was applied to tune the release kinetics of particles from three-dimensional scaffolds. On the other hand the strong complexation of siRNA onto two positively charged AuNPs was proven. The amount of siRNA payload was tuneable by varying the surface charge, ionic strength of the surrounding medium and the N/P ratio. Moreover, the biological activity and selectivity of the biotin-streptavidin conjugation was verified with respectively functionalised particles in controlled agglomeration test and in laser-triggered cell elimination experiments. In the latter, streptavidin-functionalised AuNPs resulted in excellent depletion of biotinylated cells whereas unfunctionalised control particles failed, excluding unspecific binding of these particles to the cell surface.
Cadherin-13 (CDH13) is an atypical member of the cadherin superfamily, a group of membrane proteins mediating calcium-dependent cellular adhesion. Although CDH13 shows the classical extracellular cadherin structure, the typical transmembrane and cytoplasmic domains are absent. Instead, CDH13 is attached to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor. These findings and many studies from different fields suggest that CDH13 also plays a role as a cellular receptor. Interestingly, many genome-wide association studies (GWAS) have found CDH13 as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and other neurodevelopmental disorders. In previous work from our research group, strong expression of Cdh13 mRNA in interneurons of the hippocampal stratum oriens (SO) was detected. Therefore, double-immunofluorescence studies were used to evaluate the degree of co-expression of CDH13 with seven markers of GABAergic interneuron subtypes. For this purpose, murine brains were double stained against CDH13 and the respective marker and the degree of colocalization in the SO of the hippocampus was assessed. Based on the result of this immunofluorescence study, quantitative differences in interneuron subtypes of the SO between Cdh13 knockout (ko), heterozygote (het) and wildtype (wt) mice were investigated in this dissertation using stereological methods. In addition, genotype- dependent differences in the expression of genes involved in GABAergic and glutamatergic neurotransmission were analyzed by quantitative real-time PCR (qRT-PCR). Primers targeting different GABA receptor subunits, vesicular GABA and glutamate transporter, GABA synthesizing enzymes and their interaction partners were used for this purpose.
The results of the stereological quantification of the interneuron subtypes show no significant differences in cell number, cell density or volume of the SO between Cdh13 ko, het and wt mice. On the other hand, qRT-PCR results indicate significant differences in the expression of tropomyosin-related kinase B gene (TrkB), which encodes the receptor of brain-derived neurotrophic factor (BDNF), a regulator of GABAergic neurons. This finding supports a role for CDH13 in the regulation of BDNF signaling in the hippocampus.
Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
(2018)
Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others, activates G-protein coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3-adrenergic receptor (ADRB3) in a CCAAT/enhancerbinding protein (C/EBP)-α and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, loss of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.
This paper proposes a 3-D local pose estimation system for a small Unmanned Aerial Vehicle (UAV) with a weight limit of 200 g and a very small footprint of 10 cm×10cm. The system is realized by fusing 3-D position estimations from an Ultra-Wide Band (UWB) transceiver network with Inertial Measurement Unit (IMU) sensor data and data from a barometric pressure sensor. The 3-D position from the UWB network is estimated using Multi-Dimensional Scaling (MDS) and range measurements between the transceivers. The range measurements are obtained using Double-Sided Two-Way Ranging (DS-TWR), thus eliminating the need for an additional clock synchronization mechanism. The sensor fusion is accomplished using a loosely coupled Extended Kalman Filter (EKF) architecture. Extensive evaluation of the proposed system shows that a position accuracy with a Root-Mean-Square Error (RMSE) of 0.20cm can be obtained. The orientation angle can be estimated with an RMSE of 1.93°.
Background:
ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM.
Patients and methods:
ATF5 mRNA was extracted from frozen samples of patients’ GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry.
Results:
ATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients’ age (r=0.339, P=0.028) and inversely with Ki67-staining (r=-0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan–Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t<12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084).
Conclusion:
ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.
Chronic Obstructive Pulmonary Disease (COPD) exacerbations are a considerable reason for increased morbidity and mortality in patients. Infections with influenza virus (H1N1), respiratory syncytial virus (RSV) or nontypeable Haemophilus influenzae (NTHi) are important triggers of exacerbations. To date, no treatments are available which can stop the progression of COPD. Novel approaches are urgently needed. Pre-clinical models of the disease are crucial for the development of novel therapeutic options.
In order to establish pre-clinical models which mimic aspects of human COPD exacerbations, mice were exposed to cigarette smoke (CS) and additionally infected with H1N1, RSV and/or NTHi. Clinically relevant treatments such as the corticosteroids Fluticasone propionate and Dexamethasone, the phosphodiesterase-4 (PDE-4) inhibitor Roflumilast and the long-acting muscarinic receptor antagonist Tiotropium were tested in the established models. Furthermore, a novel treatment approach using antibodies (Abs) directed against IL-1α, IL-1β or IL-1R1 was examined in the established CS/H1N1 model. Levels of IFN-γ, IL-1β, IL-2, IL-6, KC, TNF-α, RANTES, IL-17, MCP-1, MIP 1α and MIP-1β were measured in lung homogenate. Numbers of total cells, neutrophils and macrophages were assessed in bronchoalveolar lavage (BAL) fluid. Hematoxylin- and eosin- (H&E-) stained lung slices were analyzed to detect pathological changes. Quantitative polymerase-chain-reaction (qPCR) was used to investigate gene expression of ICAM-1 and MUC5 A/C. The viral/bacterial load was investigated in lung homogenate or BAL fluid. In addition to the in vivo studies, the effects of the above mentioned treatments were investigated in vitro in H1N1, RSV or NTHi-infected (primary) human bronchial epithelial cells using submerged or air-liquid-interface (ALI) cell culture systems.
Four pre-clinical models (CS/H1N1, CS/RSV, CS/NTHi, CS/H1N1/NTHi) were established depicting clinically relevant aspects of COPD exacerbations such as increased inflammatory cells and cytokines in the airways and impaired lung function.
In the CS/H1N1 model, Tiotropium improved lung function and was superior in reducing inflammation in comparison to Fluticasone or Roflumilast. Moreover, Fluticasone increased the loss of body-weight, levels of IL-6, KC and TNF-α and worsened lung function. In CS/RSV-exposed mice Tiotropium but not Fluticasone or Roflumilast treatment reduced neutrophil numbers and IL-6 and TNF α levels in the lung. The viral load of H1N1 and RSV was significantly elevated in CS/virus-exposed mice and NCI-H292 cells after Fluticasone and Dexamethasone treatment. The results from these studies demonstrate that Tiotropium has anti-inflammatory effects on CS/virus-induced inflammation and might help to explain the observed reduction of exacerbation rates in Tiotropium-treated COPD patients. Furthermore, the findings from this work indicate that treatment with Fluticasone or Dexamethasone might not be beneficial to reduce inflammation in the airways of COPD patients and supports clinical studies that link treatment with corticosteroids to an increased risk for pneumonia.
Testing of anti-IL-1α, anti-IL-1β or anti-IL-1R1 Abs in the CS/H1N1 model suggests that, in line with clinical data, antagonization of IL-1β is not sufficient to reduce pulmonary inflammation and indicates a predominant role of IL-1α in CS/virus-induced airway inflammation. In line with the in vivo findings, anti-IL-1α but not anti-IL-1β Abs reduced levels of TNF-α and IL-6 in H1N1-infected primary human bronchial epithelial ALI cell culture. Blocking the IL-1R1 provided significant inhibitory effects on inflammatory cells in vivo but was inferior compared to inhibiting both its soluble ligands IL-1α and IL-1β. Concomitant usage of Abs against IL-1α/IL-1β revealed strong effects and reduced total cells, neutrophils and macrophages. Additionally, levels of KC, IL-6, TNF-α, MCP-1, MIP-1α and MIP-1β were significantly reduced and ICAM-1 mRNA expression was attenuated. These results suggest that combined inhibition of IL-1α/IL-1β might be beneficial to reduce inflammation and exacerbations in COPD patients. Moreover, combined targeting of both IL-1α/IL-1β might be more efficient compared to inhibition of the IL-1R1.
As in the CS/virus models, corticosteroid treatment failed to reduce inflammatory cells in the CS/NTHi and CS/H1N1/NTHi models, increased the loss of body-weight and the bacterial load. Furthermore, Roflumilast administration had no significant effects on cell counts or cytokines. However, it improved compliance in the CS/NTHi model. Treatment with Azithromycin reduced the bacterial load in the CS/NTHi model and reduced numbers of total cells, neutrophils, macrophages and levels of KC and TNF-α in the CS/H1N1/NTHi model.
In conclusion, the established CS/H1N1, CS/RSV, CS/NTHi, CS/H1N1/NTHi models depict clinically relevant aspects of human COPD exacerbations in mice and provide the opportunity to investigate underlying disease mechanisms and to test novel therapies.
The analysis of how a general change, an economic shock and a modified institutional framework condition affect the HRM process, provide the motivation for the present dissertation. Thereby, the dissertation concentrates on certain areas of the HRM process, namely compensation, further training and retention, as well as changes and challenges that have been subject to a high degree of public interest in recent years. It consists of three essays, all self-contained and independently readable.
The first essay investigates whether it is possible to keep employees in the establishment by offering further training measures. Therefore, this essay uses a comparison group approach and compares only training participants with those employees who had been selected by the employer to participate in training but had to cancel it for exogenous reasons. From a methodological point of view, by means of Fixed Effects and Diff GMM estimations, the essay also controls for time-variant and invariant unobserved heterogeneity as well as endogeneity of training participation. By simultaneously considering the components from the human capital theory as well as the monopsony theory, the essay shows that portability of general human capital contents and visibility of training, induced by training certificates, independently reduce the retention effect of training. The negative effect is much stronger if training is certified by external institutions and therefore credible. In addition, the effects of visibility and portability are distinct and thus also reduce the retention effect of training separately. However, the total effect of portable, visible and credible training on retention is still positive. Therefore, further training appears to be an effective measure to keep the qualified employees in the establishment.
Second, the attention is on a short-term unpredictable economic shock: Essay 2 analyses whether and to what extent the Great Recession in 2008 and 2009 has had an impact on the individual training behaviour in establishments. From a theoretical point of view, the effects of the crisis on establishments' training activities are ambiguous. On the one hand, the reduced opportunity costs of training argue more in favour of an increase in further training. On the other hand, economic theory suggests decreasing training activities in the crisis because of reduced financial resources, uncertain future prospects, and, therefore, unclear returns on training. Using Difference-in-Differences analyses, this essay avoids endogeneity problems caused by unobservable third factors. The Great Recession in 2008 and 2009 can be seen as an exogenous and time-limited shock: this quasi-experimental setting helps to reveal the causal impact of the crisis on the training intensity and the number of training measures. Results indicate that there is a direct effect of the crisis on individual training activities in 2009 and 2010. This effect is stronger for unskilled employees than for employees with higher skill levels. Furthermore, the negative effect sets in with a time lag and lasts until the year 2010 (although there is already an economic upswing). Numerous analyses are used to check additional heterogeneities in training activities for other employee groups.
Among others, particularly the area of executive compensation was affected by the economic crisis and the ensuing regulations in institutional framework conditions. The third essay of this dissertation deals with the question whether these changes had an impact on the compensation level and structure of executive board members. The focus is on the extent to which executive compensation is converging within and between different exchange segments in Germany. Based on a sample of CEOs and non-CEOs of German DAX and MDAX establishments, the evolution of executive compensation levels and structures (i.e., fractions of base pay, short- and long-term incentives) are examined during the period from 2006 until 2012. The results of descriptive as well as multivariate Fixed Effects analyses indicate isomorphism of both, pay levels and pay structures within (intra-segment-convergence) and between (inter-segment convergence) stock exchange segments especially for CEOs. However, for the other members of the management board (non-CEOs), there is only a convergence of the compensation structure within the segments. The results do not indicate either intra- or inter-segment convergence of salary levels.
Altogether, the three essays of this dissertation provide a selection of the current changes and challenges that HRM has to deal with. From a methodological perspective, all three essays use different applied econometric estimation strategies. In order to eliminate estimation problems caused by time-invariant and variant unobserved heterogeneity and endogeneity, Fixed Effects, Diff GMM as well as Difference-in-Differences approaches are applied. In addition, sample selection, research design as well as identification strategy attempts to avoid estimation bias. The first two essays are based on a linked-employer-employee panel data set and adopt a personnel economic perspective. The third essay uses establishment-level data and is based on institutional theory. The first essay was written in cooperation with Thomas Zwick and the third essay was written in cooperation with Nathalie Haidegger-Rieß and Robert Wagner.
Bacterial functional membrane microdomains (FMMs) are membrane platforms that resemble lipid rafts of eukaryotic cells in certain functional and structural aspects. Lipid rafts are nanometer-sized, dynamic clusters of proteins and lipids in eukaryotic cell membranes that serve as signaling hubs and assembling platforms. Yet, studying these structures can often be hampered by the complexity of a eukaryotic cell. Thus, the analogous structures of prokaryotes are an attractive model to study molecular traits of this type of membrane organization.
Similar to eukaryotic lipid rafts, the bacterial FMMs are comprised of polyisoprenoid lipids, scaffold proteins and a distinct set of membrane proteins, involved in signaling or secretion. Investigating bacterial FMMs not only contributes to the understanding of the physiological importance of FMMs in bacteria, but also helps to elucidate general principles of rafts beyond prokaryotes.
In this work, a bacterial model organism was used to investigate effects of synthetic overproduction of the raft scaffolding proteins on bacterial physiology. This overexpression causes an unusual stabilization of the FMM-harbored protease FtsH and therefore the proteolytic targets of FtsH are not correctly regulated. Developmental defects and aberrances in shape are the consequence, which in turn negatively affects cell physiology. These findings may be adapted to better understand lipid raft processes in humans, where flotillin upregulation is detected along with development of neurological diseases.
Moreover, it was aimed at understanding the FMM-proteome of the human pathogen Staphylococcus aureus. An in-depth quantitative mass-spectrometry analysis reveals adaption of the protein cargo during different conditions, while maintaining a distinct set of core FMM proteins. As a case study, the assembly of the type VII secretion system was shown to be dependent on FMM integrity and more specifically on the activity of the FMM-scaffold flotillin. This secretion system is important for the virulence of this pathogen and its secretion efficiency can be targeted by small molecules that inhibit flotillin activity. This opens new venues for non-conventional antimicrobial compounds to treat staphylococcal infections.
Myocardial B-cell infiltration after LAD occlusion in mice is driven by CXCL13
After myocardial infarction, the immune system is activated and regulates wound healing and remodeling processes in the heart.
While the role of T cells has been elucidated already, the function of B cells in myocardial infarction remained relatively unclear until now. It is, however, already known that B cells are of importance in healing processes in other tissues, for example in the skin.
Our studies therefore addressed the role and function of B cells in healing and early remodeling processes in the myocardium after infarction.
Under physiological conditions, only few B cells can be found in the heart. After myocardial infarction, however, which we modelled with a permanent ligation of the left anterior descending artery (LAD) in C57BL/6J mice, we could demonstrate that B lymphocytes accumulate in the early phase after tissue injury (days one to seven) in the myocardium.
To detect B cells, we performed immunofluorescence stainings on cryosections of infarcted hearts using an anti-B220 antibody. Quantitative analysis of tissue infiltration revealed that B cells peaked at day seven. In flow cytometry, we further characterized the B cells infiltrating infarcted tissue. We found that most of them were mature B cells (IgM+, IgD+).
Next, we wanted to outline a potential mechanism responsible for B-cell infiltration to the site of tissue injury. We therefore performed ELISA experiments revealing that CXCL13 was upregulated in scar tissue.
Antibody-mediated neutralization of CXCL13 verifiably attenuated B-cell infiltration.
Treated mice also showed – in the tendency – smaller infarct sizes and an improved survival.
In conclusion, we could show that B lymphocytes infiltrate the myocardium after MI in mice following a local CXCL13 gradient and that it is, most likely, beneficial to inhibit this process.
The noninvasive magnetic resonance imaging technique allows for the investigation of functional processes in the living plant. For this purpose during this work, different NMR imaging methods were further developed and applied.
For the localisation of the intrusion of water into the germinating rape seed with the simultaneous depiction of the lipid-rich tissue via a 3D rendering, in Chap. 5 the technique of interleaved chemical selective acquisition of water and lipid was used in the germinating seed. The utilization of high-resolution MR images of germinated seeds enabled the localization of a predetermined water gap in the lipid-rich aleurone layer, which resides directly under the seed coat. The for a long time in biology prevalent discussion, whether such a gap exists or the seed soaks up the water from all sides, rather like a sponge, could hereby, at least for the rapeseed seed, be answered clearly. Furthermore, the segmentation and 3D visualization of the vascular tissue in the rapeseed seeds was enabled by the high-resolution datasets, a multiply branched structure preconstructed in the seed could be shown. The water is directed by the vascular tissue and thus awakens the seed gradually to life. This re-awakening could as well be tracked by means of invasive imaging via an oxygen sensor. In the re-awakened seeds, the lipid degradation starts, other than expected, not in the lipid-rich cotyledons but in the residual endosperm remaining from seed development and in the aleurone layer which previously protected the embryo. Within this layer, the degradation could be verified in the high-resolution MR datasets.
The method presented in Chap. 6 provides a further characteristic trait for phenotyping of seeds and lipid containing plants in general. The visualization of the compounds of fatty acids in plant seeds and fruits could be achieved by the distinct utilization of chemical shift-selective imaging techniques. Via the application of a CSI sequence the fatty acid compounds in an olive were localized in a 2D slice. In conjunction with an individually adjusted CHESS presaturation module Haa85 the high-resolution 3D visualization of saturated and unsaturated fatty acid compounds in different seeds was achieved. The ratio maps calculated from these datasets allow to draw conclusions from the developmental stage or the type of seed. Furthermore, it could be shown that the storage condition of two soybean seeds with different storage time durations lead to no degradation of the fatty acid content.
Additional structural information from inside of dry seeds are now accessible via MRI. In this work the imaging of cereal seeds could be significantly improved by the application of the UTE sequence. The hitherto existing depictions of the lipid distribution, acquired with the spin echo sequence, were always sufficient for examinations of the lipid content, yet defects in the starchy endosperm or differences in the starch concentration within the seed remained constantly unseen with this technique. In a direct comparison of the datasets acquired with the previous imaging technique (spin echo) and with UTE imaging, the advantage of data acquisition with UTE could be shown. By investigating the potential seed compounds (starch, proteins, sugar) in pure form, the constituent parts contributing to the signal could be identified as bound water (residual moisture) and starch. The application of a bi-exponential fit on the datasets of the barley seed enabled the separate mapping of magnetization and of relaxation time of two components contributing to the NMR signal. The direct comparison with histological stainings verified the previous results, thus this technique can be used for the selective imaging of starch in dry seeds.
Conclusions on the translocation characteristics in plants can be drawn by the technique proposed in Chap. 8. The associated translocation velocities can now, even in the range of several um/h, be determined in the living plant. Based on calculated concentrations of an MR contrast agent, which was taken up by the plant, these translocation velocities were estimated both in longitudinal direction, thus along the vascular bundle, and in horizontal direction, thus out of the bundle. The latter velocity is located below the contrast agent's velocity value of free diffusion. By adjusting a dynamic contrast-enhancing imaging technique (DCE-Imaging, Tof91) the acquisition duration of a T1-map was significantly reduced. By means of these maps, local concentrations of the contrast agent in plant stems and the siliques of the rapeseed plant could be determined.
Numerous questions in plant science can only be answered by non-invasive techniques such as MRI. For this reason, besides the experimental results achieved in this work, further NMR methods were tested and provided for the investigation of plants.
As an example, the study on the imaging of magnetic exchange processes are mentioned, which provided the groundwork for a possible transfer of CEST experiments (Chemical Exchange Saturation Transfer) to the plant. The results are presented in the bachelor thesis of A. Jäger Jae17, which was performed under my supervision, they find great interest under biologists.
The development of new technologies, which extend the possibilities for the investigation of living organisms, is of great importance. For this reason, I have contributed to the development of the currently unpublished method RACETE (Refocused Acquisition of Chemical Exchange Transferred Excitations [Jak17, Reu17, Gut18a]). By rephasing the transferred magnetization the utilization of properties which have not been available in chemical "`exchange"' experiments is enabled. With this method a positive contrast is generated, thus a reference experiment is not mandatory. Furthermore, the image phase, which in classical experiments contains no information about the exchanged protons, can be used for the distinct identification of multiple substances which have been excited simultaneously.
This recently at the Department of Experimental Physics V developed method can be used in particular for the identification of lipids and for the localization of sugars and amino acids, thus it can serve the enhancement and improvement of non-invasive analytical methods.
Micromegas are parallel-plate gaseous detectors with micro-pattern readout structures that are able to measure precisely and efficiently at high particle rates. Their difference with respect to other gaseous detectors is that the space in which particles ionise the gas and create electrons is separated from the region in which these electrons are multiplied (or amplified) by a thin metallic mesh. In the ionisation region, typically a few mm thick, a moderate field of a few hundred V/cm is applied. The amplification region with a homogeneous electrical field of 40--50~kV/cm is only 100--150~$\upmu$m thick. The latter guarantees that the positive ions produced in the amplification process are rapidly evacuated and the possibility to build up space charge at high rate is reduced. Critical in micromegas detectors are sparks in the thin amplification region in the presence of the high electrical field. This problem was solved in 2011 by introducing a spark protection scheme. It consists of a layer of resistive strips on top of the readout strips, separated from the latter by a thin insulation layer.
Micromegas with the spark protection scheme were selected as instrumentation of the first ATLAS forward muon station (NSW) in the upgrade of the ATLAS detector for the operation of the Large Hadron Collider (LHC) at high luminosity (HL-LHC), expected for 2026.
The main subjects of this thesis are: the characterisation of the first micromegas quadruplet prototypes for the NSW detectors; the characterisation of the materials used in the spark-protection system; and the study of the influence of the mesh distance holders (pillars) on the detector performance.
The thesis starts with a brief introduction into the LHC and ATLAS projects, followed by a chapter that explains the reason for the upgrade of the ATLAS muon system and shows the layout of the NSW.
The first of the three main chapters covers the construction and the characterisation of the first two prototypes for the NSW detectors. These detectors comprise four detection layers and have the same mechanical structure as the NSW detectors. The mechanical precision as well as the homogeneity of the detector response are discussed. The latter has been measured using X-rays and cosmic rays. The spatial resolution that can be achieved with these detectors precision has been measured at the MAMI accelerator at Mainz with low-energy electrons. The chapter is completed by a section that describes the successful integration of a data acquisition system (DAQ) into the official ATLAS DAQ system that was required for an initially planned installation of one of the prototypes on the existing Small Wheel.
The next chapter presents a study of the influence of temperature and humidity changes on the resistive strips used in the spark protection system. In addition the long-term stability of the resistive material has been measured accumulating charge equivalent to 100 years of operation in the HL-LHC and exposing the samples to intense gamma irradiation equivalent to 10 years of HL-LHC operation.
The third part covers the impact of the mesh distance holders (pillars) on the performance of the detector. This study has been performed with a 10 x 10 cm$^2$ bulk-micromegas with two different pillar shapes. Both 5.9 keV gammas from a $^{55}$Fe and 8 keV X-rays from a Cu target were used. In this context also the electrostatic charge-up of the detector is discussed.
In the Appendices one finds a summary of the fundamental physics relevant for gaseous detectors as well as some supporting material for the topics covered in the main part of the thesis.
A doubly base-stabilized diborane based on a benzylphosphine linker was prepared by a salt elimination reaction between 2-LiC\(_6\)H\(_4\)CH\(_2\)PCy\(_2\).Et\(_2\)O and B\(_2\)Br\(_4\). This compound was reduced with KC8 to its corresponding diborene, with the benzylphosphine forming a five-membered chelate. The diborene reacts with butadiene, 2-trimethylsiloxy-1,3-butadiene and isoprene to form 4,5-diboracyclohexenes, which interconvert between their 1,1- (geminal) and 1,2- (vicinal) chelated isomers. The 1,1-chelated diborene undergoes a halide-catalysed isomerisation into its thermodynamically favoured 1,2-isomer, which undergoes Diels-Alder reactions more slowly than the kinetic product.
Sterically unencumbered diborenes based on a benzylphosphine chelate undergo diboration reactions with bis(catecholato)diboron in the absence of a catalyst to yield tetraboranes. The symmetrical diborenes studied undergo 1,2- diborations, whereas an unsymmetrical derivative was found to yield a triborylborane-phosphine adduct as the result of a formal 1,1-diboration. A related borylborylene compound also underwent a 1,2-diboration to produce a borylene-borane adduct.
A new twelvefold methoxy-triethyleneglycol-jacketed tetraphenoxy-perylene bisimide (MEG-PBI) amphiphile was synthesized that self-assembles into two types of supramolecular aggregates in water: red-coloured aggregates of low order and with weak exciton coupling among the PBIs and blue-coloured strongly coupled J-aggregates consisting of a highly ordered hydrogen-bonded triple helix of PBIs. At room temperature this PBI is miscible with water at any proportions which enables the development of robust dye aggregates in solution, in hydrogel states and in lyotropic liquid crystalline states. In the presence of 60–95 wt% water, self-standing coloured hydrogels exhibit colour changes from red to blue accompanied by a fluorescence light-up in the far-red region upon heating in the range of 30–50 °C. This phenomenon is triggered by an entropically driven temperature-induced hydrogen-bond-directed slipped stacking arrangement of the MEG-PBI chromophores within structurally well-defined J-aggregates. This versatile aqua material is the first example of a stable PBI J-aggregate in water. We anticipate that this study will open a new avenue for the development of biocompatible functional materials based on self-assembled dyes and inspire the construction of other hydrogen-bonded supramolecular materials in the highly competitive solvent water.
In this thesis, the synthesis and photophysics of a great variety of squaraine dyes are presented. This variety is based on four parent squaraines containing either indolenine or quinoline heterocycles. By a suitable choice of the donor and acceptor unit, the optical properties can already be adapted to the properties desired on the stage of the monomer.
To promote a further derivatisation of these dyes, diverse functional groups are attached to the monomers using transition metal-catalysed C-C coupling reactions. However, this has to be preceded by the synthesis of bromine-functionalised derivatives as a direct halogenation of squaraine dyes is not feasible. Therefore, the halogen function is already introduced in precursor molecules giving rise to a molecular building block system containing bromine-, boronic ester-, and alkyne-functionalised monomer units, which pave the way to a plethora of squaraine oligomers and polymers.
The indolenine homopolymer pSQB-1 as well as the corresponding small molecular weight oligomers dSQB-1 and tSQB were synthesized applying Ni-mediated Yamamoto and Pd-catalysed Suzuki coupling methodologies, respectively. The motivation for this project relied on the fundamental investigations by Völker et al. on pSQB-V. A progressive red-shift of the lowest energy absorption maximum from the dimer to the polymer was observed in CHCl3 compared to the monomer. With increasing number of monomer units, the exciton coupling decreases from the dimer to the polymer. In addition, the shape of the absorption band manifold shows a strong dependence on the solvent, which was also observed by Völker et al. J-type aggregate behavior is found in chlorinated solvents such as CHCl3 and DCM, whereas H-type aggregates are formed in acetone. Temperature-dependent absorption studies in PhCN reveals a reversible equilibrium of diverse polymer conformers, which manifests itself in a gradual change from H-aggregate behavior to a mixture with a more pronounced J-aggregate behavior upon raising the temperature. It isassumed that both characteristic aggregate bands correlate in borderline cases with two polymer structures which can be assigned to a zig-zag and a helical structure. As no experimental evidence for these structures could hitherto be provided by NMR, TD-DFT computations on oligomers (22-mers) can reproduce very closely the characteristic features of the spectra for the two conformational isomers.
The subsequent chapters are motivated by the goal to influence the optical properties through a control of the superstructure and thus of the intramolecular aggregate formation.
On the one hand, bulky groups are implemented in the 3-position of the indolenine scaffold to provoke steric repulsion and thus favoring J-aggregate behavior at the expense of helical arrangements. The resulting homopolymer pDiPhSQB bearing two phenyl groups per indolenine exhibits J-type aggregate behavior with red-shifted absorption maxima in all considered solvents which is explained to be caused by the formation of elongated zig-zag structures. Furthermore, single-crystal X-ray analysis of monomer DiPhSQB-2-Br2 reveals a torsion of the indolenine moieties as a consequence of steric congestion. The twist of the molecular geometry and the resulting loss of planarity leads to a serious deterioration of the fluorescence properties, however a significant bathochromic shift of ca. 1 200 cm-1 of the lowest absorption band was observed compared to parent SQB, which is even larger than the shift for dSQB-1 (ca. 1 000 cm-1).
On the other hand, a partial stiffening of the polymer backbone is attempted to create a bias for elongated polymer chains. In this respect, the synthetic approach is to replace every second biarylaxis with the rigid transoid benzodipyrrolenine unit. Despite a rather low average degree of polymerization < 10, exclusively red-shifted absorption maxima are observed in all solvents used.
In order to complete the picture of intramolecular aggregates through the selective design of H-aggregates, a squaraine-squaraine copolymer was synthesised containing the classic cisoid indolenine as well as the cisoid quinoline building block. Taking advantage of the highly structure directing self-assembly character of the quinoline moiety, the copolymer pSQBC indeed showes a broad, blue-shifted main absorption band in comparison with the monomer unit dSQBC. The shape of the absorption band manifold solely exhibited a minor solvent and temperature dependence indicating a persistent H-aggregate behaviour. Hence, as a proof of concept, it is shown that the optical properties of the polymers (H- and J-aggregate) and the corresponding superstructure can be inherently controlled by an adequate design of monomer precursors.
The last chapter of this work deals, in contrast to all other chapters, with intermolecular aggregates. It is shown that the two star-shaped hexasquarainyl benzenes hSQA-1 and hSQA-2 exhibit a strong propensity for self-organisation. Concentration- and temperature-dependent studies reveal a great driving force for self-assembly in acetone. While the larger hSQA-2 instantaneously forms stable aggregates, the aggregates of hSQA-1 shows a pronounced kinetic stability. Taking advantage of the kinetic persistency of these aggregates, the corresponding kinetic activation parameters for aggregation and deaggregation can be assessed. The absorption spectra of both hexasquarainyl benzenes in the aggregated state reveal some striking differences. While hSQA-1 features an intensive, very narrow and blue-shifted absorption band, two red-shifted bands are observed for hSQA-2, which are closely located at the monomer absorption. The very small bandwidth of hSQA-1 are interpreted to be caused by exchange narrowing and pointed towards highly ordered supramolecular aggregates. The concentration-dependent data of the two hexasquarainyl benzenes can be fitted to the dimer-model with excellent correlation coefficients, yielding binding constants in excess of 10^6 M-1, respectively. Such high binding constants are very surprising, considering the unfavourable bulky 3,3-dimethyl groups of the indolenine units which should rather prevent aggregation. Joint theoretical and NMR spectroscopic methods were applied to unravel the supramolecular aggregate structure of hSQA-1, which is shown to consist of two stacked hexasquarainyl benzenes resembling the picture of two stacked bowls.
The photochemistry and photophysics of transition metal complexes are of great interest, since such materials can be exploited for a wide range of applications such as in photocatalysis, sensing and imaging, multiphoton-absorption materials and the fabrication of OLEDs. A full understanding of the excited state behavior of transition metal compounds is therefore important for the design of new materials for the applications mentioned above. In principle, the luminescence properties of this class of compounds can be tuned by changing the metal or subtle changes in the ligand environment.
Furthermore, transition-metal complexes continue to play a major role in modern synthetic chemistry. In particular, they can realize selective transformations that would either be difficult or impossible by conventional organic chemistry. For example, they enable the efficient and selective formation of carbon–carbon bonds. One famous example of these types of transformations are metal-catalyzed cyclization reactions. Herein, metallacyclopentadiene complexes are considered as key intermediates in a number of metal-mediated or -catalyzed cyclization reactions, i.e. the [2+2+2] cyclotrimerization of alkynes. Recent research has focused on the synthesis and characterization of these metallacyclic intermediates such as MC4 ring systems. Metallacyclopentadienes are structurally related to main group EC4 systems such as boroles, siloles, thiophenes and phospholes. Overall, this group of compounds (EC4 analogues) is well known and has attracted significant attention due to their electron-transport and optical properties. Unlike transition metal analogues, however, these EC4 systems show no phosphorescence, which is due to inefficient SOC compared to 2nd and 3rd row transition metals, which promoted us to explore the phosphorescence potential of metallacyclopentadienes.
In 2001, Marder et al. developed a one-pot high-yield synthesis of luminescent 2,5 bis(arylethynyl)rhodacyclopentadienes by reductive coupling of 1,4-diarylbuta-1,3-diynes at a suitable rhodium(I) precursor. Over the past years, a variety of ligands (e.g. TMSA, S,S’ diethyldithiocarbamate, etc.) and 1,4-bis(p-R-phenyl)-1,3-butadiynes or linked , bis(p-R-arylethynyl)alkanes (R = electron withdrawing or donating groups) were investigated and always provided a selective formation of 2,5 bis(arylethynyl)rhodacyclopentadienes, which were reported to be fluorescent despite presence of the heavy atom. To examine the influence of the ligand sphere around the rhodium center on the intersystem-crossing (ISC) processes in the above-mentioned fluorescent rhodacyclopentadienes and to increase the metal character in the frontier orbitals by destabilizing the Rh filled d-orbitals, a -electron donating group was introduced, namely acetylacetonato (acac). Interestingly, in 2010 Tay reacted [Rh(κ2-O,O-acac)(PMe3)2] with ,-bis(p-R-arylbutadiynyl)alkanes and observed not only the fluorescent 2,5 bis(arylethynyl)rhodacyclopentadienes, but also rhodium 2,2’-bph complexes as products, which were reported to be phosphorescent in preliminary photophysical studies.
In this work, the reaction behavior of [Rh(κ2-O,O-acac)(L)2] (L = PMe3, P(p-tolyl)3) with different ,-bis(p-R-arylbutadiynyl)alkanes was established. Furthermore, the separation of the two isomers 2,5-bis(arylethynyl)rhodacyclopentadienes (A) and rhodium 2,2’-bph complexes (B), and the photophysical properties of those were explored in order to clarify their fundamentally different excited state behaviors.
Reactions of [Rh(κ2-O,O-acac)(P(p-tolyl3)2)] with ,-bis(arylbutadiynyl)alkanes gives exclusively weakly fluorescent 2,5-bis(arylethynyl)rhodacyclopentadienes. Changing the phosphine ligands to PMe3, reactions of [Rh(κ2-O,O-acac)(PMe3)2] and , bis(arylbutadiynyl)alkanes afford two isomeric types of MC4 metallacycles with very different photophysical properties, as mentioned before.
As a result of a normal [2+2] reductive coupling at rhodium, 2,5 bis(arylethynyl)rhodacyclopentadienes (A) are formed, which display intense fluorescence. Rhodium 2,2’-bph complexes (B), which show phosphorescence, have been isolated as a second isomer originating from an unusual [4+2] cycloaddition reaction and a subsequent -H-shift. Control of the isomer distribution, of 2,5-bis(arylethynyl)rhodacyclopentadienes (A) and rhodium biphenyl complexes (B), is achieved by modification of the linked , bis(arylbutadiynyl)alkane.
Changing the linker length from four CH2 to three CH2 groups, dramatically favors the formation of the rhodium biphenyl isomer B, providing a fundamentally new route to access photoactive metal biphenyl compounds in good yields. This is very exciting as the photophysical properties of only a limited number of bph complexes of Ir, Pd and Pt had been explored. The lack of photophysical reports in the literature is presumably due to the limited synthetic access to various substituted 2,2’-bph transition metal complexes.
On the other hand, as the reaction of [Rh(κ2-O,O-acac)(P(p-tolyl)3)2] with , bis(arylbutadiynyl)alkanes provides a selective reaction to give weakly fluorescent 2,5 bis(arylethynyl)rhodacyclopentadiene complexes with P(p-tolyl)3 as phosphine ligands, a different synthetic access to 2,5-bis(arylethynyl)rhodacyclopentadiene complexes with PMe3 as phosphine ligands was developed, preventing the time-consuming separation of the isomers. The weak rhodium-phosphorus bonds of 2,5-bis(arylethynyl)rhodacyclopentadiene complexes bearing P(p tolyl)3 as phosphine ligands, relative to those of related PMe3 complexes, allowed for facile ligand exchange reactions. In the presence of an excess of PMe3, a stepwise reaction was observed, giving first the mono-substituted, mixed-phosphine rhodacyclopentadiene intermediates and, subsequently, full conversion to the highly fluorescent 2,5 bis(arylethynyl)-rhodacyclopentadienes bearing only PMe3 ligands (by increasing the reaction temperature).
With spectroscopically pure 2,5-bis(arylethynyl)rhodacyclopentadiene complexes A (bearing PMe3 as phosphine ligands) and rhodium 2,2-bph complexes B in hand, photophysical studies were conducted. The 2,5-bis(arylethynyl)rhodacyclopentadienes (A) are highly fluorescent with high quantum yields up to 54% and very short lifetimes (τ = 0.2 – 2.5 ns) in solution at room temperature. Even at 77 K in glass matrices, no additional phosphorescence is observed which is in line with previous observations made by Steffen et al., who showed that SOC mediated by the heavy metal atom in 2,5-bis(arylethynyl)rhodacyclopentadienes and 2,5 bis(arylethynyl)iridacyclopentadienes is negligible. The origin of this fluorescence lies in the pure intra-ligand (IL) nature of the excited states S1 and T1. The HOMO and the LUMO are nearly pure and * ligand orbitals, respectively, and the HOMO is energetically well separated from the filled rhodium d orbitals. The absence of phosphorescence in transition metal complexes due to mainly IL character of the excited states is not unusual, even for heavier homologues than rhodium with greater SOC, resulting in residual S1 emission (fluorescence) despite ISC S1→Tn being sufficiently fast for population of T1 states. However, there are very few complexes that exhibit fluorescence with the efficiency displayed by our rhodacyclopentadienes, which involves exceptionally slow S1→Tn ISC on the timescale of nanoseconds rather than a few picoseconds or faster.
In stark contrast, the 2,2’-bph rhodium complexes B are exclusively phosphorescent, as expected for 2nd-row transition metal complexes, and show long-lived (hundreds of s) phosphorescence (Ф = 0.01 – 0.33) at room temperature in solution. As no fluorescence is detected even at low temperature, it can be assumed that S1→Tn ISC must be faster than both fluorescence and non-radiative decay from the S1 state. This contrasts with the behavior of the isomeric 2,5-bis(arylethynyl)rhodacyclopentadienes for which unusually slow ISC occurs on a timescale that is competitive with fluorescence (vide supra). The very small values for the radiative rate constants, however, indicate that the nature of the T1 state is purely 3IL with weak SOC mediated by the Rh atom. The phosphorescence efficiency of these complexes in solution at room temperature is even more impressive, as non-radiative coupling of the excited state with the ground state typically inhibits phosphorescence. Instead, the rigidity of the organic -system allows the ligand-based excited triplet state to exist in solution for up to 646 s and to emit with high quantum yields for biphenyl complexes. The exceptionally long lifetimes and small radiative rate constants of the rhodium biphenyl complexes are presumably a result of the large conjugated -system of the organic ligand. According to TD DFT studies, the T1 state involves charge-transfer from the biphenyl ligand into the arylethynyl moiety away from the rhodium atom. This reduces the SOC of the metal center that would be necessary for fast phosphorescence. These results show that the π-chromophoric ligand can gain control over the photophysical excited state behavior to such an extent that even heavy transition metal atoms like rhodium participate in increasing the fluorescence such as main-group analogues do. Furthermore, in the 2,2’-bph rhodium complexes, the rigidity of the organic -system allows the ligand-based excited triplet state to exist in solution for up to hundreds of s and to emit with exceptional quantum yields.
Therefore, investigations of the influence of the ligand sphere around the rhodium center have been made to modify the photophysical properties and furthermore to explore the reaction behavior of these rhodium complexes. Bearing in mind that the P(p-tolyl)3 ligands can easily be replaced by the stronger -donating PMe3 ligands, ligand exchange reactions with N heterocyclic carbenes (NHCs) as even stronger -donors was investigated. Addition of two equivalents of NHCs at room temperature led to the release of one equivalent of P(p-tolyl3) and formation of the mono-substituted NHC rhodium complex. The reaction of isolated mono-NHC complex with another equivalent of NHC at room temperature did not result in the exchange of the second phosphine ligand. Moderate heating of the reaction to 60 °C, however, resulted in the formation of tetra-substituted NHC rhodium complex [Rh(nPr2Im)4]+[acac]-. To circumvent the loss of the other ligands in the experiments described above, a different approach was investigated to access rhodacyclopentadienes with NHC instead of phosphine ligands.
Reaction of the bis-NHC complex [Rh(κ2-O,O-acac)(nPr2Im)2] with , bis(arylbutadiynyl)alkanes at room temperature resulted 2,5-bis(arylethynyl)-rhodacyclopentadienes with the NHC ligands being cis or trans to each other as indicated by NMR spectroscopic measurements and single-crystal X-ray diffraction analysis. Isolation of clean material and a fundamental photophysical study could not be finished for reasons of time within the scope of this work.
Furthermore, shortening of the well conjugated -system of the chromophoric ligand (changing from tetraynes to diynes) was another strategy to examine the reaction behavior of theses ligands with rhodium(I) complexes and to modify the excited state behavior of the formed rhodacyclopentadienes. The reaction of [Rh(κ2-O,O-acac)(PMe3)2] with 1,7 diaryl 1,6-heptadiynes (diynes) leads to the selective formation of 2,5 bis(aryl)rhodacyclopentadienes. These compounds, however, are very weakly fluorescent with quantum yields ФPL < 1, and very short emission lifetimes in toluene at room temperature. Presumably, vibrational modes of the bis(phenyl)butadiene backbone leads to a higher rate constant for non-radiative decay and is thus responsible for the low quantum yields compared to their corresponding PMe3 complexes with the bis(phenylethynyl)butadiene backbone at room temperature. No additional phosphorescence, even at 77 K in the glass matrix is observed.
Chancing the phosphine ligands to P(p-tolyl)3, reactions of [Rh(κ2-O,O-acac)(P(p-tolyl3)2)] with 1,7-diaryl-1,6-heptadiynes, however, resulted in a metal-mediated or -catalyzed cycloaddition reaction of alkynes and leads to full conversion to dimerization and trimerization products and recovery of the rhodium(I) starting material. This is intuitive, considering that P(Ar)3 (Ar = aryl) ligands are considered weaker -donor ligands and therefore have a higher tendency to dissociate. Therefore, rhodium(I) complexes with aryl phosphines as ligands have an increasing tendency to promote catalytic reactions, while the stronger -donating ligands (PMe3 or NHCs) promote the formation of stable rhodium complexes.
Finally, in Chapter 4, the findings of the work conducted on N-heterocyclic carbenes (NHCs) and cyclic (alkyl)(amino)carbenes (CAACs) is presented. These compounds have unique electronic and steric properties and are therefore of great interest as ligands and organo-catalysts. In this work, studies of substitution reactions involving novel carbonyl complexes of rhodium and nickel are reported. For characterization and comparison of CAACmethyl with the large amount of data available for NHC and sterically more demanding CAAC ligands, an overview on physicochemical data (electronics, sterics and bond strength) is provided.
The reaction of [Rh(-Cl)(CO)2]2 with 2 equivalents of CAACmethyl at low temperature afforded the mononuclear complex cis-[(RhCl(CO)2(CAACmethyl)]. However, reacting [Rh( Cl)(CO)2]2 with CAACmethyl at room temperature afforded a mixture of complexes. The mononuclear complex [(RhCl(CO)(CAACmethyl)2], the chloro-bridged complexes [(Rh2( Cl)2(CO)3(CAACmethyl)], [Rh(-Cl)(CO)(CAACmethyl)]2 and a carbon monoxide activation product were formed. The carbon monoxide activation product is presumably formed via the reaction of two equivalents of the CAAC with CO to give the bis-carbene adduct of CO, and subsequent rearrangement via migration of the Dipp moiety. While classical N-heterocyclic carbenes are not electrophilic enough to react with CO, related diamidocarbenes and alkyl(amino)carbenes undergo addition reactions with CO to give the corresponding ketenes. Consequently, to obtain the CAAC-disubstituted mononuclear complex selectively, 8 equivalents of CAACmethyl were reacted with 1 equivalent of [Rh(-Cl)(CO)2]2. For the evaluation of TEP values, [Ni(CO)3(CAAC)] was synthesized in collaboration with the group of Radius. With the complexes [(RhCl(CO)(CAACmethyl)2] and [Ni(CO)3(CAAC)] in hand, it was furthermore possible to examine the electronic and steric parameters of CAACmethyl. Like its bulkier congeners CAACmenthyl and CAACcy, the methyl-substituted CAAC is proposed to be a notably stronger -donor than common NHCs. While it has a very similar TEP value of 2046 cm-1, it additionally possess superior -acceptor properties (P = 67.2 ppm of phosphinidene adduct).
CAACs appear to be very effective in the isolation of a variety of otherwise unstable main group and transition metal diamagnetic and paramagnetic species. This is due to their low-lying LUMO and the small singlet-triplet gap. These electronic properties also allow free CAACs to activate small molecules with strong bonds. They also bind strongly to transition metal centers, which enables their use under harsh conditions. One recent development is the use of CAACs as ligands in transition metal complexes, which previously were only postulated as short-lived catalytic intermediates.[292,345] The availability of these reactive species allows for a better understanding of known catalytic reactions and the design of new catalysts and, moreover, new applications. For example Radius et al.[320] prepared a CAAC complex of cobalt as a precursor for thin-film deposition and Steffen et al.[346] reported a CAAC complex of copper with very high photoluminescent properties, which could be used in LED devices. With the development of cheap and facile synthetic methods for the preparation of CAACs and their corresponding transition metals complexes, as well as the knowledge of their electronic properties, it is safe to predict that applications in and around this field of chemistry will continue to increase.
The catalytic splitting of water into its elements is an important reaction to establish hydrogen as a solar fuel. The bottle-neck of this process is considered to be the oxidative half reaction generating oxygen, and good catalysts are required to handle the complicated redox chemistry involved. As can be learned from nature, the incorporation of the catalytically active species into an appropriate matrix can help to improve the overall performance. Thus, the aim of the present thesis was to establish novel supramolecular approaches to improve water oxidation catalysis using the catalytically active {Ru(bda)} fragment as key motive (bda = 2,2'-bipyridine-6,6'-dicarboxylate).
First, the synthesis of ruthenium catalysts gathering three {Ru(bda)} water oxidation subunits in a macrocyclic fashion is described. By using bridging bipyridine ligands of different lengths, metallosupramolecular macrocycles with distinct sizes have been obtained. Interestingly, an intermediate ring size has been proven to be optimal for the catalytic water oxidation. Detailed kinetic, spectroscopic, and theoretical studies helped to identify the reaction mechanism and to rationalize the different catalytic activities. Furthermore, solubilizing side chains have been introduced for the most active derivative to achieve full water solubility.
Secondly, the {Ru(bda)} fragment was embedded into supramolecular aggregates to generate more stable catalytic systems compared to a homogeneous reference complex. Therefore, the catalyst fragment was equipped with axial perylene bisimide (PBI) ligands, which facilitate self-assembly. Moreover, the influence of the different accessible aggregate morphologies on the catalytic performance has been investigated.
The thesis describes the development of new synthetic strategies towards planar nanometer-sized and electron-deficient polycyclic aromatic dicarboximides, which are rather unexplored compared with the large variety of electron-rich polycyclic aromatic hydrocarbons and nanographenes. Thus, new polycyclic aromatic systems containing a different number of dicarboximide groups were designed since this class of compounds has revealed its significance in the past due to a range of desirable molecular properties and its high thermal and photochemical stability. The synthetic concept towards these systems includes different C–C coupling techniques that were combined within coupling cascade reactions. Therefore, this thesis provides new insights into the reactivity of aromatic substrates and elucidates mechanistic aspects of C–C coupling cascade reactions to facilitate the precise design of new and desirable materials based on polycyclic aromatic dicarboximides. Furthermore, structure-property relationships as well as the optical and electrochemical properties were investigated by UV/Vis absorption and fluorescence spectroscopy and cyclic or square wave voltammetry. Insights into the molecular structures in the solid state were obtained by single-crystal X-ray analysis. In subsequent studies, highly electron-deficient perylene bisimides and their reduced species have been investigated in detail. Thus, core-functionalized perylene bisimides were synthesized and UV/Vis absorption spectroscopy, spectroelectrochemistry and cyclic or square wave voltammetry were used to determine their optical properties and the stability of the individual reduced species.
Due to the earth´s rotation around itself and the sun, rhythmic daily and seasonal changes in illumination, temperature and many other environmental factors occur. Adaptation to these environmental rhythms presents a considerable advantage to survival. Thus, almost all living beings have developed a mechanism to time their behavior in accordance. This mechanism is the endogenous clock. If it fulfills the criteria of (1) entraining to zeitgebers (2) free-running behavior with a period of ~ 24 hours (3) temperature compensation, it is also referred to as “circadian clock”. Well-timed behavior is crucial for eusocial insects, which divide their tasks among different behavioral castes and need to respond to changes in the environment quickly and in an orchestrated fashion. Circadian rhythms have thus been studied and observed in many eusocial species, from ants to bees. The underlying mechanism of this clock is a molecular feedback loop that generates rhythmic changes in gene expression and protein levels with a phase length of approximately 24 hours. The properties of this feedback loop are well characterized in many insects, from the fruit fly Drosophila melanogaster, to the honeybee Apis mellifera. Though the basic principles and components of this loop are seem similar at first glance, there are important differences between the Drosophila feedback loop and that of hymenopteran insects, whose loop resembles the mammalian clock loop. The protein PERIOD (PER) is thought to be a part of the negative limb of the hymenopteran clock, partnering with CRYPTOCHROME (CRY). The anatomical location of the clock-related neurons and the PDF-network (a putative in- and output mediator of the clock) is also well characterized in Drosophila, the eusocial honeybee as well as the nocturnal cockroach Leucophea maderae. The circadian behavior, anatomy of the clock and its molecular underpinnings were studied in the carpenter ant Camponotus floridanus, a eusocial insect Locomotor activity recordings in social isolation proved that the majority of ants could entrain to different LD cycles, free-ran in constant darkness and had a temperature-compensated clock with a period slightly shorter than 24 hours. Most individuals proved to be nocturnal, but different types of activity like diurnality, crepuscularity, rhythmic activity during both phases of the LD, or arrhythmicity were also observed. The LD cycle had a slight influence on the distribution of these activities among individuals, with more diurnal ants at shorter light phases. The PDF-network of C. floridanus was revealed with the anti-PDH antibody, and partly resembled that of other eusocial or nocturnal insects. A comparison of minor and major worker brains, only revealed slight differences in the number of somata and fibers crossing the posterior midline. All in all, most PDF-structures that are conserved in other insects where found, with numerous fibers in the optic lobes, a putative accessory medulla, somata located near the proximal medulla and many fibers in the protocerebrum. A putative connection between the mushroom bodies, the optic lobes and the antennal lobes was found, indicating an influence of the clock on olfactory learning. Lastly, the location and intensity of PER-positive cell bodies at different times of a 24 hour day was established with an antibody raised against Apis mellifera PER. Four distinct clusters, which resemble those found in A. mellifera, were detected. The clusters could be grouped in dorsal and lateral neurons, and the PER-levels cycled in all examined clusters with peaks around lights on and lowest levels after lights off.
In summary, first data on circadian behavior and the anatomy and workings of the clock of C. floridanus was obtained. Firstly, it´s behavior fulfills all criteria for the presence of a circadian clock. Secondly, the PDF-network is very similar to those of other insects. Lastly, the location of the PER cell bodies seems conserved among hymenoptera. Cycling of PER levels within 24 hours confirms the suspicion of its role in the circadian feedback loop.
Imagine a technology that automatically creates a full 3D thermal model of an environment and detects temperature peaks in it. For better orientation in the model it is enhanced with color information. The current state of the art for analyzing temperature related issues is thermal imaging. It is relevant for energy efficiency but also for securing important infrastructure such as power supplies and temperature regulation systems. Monitoring and analysis of the data for a large building is tedious as stable conditions need to be guaranteed for several hours and detailed notes about the pose and the environment conditions for each image must be taken. For some applications repeated measurements are necessary to monitor changes over time. The analysis of the scene is only possible through expertise and experience.
This thesis proposes a robotic system that creates a full 3D model of the environment with color and thermal information by combining thermal imaging with the technology of terrestrial laser scanning. The addition of a color camera facilitates the interpretation of the data and allows for other application areas. The data from all sensors collected at different positions is joined in one common reference frame using calibration and scan matching. The first part of the thesis deals with 3D point cloud processing with the emphasis on accessing point cloud data efficiently, detecting planar structures in the data and registering multiple point clouds into one common coordinate system. The second part covers the autonomous exploration and data acquisition with a mobile robot with the objective to minimize the unseen area in 3D space. Furthermore, the combination of different modalities, color images, thermal images and point cloud data through calibration is elaborated. The last part presents applications for the the collected data. Among these are methods to detect the structure of building interiors for reconstruction purposes and subsequent detection and classification of windows. A system to project the gathered thermal information back into the scene is presented as well as methods to improve the color information and to join separately acquired point clouds and photo series.
A full multi-modal 3D model contains all the relevant geometric information about the recorded scene and enables an expert to fully analyze it off-site. The technology clears the path for automatically detecting points of interest thereby helping the expert to analyze the heat flow as well as localize and identify heat leaks. The concept is modular and neither limited to achieving energy efficiency nor restricted to the use in combination with a mobile platform. It also finds its application in fields such as archaeology and geology and can be extended by further sensors.
A search is conducted for a beyond-the-Standard-Model boson using events where a Higgs boson with mass 125 GeV decays to four leptons (l = e or mu). This decay is presumed to occur via an intermediate state which contains one or two on-shell, promptly decaying bosons: H -> ZX/XX -> 4l , where X is a new vector boson Z(d) or pseudoscalar a with mass between 1 and 60 GeV. The search uses pp collision data collected with the ATLAS detector at the LHC with an integrated luminosity of 36.1 fb(-1) at a centre-of-mass energy root s = 13TeV. No significant excess of events above Standard Model background predictions is observed; therefore, upper limits at 95% confidence level are set on model-independent fiducial cross-sections, and on the Higgs boson decay branching ratios to vector and pseudoscalar bosons in two benchmark models.
Influence of interleukin-6-type cytokine oncostatin M on murine aortic vascular smooth muscle cells
(2018)
Oncostatin M (OSM) is a cytokine of the interleukin-6 family and released in the early
phase of inflammation by neutrophils, activated macrophages, dendritic cells, and T
lymphocytes. Its roles in physiology and disease are not entirely understood yet. It
has been shown recently that substantial amounts of OSM are found in atherosclerotic
plaques.
The first part of this thesis addresses the effects of OSM on vascular smooth muscle
cells (VSMCs). This cell type is known to contribute to atherogenesis and expresses
the type I and type II OSM receptor complexes. This study revealed that OSM is a
strong inducer of an array of genes which have recently been shown to play important
roles in atherosclerosis. Investigation of VSMCs isolated from OSMRbeta-deficient
(Osmr-/-) mice proved that the regulation of these target genes is entirely dependent
on the activation of the type II OSMR complex. In addition to OSM, other cytokines
expressed by T lymphocytes were found to contribute to plaque development. According
to earlier publications, the influence of IL-4, IL-13, and IL-17 on the progression of
plaques were discussed controversially. Nevertheless, for the regulation of investigated
atherosclerotic target genes and receptor complexes in VSMCs, they seemed to play a
minor role compared to OSM. Only the expression of the decoy receptor IL-13Ralpha2 - a
negative feedback mechanism for IL-13-mediated signalling - was strongly induced after
treatment with all mentioned cytokines, especially when VSMCs were primed with OSM
before stimulation.
The second part of this thesis focuses on the role of OSM during the progression of
atherosclerosis in vivo. Therefore, Ldlr-/-Osmr-/- mice were generated by crossing Ldlr-/-
mice - a typical mouse model for atherosclerosis - with Osmr-/- mice. These double-deficient
mice together with Ldlr-/-Osmr+/+ mice were set on cholesterol rich diet (Western
diet, WD) for 12 weeks before they were sacrificed. Determination of body and
organ weight, staining of aortas and aortic roots as well as gene expression profiling
strongly suggested that Ldlr-/-Osmr-/- mice are less susceptible for plaque development
and weight gain compared to Ldlr-/-Osmr+/+ mice. However, further experiments and
additional controls (C57Bl/6 and Osmr-/- mice) on WD are necessary to clarify the
underlying molecular mechanisms.
Taken together, the interleukin-6-type cytokine OSM is a strong inducer of an array of
target genes involved in de-differentiation and proliferation of VSMCs, a process known
to contribute substantially to atherogenesis. Further in vivo studies will help to clarify
the role of OSM in atherosclerosis.
This work summarizes the results of studies on several major aspects of platelet activation and platelet receptor regulation. Therefore, this thesis is divided into four parts.
Platelet activation and aggregation at sites of vascular injury is critical to prevent excessive blood loss, but may also lead to life-threatening ischemic disease states, such as myocardial infarction and stroke. Agonist-induced elevation in cytosolic Ca2+ concentrations is essential for platelet activation in hemostasis and thrombosis. The principal route of Ca2+ influx in platelets is store-operated calcium entry (SOCE). The calcium sensor molecule stromal interaction molecule 1 (STIM1) regulates SOCE by activating the membrane calcium channel protein Orai1, but the exact mechanisms of this interaction are not fully understood. Using affinity chromatography to screen for STIM1 interacting proteins in platelets, bridging integrator 2 (BIN2), an adapter protein belonging to the family of BAR proteins that is mainly expressed in the hematopoietic system, was identified. Newly generated BIN2 KO mice were viable and fertile but their platelets displayed markedly impaired SOCE in response to thapsigargin (TG) as well as agonists acting on immunoreceptor tyrosine-based activation motif (ITAM) or G protein-coupled receptors. This SOCE defect resulted in impaired (hem)ITAM induced platelet activation, aggregate formation under flow and procoagulant activity. As a consequence, mice lacking BIN2 in platelets were protected from occlusive arterial thrombus formation and thrombo-inflammatory cerebral infarct progression in a model of experimental stroke. These results identify BIN2 as a critical regulator of platelet SOCE in thrombosis and thrombo-inflammatory disease.
Integrin αIIbβ3 plays a central role in the adhesion and aggregation of platelets. Integrin activation requires the transmission of a signal from the small cytoplasmic tails of the α or β
subunit to the large extracellular domains resulting in conformational changes of the extracellular domains to enable ligand binding. It was hypothesized that Hic-5 is a novel regulator of integrin αIIbβ3 activation in mice. As demonstrated in the second part of this thesis, lack of Hic-5 had no detectable effect on platelet integrin activation and function in vitro and in vivo under all tested conditions. These results indicate that Hic-5 is dispensable for integrin αIIbβ3 activation and consequently for arterial thrombosis and hemostasis in mice.
The Rho GTPase family members RhoA and Rac1 play major roles in platelet activation at sites of vascular injury. Little is known about possible redundant functions of these Rho GTPases in regulating platelet function. To investigate functional redundancies of RhoA and Rac1 in platelet production and function, mice with MK- and platelet-specific double- deficiencies in RhoA and Rac1 were generated. RhoA/Rac1 double-deficiency phenocopied the respective single knockouts without any additional effects in the double-knockout animals, demonstrating for the first time a functional non-redundancy of RhoA and Rac1 in platelet function.
Antibodies against platelet glycoproteins (GP) trigger platelet destruction in immune thrombocytopenia (ITP) by binding to Fcγ receptors (FcγRs) on immune cells. However, antibodies against the platelet collagen receptor GPVI exert powerful anti-thrombotic action in vivo by inducing ectodomain shedding of the receptor associated with a transient thrombocytopenia. As shown in the final part of this thesis, blockade or deficiency of the inhibitory FcγRIIB abolished sequestration of anti-GPVI opsonized platelets in the hepatic vasculature and GPVI shedding. This process was mediated by liver sinusoidal endothelial cells (LSEC), the major FcγRIIB expressing cell type in the body. Furthermore, LSEC FcγRIIB mediated hepatic platelet sequestration and contributed to thrombocytopenia in mice treated with antibodies against αIIbβ3, the major target antigen in human ITP. These results reveal a novel and unexpected function of hepatic FcγRIIB in the processing of antibody-opsonized platelets.
The brain is the central organ of an animal controlling its behavior. It integrates internal information from the body and external stimuli from the surrounding environment to mediate an appropriate behavioral response. Since the environment is constantly changing, a flexible adjustment of the brain to new conditions is crucial for the animals’ fitness. The ability of the nervous system to adapt to new challenges is defined as plasticity. Over the last few decades great advances have been made in understanding the cellular and molecular mechanisms underlying neuronal plasticity. Plasticity may refer to structural changes physically remodeling the neuronal circuit, or to functional adaptations which are manifested in modified synaptic transmission, and in altered response and firing properties of single neurons. These structural and functional modifications are mediated by a complex interplay of environmental stimuli, intracellular signal transduction cascades, protein modifications, gene translation and transcription, and epigenetic gene regulatory mechanisms. However, especially the molecular mechanisms of environmentally-induced structural neuronal plasticity are still poorly understood.
In this thesis the honey bee was used as an innovative model organism to investigate this issue. The honey bee with its rich behavioral repertoire, highly sophisticated and plastic neuronal system, sequenced genome and full epigenetic machinery is well suited for studying the molecular underpinnings of environmentally-induced neuronal plasticity. Adult honey bees progress through a series of tasks within the dark hive until after about three weeks they start with foraging activities in the external world. The transition from in-hive to outside tasks is associated with remarkable structural neuronal plasticity. Subdivisions of the mushroom body, a brain region related to higher cognitive functions, are increased in volume. The volume expansion is mediated by a remarkable outgrowth of the dendritic network of mushroom body intrinsic neurons, so called Kenyon cells. In parallel, prominent synaptic structures, referred to as microglomeruli, are pruned. Most interestingly for this thesis, the pruning of microglomeruli and the dendritic expansion in Kenyon cells can be induced by a simple light exposure paradigm.
In the first chapter of the present thesis I used this paradigm to induce synaptic plasticity in the mushroom bodies under controlled lab conditions to search for correlating molecular changes which possibly mediate the observed plasticity. I compared the brain transcriptome of light-exposed and dark-kept control bees by whole transcriptome sequencing. This revealed a list of differentially expressed genes (DEGs). The list contains conserved genes which have reported functions in neuronal plasticity, thereby introducing them as candidate genes for plasticity in the honey bee brain. Furthermore, with this transcriptomic approach I discovered many candidate genes with unknown functions or functions so far unrelated to neuronal plasticity suggesting that these novel genes may have yet unrecognized roles in neuronal plasticity. A number of DEGs are known to be methylated or to exert epigenetic modifications on themselves speaking for a strong impact of epigenetic mechanisms in light-induced structural plasticity in the honey bee brain. This notion is supported by a differential methylation pattern of one examined DEG between light-exposed and dark-kept bees as shown in this thesis. Also a plasticity-related microRNA, which is predicted to target genes associated with cytoskeleton formation, was found to be upregulated in light-exposed bees. This speaks for a translation regulatory mechanism in structural plasticity in the honey bee.
Another interesting outcome of this study is the age-dependent expression of DEGs. For some plasticity-related DEGs, the amplitude of light-induced expression differs between one- and seven-day-old bees, and also the basal expression level of many DEGs in naive dark-kept control bees significantly varies between the two age groups. This suggests that the responsiveness of plasticity-related genes to environmental stimuli is also under developmental (age-dependent) control, which may be important for normal maturation and for the regulation of age-related changes in behavior. Indeed, I was able to demonstrate in phototaxis experiments that one- and seven-day-old bees show different behaviors in response to light exposure and thus the correlating age-dependent transcriptional differences may serve as mechanisms promoting age-related changes in behavior.
Together the results of the transcriptomic study demonstrate the successfulness of my approach to identify candidate molecular mechanisms for environmentally-induced structural plasticity in the honey bee brain. Furthermore, the thesis provides seminal evidence for the implication of DNA methylation in this process.
To better understand the role of DNA methylation for neuronal and behavioral plasticity in the honey bee, the second chapter of the thesis aims at characterizing this molecular process under more natural conditions. Therefore, I examined the expression of the DNA methyltransferase 3 (DNMT3) and of Ten-eleven translocation methylcytosine dioxygenase (TET) between in-hive bees and foragers. DNMT3 is responsible for DNA de novo methylation, whereas TET promotes DNA demethylation by converting methylcytosine (5mC) to hydroxymethylcytosine (5hmC). The data suggest that age and experience determine the expression of these two epigenetic key genes. Additionally, in this context, two examined DEGs are shown to be differentially methylated between nurses and foragers. One of these two DEGs, the plasticity related gene bubblegum (bgm), also exhibits an altered DNA methylation pattern in response to light exposure. Hence, these results of my thesis provide additional evidence for the importance of DNA methylation in behavioral and neuronal plasticity.
Results from the second chapter of this thesis also suggest additional functions of DNMT3 and TET to their traditional roles in DNA methylation/demethylation. I show that TET is far more expressed in the honey bee brain than DNMT3. This stands in contrast to the relative scarcity of 5hmC compared to 5mC and points at extra functions of this gene like RNA modifications as reported for Drosophila. Antibody staining against the DNMT3 gene product revealed an unexpected rare localization of the enzyme in the nucleus, but a surprisingly high abundance in the cytoplasm. The role of cytoplasmic DNMT3 is unknown. One possibility for the high abundance in the cytoplasm is a regulatory mechanism for DNA methylation by cytoplasmic-nuclear trafficking, or an additional function of DNMT3 in RNA modification, similar to TET.
Altogether, this thesis points at future research directions for neuronal plasticity by providing promising evidence for the involvement of epigenetic mechanisms and of a number of new candidate genes in environmentally induced structural plasticity in the honey bee brain. Furthermore, I present data suggesting so far unrecognized functions of DNMT3 which certainly need to be experimentally addressed in the future to fully understand the role of this enzyme.
Characterization of motility and erythrocyte adherence as virulence factors in African trypanosomes
(2018)
Pathogens causing African animal trypanosomiasis (AAT), the major livestock disease in sub-Saharan Africa, belong to the salivarian group of the African trypanosomes, which are transmitted by the bite of the tsetse fly (Glossina spec.). T. vivax, T. congolense and T. brucei brucei are major pathogens of cattle in particular, causing nagana, with dramatic socio-economic consequences for the affected regions. The parasites additionally have a huge reservoir of other livestock and wild animal hosts. T. brucei, the species which also includes the subspecies pathogenic to humans causing sleeping sickness, has been extensively studied as the cultivatable model trypanosome. But less is known about the other salivarian species, which are not routinely held in culture, if at all possible. A hallmark of trypanosomal lifestyle is the protozoan flagellates incessant motility, which enables them to populate an enormous range of habitats in very diverse hosts. We were now able to characterize, for the first time with high spatiotemporal resolution microscopy, the swimming behaviour and mechanism of the most relevant salivarian species isolated directly from blood. We show the influence of viscosity on the motility of bloodstream form (BSF) cells and simulate their movement between erythrocytes, giving a clear picture of how all analyzed species move under varying environmental conditions. We show that although the basic mechanism of flagellar motility applies to all analyzed species, there are clear morphological differences that produce different reactions to the physical environment. We could define specific conditions for highly increased swimming persistence and speed for compared to the behaviour in standard culture. These results have important implications for the parasites survival strategies in the host, e.g. regarding the capacity for antibody clearance. Although we show all species to effectively remove antibodies from the cell surface, T. congolense differed markedly in its motility behaviour, which gives rise to interesting questions about this species behaviour in the bloodstream. Most of the T. congolense parasites (and to a lesser extent T. vivax) adhere to sheep erythrocytes. Further in vitro studies showed that T. congolense and T. vivax adhered to rabbit, goat, pig and cattle erythrocytes- but binding behaviour was absent in murine blood. Notably, both T. brucei and T. evansi lacked adherence to all studied host erythrocytes. Generally, attachment to blood cells caused reduction of swimming velocities. Judging from its cell architecture, as well as the motility studies in higher media viscosity and in micropillar arrays, T. congolense is not adapted to swim at high speeds in the mammalian bloodstream. Low swimming speeds could allow these purely intravascular parasites to remain bound to the host erythrocytes.
Platelet aggregation at sites of vascular injury is essential to limit posttraumatic blood loss, but may also cause acute ischemic disease states such as myocardial infarction or stroke. Stable thrombus formation requires a series of molecular events involving platelet receptors and intracellular signal transduction, which contribute to adhesion, activation and aggregation of platelets. In this thesis, the cellular regulation of platelet surface receptors and their involvement in thrombus formation was investigated using genetically modified mice.
In the first part of the study, the functional relevance of the immunoreceptor tyrosine-based activation motif (ITAM)-coupled collagen receptor GPVI and of the recently identified hemITAM-bearing C-type lectin-like receptor 2 (CLEC-2) for in vivo thrombus formation was analyzed. Megakaryocyte/ platelet-specific CLEC-2 knock out mice displayed a defective lymphatic development and were protected from occlusive arterial thrombus formation. These phenotypes were more pronounced in mice with a GPVI/CLEC-2 double deficiency. Hemostasis was not compromised in CLEC-2 or GPVI single-deficient animals, as they showed only mildly prolonged tail bleeding times. Combined depletion of both receptors resulted in markedly prolonged bleeding times revealing an unexpected redundant function of the two receptors in hemostasis as well as thrombosis. These findings might have important implications for the development of anti-CLEC-2/ anti-GPVI agents as therapeutics.
In the second part, mechanisms underlying the cellular regulation of CLEC-2 were studied. Previous studies have shown that injection of the anti-CLEC-2 antibody INU1 results in complete immunodepletion of platelet CLEC-2 in mice, which is preceded by a severe transient thrombocytopenia thereby limiting its potential therapeutic use. It is demonstrated that INU1-induced CLEC-2 immunodepletion occurs through Src family kinase (SFK)-dependent receptor internalization in vitro and in vivo, presumably followed by intracellular degradation. In mice with spleen tyrosine kinase (Syk) deficiency, INU1-induced CLEC-2 internalization/ degradation was fully preserved, whereas the associated thrombocytopenia was largely prevented. These results show that CLEC-2 can be downregulated from the platelet surface through internalization in vitro and in vivo and that this can be mechanistically uncoupled from the associated antibody-induced thrombocytopenia.
Since INU1 IgG induced a pronounced thrombocytopenia, the in vivo effects of monovalent INU1 F(ab) fragments were analyzed. Very unexpectedly, injection of the F(ab) fragments resulted in widespread thrombus formation leading to persistent neurological deficits of the animals. This intravascular thrombus formation is the result of CLEC-2-dependent platelet activation and aggregation. The mechanism underlying the thrombus formation is still unknown and depends potentially on binding of a yet unidentified ligand to F(ab)-opsonized CLEC-2 on platelets.
The control of energy homeostasis is of pivotal importance for all living organisms. In the last years emerged the idea that many stress responses that are apparently unrelated, are actually united by a common increase of the cellular energy demand. Therefore, the so called energy signaling is activated by many kind of stresses and is responsible for the activation of the general stress response. In Arabidopsis thaliana the protein family SnF1- related protein kinases (SnRK1) is involved in the regulation of many physiological processes but is more known for its involvement in the regulation of the energy homeostasis in response to various stresses. To the SnRK1 protein family belong SnRK1.1 (also known as KIN10), SnRK1.2 (KIN11), and SnRK1.3 (KIN12). SnRK1 exerts its function regulating directly the activity of metabolic enzymes or those of key transcription factors (TFs). The only TFs regulated by SnRK1 identified so far is the basic leucine zipper (bZIP) 63. bZIP63 belongs to the C group of bZIPs (C-bZIPs) protein family together with bZIP9, bZIP10, and bZIP25. SnRK1.1 phosphorylates bZIP63 on three amino acids residues, serine (S) 29, S294, and S300. The phosphorylation of tbZIP63 is strongly related to the energy status of the plant, shifting from almost absent during the normal growth to strongly phosphorylated when the plant is exposed to extended dark. bZIPs normally bind the DNA as dimer in order to regulate the expression of their target genes. C-bZIPs preferentially form dimers with S1-bZIPs, constituting the so called C/S1- bZIPs network. The SnRk1 dependent phosphorylation of bZIP63 regulates its activation potential and its dimerization properties. In particular bZIP63 shift its dimerization preferences according to its phosphorylation status. The non-phosphorylated form of bZIP63 dimerize bZIP1, the phosphorylates ones, instead, forms dimer with bZIP1, bZIP11, and bZIP63 its self. Together with bZIP63, S1-bZIPs are important mediator of part of the huge transcriptional reprogramming induced by SnRK1 in response to extended dark. S1-bZIPs regulate, indeed, the expression of 4'000 of the 10'000 SnRK1-regulated genes in response to energy deprivation. In particular S1-bZIPs are very important for the regulation of many genes encoding for enzymes involved in the amino acid metabolism and for their use as alternative energy source. After the exposition for some hours to extended dark, indeed, the plant make use of every energy substrate and amino acids are considered an important energy source together with lipids and proteins. Interestingly, S1- bZIPs regulate the expression of ETFQO. ETFQO is a unique protein that convoglia the electrons provenienti from the branch chain amino acids catabolism into the mitochondrial electron transport chain. The dimer formed between bZIP63 and bZIP2 recruits SnRK1.1 directly on the chromatin of ETFQO promoter. The recruitment of SnRK1 on ETFQO promoter is associated with its acetylation on the lysine 14 of the histone protein 3 (K14H3). This chromatin modification is normally asociated with an euchromatic status of the DNA and therefore with its transcriptional activation. Beside the particular case of the regulation of ETFQO gene, S1-bZIPs are involved in the regulation of many other genes activated in response of different stresses. bZIP1 is for example an important mediator of the salt stress response. In particular bZIP1 regulates the primary C- and N-metabolism. The expression of bZIP1, in response of both salt ans energy stress seems to be regulated by SnRK1, as it is the expression of bZIP53 and bZIP63.
Beside its involvement in the regulation of the energy stress response and salt response, SnRK1 is the primary activators of the lipids metabolism during see germination. SnRK1, indeed, controls the expression of CALEOSINs and OLEOSINs. Those proteins are very important for lipids remobilization from oil droplets. Without their expression seed germination and subsequent establishment do not take place because of the absence of fuel to sustain these highly energy costly processes, which entirely depend on the catabolism of seed storages.
African trypanosomes are the causative agents of fatal diseases in humans and livestock. Trypanosomes show a complex lifecycle and shuttle between the transmitting vector, the tsetse (Glossina spec.), and the mammalian host. As a result of this the parasite undergoes tremendous changes in morphology and metabolism to adapt to the different living environments.
The two best-studied lifecycle stages are the procyclic forms (PCF) that live in the tsetse fly and the proliferative bloodstream form (BSF) that resides in the mammalian blood. The most conspicuous weapon that trypanosomes use to evade the host immune attack is a dense layer of a single protein type, the variant surface glycoprotein (VSG), which shields the entire cell surface. Immune evasion required high rates of surface membrane turnover and surface coat recycling.
Trypanosomes show highly polarised cell architecture with all major eukaryotic organelles (endoplasmic reticulum, Golgi apparatus, endosomal apparatus, lysosome, mitochondrion and peroxisome-like glycosomes) generally present in single copy. Furthermore, trypanosomes possess a single flagellum, which is important not only for cellular motility but also for cell division.
How the duplication of all these cellular components is coordinated in order to progresss through the cell division cycle is poorly understood.
We used trypanosomes as a model organism due to the relative simplicity and the polarised nature of their cell architecture and determined the duplication of all their compartments. This was only possible due to a new synchronisation approach developed during this project.
In the first part of the thesis a precise temporal map of the cell division cycle of the BSF T. brucei cell division cycle was generated. By the use of well-described morphological markers (K/N status, new flagellum outgrowth and DNA synthesis) the position of individual cells was determined with high temporal resolution; this allowed us for the first time to synchronise a cell population in silico without affecting the naturally asynchronous growth.
In the second part of the thesis we used this tool to follow duplication events of the Major organelles during progression through the cell division cycle. We precisely determined the time points of organelle duplication and found that it is ordered in trypanosomes. Furthermore we found that BSF T. brucei cells do not grow continuously, cell size start to increase rapidly, during a short period of time, late in the cell division cycle. We speculate that the initiation of cell volume increase is temporally separated from the formation of all secretory organelles in order to ensure maintenance of the protective coat, which must remain intact at all times in order for BSF trypanosomes to be able to evade the host immune response.
Background
Cancer vaccines can effectively establish clinically relevant tumor immunity. Novel sequencing approaches rapidly identify the mutational fingerprint of tumors, thus allowing to generate personalized tumor vaccines within a few weeks from diagnosis. Here, we report the case of a 62-year-old patient receiving a four-peptide-vaccine targeting the two sole mutations of his pancreatic tumor, identified via exome sequencing.
Methods
Vaccination started during chemotherapy in second complete remission and continued monthly thereafter. We tracked IFN-γ+ T cell responses against vaccine peptides in peripheral blood after 12, 17 and 34 vaccinations by analyzing T-cell receptor (TCR) repertoire diversity and epitope-binding regions of peptide-reactive T-cell lines and clones. By restricting analysis to sorted IFN-γ-producing T cells we could assure epitope-specificity, functionality, and TH1 polarization.
Results
A peptide-specific T-cell response against three of the four vaccine peptides could be detected sequentially. Molecular TCR analysis revealed a broad vaccine-reactive TCR repertoire with clones of discernible specificity. Four identical or convergent TCR sequences could be identified at more than one time-point, indicating timely persistence of vaccine-reactive T cells. One dominant TCR expressing a dual TCRVα chain could be found in three T-cell clones. The observed T-cell responses possibly contributed to clinical outcome: The patient is alive 6 years after initial diagnosis and in complete remission for 4 years now.
Conclusions
Therapeutic vaccination with a neoantigen-derived four-peptide vaccine resulted in a diverse and long-lasting immune response against these targets which was associated with prolonged clinical remission. These data warrant confirmation in a larger proof-of concept clinical trial.
This work summarizes the results of studies on three major aspects of platelet signaling and of the pathogenesis of immune thrombocytopenia. Therefore, this thesis is divided into three parts. i) Platelet activation and subsequent thrombus formation at sites of vascular injury is crucial for normal hemostasis, but it can also trigger myocardial infarction and stroke. The initial capture of flowing platelets to the injured vessel wall is mediated by the interaction of the glycoprotein (GP) Ib-V-IX complex with von Willebrand factor (vWF) immobilized on the exposed subendothelial extracellular matrix (ECM). The central importance of GPIb for platelet adhesion is well established, whereas GPV is generally considered to be of minor relevance for platelet physiology and thrombus formation. This study intended to clarify the relevance of this receptor during thrombus formation using Gp5-/- mice and mice with different double-deficiencies in GPV and in other platelet receptors. It was found that GPV and the collagen receptor integrin a2b1 have partially redundant functions in collagentriggered platelet aggregation. Further, it was revealed that GPV limits thrombus formation and impairs hemostasis in vivo. The data presented here demonstrate that the protective effect of GPVI-deficiency (another platelet collagen receptor) in arterial thrombosis and ischemic stroke depends on the expression of GPV. Moreover, it was demonstrated that lack of GPV restores the hemostatic function of mice lacking both GPVI and a2b1 or mice lacking GPVI and the C-type lectin receptor 2 (CLEC-2). Conclusively, GPV-depletion or blockade might have the potential to treat hemorrhagic disease states. ii) Platelets contain the two phospholipase (PL) D isoforms, PLD1 and PLD2, both of which presumably become activated upon platelet stimulation. However, the function of PLD in the process of platelet activation and aggregation has not been definitively explored. Thus, PLD-deficient mice were analyzed. Mice lacking PLD1 or PLD2 were viable, fertile and had normal platelet counts. PLD1 was found to be responsible for the inducible PLD-activity in platelets and to contribute to efficient integrin activation under static conditions. Moreover, flow adhesion experiments revealed that PLD1 is essential for efficient GPIb-mediated integrin activation. Consequently, Pld1-/- mice were protected from arterial thrombosis and ischemic brain infarction without affecting tail bleeding times. Hence, inhibition of PLD1 might be a novel approach for antithrombotic therapy. iii) Cellular activation of platelets or immune cells results in increased cytosolic calcium (Ca2+) levels. Store-operated calcium entry (SOCE) via the STIM1-Orai1 axis is the main route of Ca2+ entry downstream of immunoreceptor tyrosine-based activating motif (ITAM) receptor stimulation in mast cells and T cells. However, the requirement of Ca2+-mobilization in Fcg receptor (FcgR)-signaling and the relevance of STIM2 for T cell SOCE have been unclear. To address these questions, genetically modified mice lacking central molecules of the SOCE machinery were analyzed. Ca2+-measurements revealed that both STIM isoforms contribute to Ca2+-mobilization downstream of T cell receptor activation. Additionally, it was found that FcgR stimulation results in SOCE and is mediated by STIM1 and probably Orai1. Animal models of immune thrombocytopenia (ITP) revealed that SOCE is essential for platelet clearance and that both STIM isoforms contribute to the pathology of ITP. Moreover, in this work it was also demonstrated that STIM1 and Orai1 are essential in IgG-mediated systemic anaphylaxis. STIM2 contributes to IgG-mediated, but not to IgE-mediated anaphylaxis. The data indicate that interference with SOCE might become a new strategy to prevent or treat IgG-dependent autoimmune diseases.
Narrow resonances decaying into WW, WZ or ZZ boson pairs are searched for in 36.7 fb(-1) of proton-proton collision data at a centre-of-mass energy of root s = 13 TeV recorded with the ATLAS detector at the Large Hadron Collider in 2015 and 2016. The diboson system is reconstructed using pairs of large-radius jets with high transverse momentum and tagged as compatible with the hadronic decay of high-momentum Wor Zbosons, using jet mass and substructure properties. The search is sensitive to diboson resonances with masses in the range 1.2-5.0 TeV. No significant excess is observed in any signal region. Exclusion limits are set at the 95% confidence level on the production cross section times branching ratio to dibosons for a range of theories beyond the Standard Model. Model-dependent lower limits on the mass of new gauge bosons are set, with the highest limit set at 3.5 TeV in the context of mass-degenerate resonances that couple predominantly to bosons. (c) 2017 The Author(s). Published by Elsevier B.V.
The production of a top quark in association with a Z boson is investigated. The proton-proton collision data collected by the ATLAS experiment at the LHC in 2015 and 2016 at a centre-of-mass energy of root s = 13 TeV are used, corresponding to an integrated luminosity of 36.1 fb(-1). Events containing three identified leptons (electrons and/or muons) and two jets, one of which is identified as a b-quark jet are selected. The major backgrounds are diboson, tt($)over-bar and Z + jets production. A neural network is used to improve the background rejection and extract the signal. The resulting significance is 4.2 sigma in the data and the expected significance is 5.4 sigma. The measured cross-section for tZq production is 600 +/- 170(stat.)+/- 140(syst.)fb. (C) 2018 The Author(s). Published by Elsevier B.V.
A search for heavy resonances decaying into a Higgs boson (H) and a new particle (X) is reported, utilizing 36.1 fb(-1) of proton-proton collision data at root s = 13 TeV collected during 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. The particle Xis assumed to decay to a pair of light quarks, and the fully hadronic final state XH -> q (q) over bar 'b (b) over bar is analysed. The search considers the regime of high XH resonance masses, where the X and H bosons are both highly Lorentz-boosted and are each reconstructed using a single jet with large radius parameter. A two-dimensional phase space of XH mass versus X mass is scanned for evidence of a signal, over a range of XH resonance mass values between 1 TeV and 4 TeV, and for X particles with masses from 50 GeV to 1000 GeV. All search results are consistent with the expectations for the background due to Standard Model processes, and 95% CL upper limits are set, as a function of XH and X masses, on the production cross-section of the XH -> q (q) over bar 'b (b) over bar resonance. (c) 2018 The Author(s). Published by Elsevier B.V.
PURPOSE. To investigate the effect of selective retina therapy (SRT) on the release of AMD-relevant cell mediators, such as matrix metalloproteinases (MMPs), VEGF, and pigment epithelium derived factor (PEDF) using different laser spot sizes and densities.
METHODS. Porcine RPE-choroid explants were treated with a pulsed 532 nm Nd:YAG laser using (1) large spot sizes, (2) small spot sizes with a high-density (hd) treatment, and (3) small spot sizes with a low-density (1d) treatment. Explains were cultivated in modified Ussing chambers. RPE regeneration and RPE cell death were investigated by calcein-AM staining and immunofluorescence. The MMP release was examined via zymography and immunofluorescence. VEGF and PEDF secretion was analyzed by ELISA.
RESULTS. During pigment epithelium regeneration (PER), mitosis and RPE cell migration were observed. Four days after SRT (large spot size) the content of active MMP2 increased significantly (P < 0.01). Hd treatment with small spot sizes resulted also in an increase of active MMP2 (P < 0.05). In immunofluorescence explants showed a localized expression of MMP2 within the healing lesions after irradiation. The PEDF level increased significantly (P = 0.01) after SRT with large spot sizes. VEGF secretion decreased significantly (P < 0.05) following SRT with large spot sizes and with hd treatment of small spot sizes.
CONCLUSIONS. SRT induces a cytokine profile, which may improve the flux across Brach's membrane, slows down progression of early AMD by RPE regeneration, and inhibits the formation of choroidal neovascularization. The cytokine release depends on the size and density of applied laser spots.
A search for an invisibly decaying Higgs boson or dark matter candidates produced in association with a leptonically decaying Z boson in proton-proton collisions at root s = 13 TeV is presented. This search uses 36.1 fb(-1) of data collected by the ATLAS experiment at the Large Hadron Collider. No significant deviation from the expectation of the Standard Model backgrounds is observed. Assuming the Standard Model ZH production cross-section, an observed (expected) upper limit of 67% (39%) at the 95% confidence level is set on the branching ratio of invisible decays of the Higgs boson with mass m(H) = 125 GeV. The corresponding limits on the production cross-section of the ZH process with the invisible Higgs boson decays are also presented. Furthermore, exclusion limits on the dark matter candidate and mediator masses are reported in the framework of simplified dark matter models. (c) 2017 The Author(s). Published by Elsevier B.V.
Phosphines are important ligands in homogenous catalysis and have been crucial for many advances, such as in cross-coupling, hydrofunctionalization, or hydrogenation reactions. Herein we report the synthesis and application of a novel class of phosphines bearing ylide substituents. These phosphines are easily accessible via different synthetic routes from commercially available starting materials. Owing to the extra donation from the ylide group to the phosphorus center the ligands are unusually electron-rich and can thus function as strong electron donors. The donor capacity surpasses that of commonly used phosphines and carbenes and can easily be tuned by changing the substitution pattern at the ylidic carbon atom. The huge potential of ylide-functionalized phosphines in catalysis is demonstrated by their use in gold catalysis. Excellent performance at low catalyst loadings under mild reaction conditions is thus seen in different types of transformations.
The aim of this work is to provide further insight into the qualitative behavior of mechanical systems that are well described by Lennard-Jones type interactions on an atomistic scale. By means of Gamma-convergence techniques, we study the continuum limit of one-dimensional chains of atoms with finite range interactions of Lennard-Jones type, including the classical Lennard-Jones potentials. So far, explicit formula for the continuum limit were only available for the case of nearest and next-to-nearest neighbour interactions. In this work, we provide an explicit expression for the continuum limit in the case of finite range interactions. The obtained homogenization formula is given by the convexification of a Cauchy-Born energy density. Furthermore, we study rescaled energies in which bulk and surface contributions scale in the same way. The related discrete-to-continuum limit yields a rigorous derivation of a one-dimensional version of Griffith' fracture energy and thus generalizes earlier derivations for nearest and next-to-nearest neighbors to the case of finite range interactions. A crucial ingredient to our proofs is a novel decomposition of the energy that allows for re fined estimates.
IgG3 is the IgG subclass with the strongest effector functions among all four IgG subclasses and the highest degree of allelic variability among all constant immunoglobulin genes. Due to its genetic position, IgG3 is often the first isotype an antibody switches to before IgG1 or IgG4. Compared with the other IgG subclasses, it has a reduced half-life which is probably connected to a decreased affinity to the neonatal Fc receptor (FcRn). However, a few allelic variants harbor an amino acid replacement of His435 to Arg that reverts the half-life of the resulting IgG3 to the same level as the other IgG subclasses. Because of its functional impact, we hypothesized that the p.Arg435His variation could be associated with susceptibility to autoantibody-mediated diseases like pemphigus vulgaris (PV) and bullous pemphigoid (BP). Using a set of samples from German, Turkish, Egyptian, and Iranian patients and controls, we were able to demonstrate a genetic association of the p.Arg435His variation with PV risk, but not with BP risk. Our results suggest a hitherto unknown role for the function of IgG3 in the pathogenesis of PV.
A search is conducted for new resonances decaying into a W or Z boson and a 125 GeV Higgs boson in the nu(nu) over barb (b) over bar, l(+/-)nu b (b) over bar, and l(+)l(-)b (b) over bar final states, where l(+/-) = e(+/-) or mu(+/-), in pp collisions at root s = 13 TeV. The data used correspond to a total integrated luminosity of 36.1 fb(-1) collected with the ATLAS detector at the Large Hadron Collider during the 2015 and 2016 data-taking periods. The search is conducted by examining the reconstructed invariant or transverse mass distributions of Wh and Zh candidates for evidence of a localised excess in the mass range of 220 GeV up to 5 TeV. No significant excess is observed and the results are interpreted in terms of constraints on the production cross-section times branching fraction of heavy W' and Z' resonances in heavy-vector-triplet models and the CP-odd scalar boson A in two-Higgs-doublet models. Upper limits are placed at the 95% confidence level and range between 9.0 x 10(-4) pb and 7.3 x 10(-1) pb depending on the model and mass of the resonance.
Conjugative transposition drives the emergence of multidrug resistance in diverse bacterial pathogens, yet the mechanisms are poorly characterized. The Tn1549 conjugative transposon propagates resistance to the antibiotic vancomycin used for severe drug-resistant infections. Here, we present four high-resolution structures of the conserved Y-transposase of Tn1549 complexed with circular transposon DNA intermediates. The structures reveal individual transposition steps and explain how specific DNA distortion and cleavage mechanisms enable DNA strand exchange with an absolute minimum homology requirement. This appears to uniquely allow Tn916-like conjugative transposons to bypass DNA homology and insert into diverse genomic sites, expanding gene transfer. We further uncover a structural regulatory mechanism that prevents premature cleavage of the transposon DNA before a suitable target DNA is found and generate a peptide antagonist that interferes with the transposase-DNA structure to block transposition. Our results reveal mechanistic principles of conjugative transposition that could help control the spread of antibiotic resistance genes.
Background: Corynebacterium urealyticum, a pathogenic, multidrug resistant member of the mycolata, is known as causative agent of urinary tract infections although it is a bacterium of the skin flora. This pathogenic bacterium shares with the mycolata the property of having an unusual cell envelope composition and architecture, typical for the genus Corynebacterium. The cell wall of members of the mycolata contains channel-forming proteins for the uptake of solutes. Results: In this study, we provide novel information on the identification and characterization of a pore-forming protein in the cell wall of C. urealyticum DSM 7109. Detergent extracts of whole C. urealyticum cultures formed in lipid bilayer membranes slightly cation-selective pores with a single-channel conductance of 1.75 nS in 1 M KCl. Experiments with different salts and non-electrolytes suggested that the cell wall pore of C. urealyticum is wide and water-filled and has a diameter of about 1.8 nm. Molecular modelling and dynamics has been performed to obtain a model of the pore. For the search of the gene coding for the cell wall pore of C. urealyticum we looked in the known genome of C. urealyticum for a similar chromosomal localization of the porin gene to known porH and porA genes of other Corynebacterium strains. Three genes are located between the genes coding for GroEL2 and polyphosphate kinase (PKK2). Two of the genes (cur_1714 and cur_1715) were expressed in different constructs in C. glutamicum Delta porA Delta porH and in porin-deficient BL21 DE3 Omp8 E. coli strains. The results suggested that the gene cur_1714 codes alone for the cell wall channel. The cell wall porin of C. urealyticum termed PorACur was purified to homogeneity using different biochemical methods and had an apparent molecular mass of about 4 kDa on tricine-containing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Conclusions: Biophysical characterization of the purified protein (PorACur) suggested indeed that cur_1714 is the gene coding for the pore-forming protein in C. urealyticum because the protein formed in lipid bilayer experiments the same pores as the detergent extract of whole cells. The study is the first report of a cell wall channel in the pathogenic C. urealyticum.
Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN--like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1, which are associated with immune escape of cancer. Interestingly, differential expression of these genes was observed within the different cell lines and when comparing IL27 to IFN-. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3/-CD28 activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion. The levels of other T(H)1 cytokines were also enhanced or restored upon administration of anti-PD-L1. In addition, we show that the suppression of IL27 signaling by IL6-type cytokine pre-stimulationmimicking a situation occurring, for example, in IL6-secreting tumors or in tumor inflammation-induced cachexiacan be antagonized by antibodies against IL6-type cytokines or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased antigen presentation) might thus be increased by combining IL27 with blocking antibodies against PD-L1 or/and IL6-type cytokines.
The use of functional near-infrared spectroscopy (fNIRS) in block designs provides measures of cortical activity in ecologically valid environments. However, in some cases, the use of block designs may be problematic when data are not corrected for performance in a time-restricted block. We sought to investigate the effects of task complexity and processing speed on hemodynamic responses in an fNIRS block design. To differentiate the effects of task complexity and processing speed, 20 subjects completed the trail making test (TMT) in two versions (TMT-A versus TMT-B) and three different speed levels (slow versus moderate versus fast). During TMT-A, subjects are asked to connect encircled numbers in numerically ascending order (1-2-3 ... ). In the more complex TMT-B, subjects are instructed to connect encircled numbers and letters in alternating ascending order (1-A-2-B ... ). To illustrate the obscuring effects of processing speed on task complexity, we perform two different analyses. First, we analyze the classical measures of oxygenated blood, and second, we analyze the measures corrected for the number of processed items. Our results show large effects for processing speed within the bilateral inferior frontal gyrus, left dorsolateral prefrontal cortex, and superior parietal lobule (SPL). The TMT contrast did not show significant effects with classical measures, although trends are observed for higher activation during TMT-B. When corrected for processed items, higher activity for TMT-B in comparison to TMT-A is found within the SPL. The results are discussed in light of recent research designs, and simple to use correction methods are suggested. (c) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA (R) trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk.
Methods: CARMELINA (R) is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, >= 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA (R) was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided a-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure.
Results: Between July 2013 and August 2016, 6980 patients were randomized and took >= 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean +/- SD age was 65.8 +/- 9.1 years, HbA1c 7.9 +/- 1.0%, BMI 31.3 +/- 5.3 kg/m(2), and eGFR 55 +/- 25 mL/min/1.73 m(2). A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m(2) or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common.
Conclusions: CARMELINA (R) will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk.
Human herpesvirus 6A (HHV-6A) replicates in peripheral blood mononuclear cells (PBMCs) and various T-cell lines in vitro. Intriguingly, the virus can also establish latency in these cells, but it remains unknown what influences the decision between lytic replication and the latency of the virus. Incoming virus genomes are confronted with the nuclear domain 10 (ND10) complex as part of an intrinsic antiviral response. Most herpesviruses can efficiently subvert ND10, but its role in HHV-6A infection remains poorly understood. In this study, we investigated if the ND10 complex affects HHV-6A replication and contributes to the silencing of the virus genome during latency. We could demonstrate that ND10 complex was not dissociated upon infection, while the number of ND10 bodies was reduced in lytically infected cells. Virus replication was significantly enhanced upon knock down of the ND10 complex using shRNAs against its major constituents promyelocytic leukemia protein (PML), hDaxx, and Sp100. In addition, we could demonstrate that viral genes are more efficiently silenced in the presence of a functional ND10 complex. Our data thereby provides the first evidence that the cellular ND10 complex plays an important role in suppressing HHV-6A lytic replication and the silencing of the virus genome in latently infected cells.
Background:
Studies have reported on the incidence of sedation-related adverse events (AEs), but little is known about their impact on health care costs and resource use.
Methods: Health care providers and payers in five countries were recruited for an online survey by independent administrators to ensure that investigators and respondents were blinded to each other. Surveys were conducted in the local language and began with a "screener" to ensure that respondents had relevant expertise and experience. Responses were analyzed using Excel and R, with the Dixon's Q statistic used to identify and remove outliers. Global and country-specific average treatment patterns were calculated via bootstrapping; costs were mean values. The sum product of costs and intervention probability gave a cost per AE.
Results: Responses were received from 101 providers and 26 payers, the majority having. 5 years of experience. At a minimum, the respondents performed a total of 3,430 procedural sedations per month. All AEs detailed occurred in clinical practice in the last year and were reported to cause procedural delays and cancellations in some patients. Standard procedural sedation costs ranged from (sic)74 (Germany) to $2,300 (US). Respondents estimated that AEs would increase costs by between 16% (Italy) and 179% (US). Hypotension was reported as the most commonly observed AE with an associated global mean cost (interquartile range) of $43 ($27-$68). Other frequent AEs, including mild hypotension, bradycardia, tachycardia, mild oxygen desaturation, hypertension, and brief apnea, were estimated to increase health care spending on procedural sedation by $2.2 billion annually in the US.
Conclusion: All sedation-related AEs can increase health care costs and result in substantial delays or cancellations of subsequent procedures. The prevention of even minor AEs during procedural sedation may be crucial to ensuring its value as a health care service.
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with potential severe consequences. Its pathogenesis involves hyperglycemia-linked mechanisms, which may include changes in the expression of neurotrophic growth factors. We analyzed the expression of 29 factors potentially related to nerve degeneration and regeneration in skin biopsies from 13 type 1 diabetic pancreas and kidney recipients with severe DPN including severe depletion of intraepidermal nerve fibers (IENF) in lower limb skin biopsies (group Tx1 1st examination). The investigation was repeated after a median 28-month period of normoglycemia achieved by pancreas transplantation (group Tx1 2nd examination). The same tests were performed in 13 stable normoglycemic pancreas and kidney recipients 6-12 years posttransplantation (group Tx2), in 12 matched healthy controls (group HC), and in 12 type 1 diabetic subjects without severe DPN (group DM). Compared to DM and HC groups, we found a significantly higher (p < 0.05-0.001) expression of NGF (nerve growth factor), NGFR (NGF receptor), NTRK1 (neurotrophic receptor tyrosine kinase 1), GDNF (glial cell-derived neurotrophic factor), GFRA1 (GDNF family receptor alpha 1), and GFAP (glial fibrillary acidic protein) in both transplant groups (Tx1 and Tx2). Enhanced expression of these factors was not normalized following the median 28-month period of normoglycemia (Tx1 2nd examination) and negatively correlated with IENF density and with electrophysiological indices of DPN (vibration perception threshold, electromyography, and autonomic tests). In contrast to our expectation, the expression of most of 29 selected factors related to neural regeneration was comparable in subjects with severe peripheral nerve fiber depletion and healthy controls and the expression of six factors was significantly upregulated. These findings may be important for better understanding the pathophysiology of nerve regeneration and for the development of intervention strategies.
The Dual Olfactory Pathway in the Honeybee Brain: Sensory Supply and Electrophysiological Properties
(2018)
The olfactory sense is of utmost importance for honeybees, Apis mellifera. Honeybees use olfaction for communication within the hive, for the identification of nest mates and non-nest mates, the localization of food sources, and in case of drones (males), for the detection of the queen and mating. Honeybees, therefore, can serve as excellent model systems for an integrative analysis of an elaborated olfactory system.
To efficiently filter odorants out of the air with their antennae, honeybees possess a multitude of sensilla that contain the olfactory sensory neurons (OSN). Three types of olfactory sensilla are known from honeybee worker antennae: Sensilla trichoidea, Sensilla basiconica and Sensilla placodea. In the sensilla, odorant receptors that are located in the dendritic arborizations of the OSNs transduce the odorant information into electrical information. Approximately 60.000 OSN axons project in two parallel bundles along the antenna into the brain. Before they enter the primary olfactory brain center, the antennal lobe (AL), they diverge into four distinct tracts (T1-T4). OSNs relay onto ~3.000-4.000 local interneurons (LN) and ~900 projection neurons (PN), the output neurons of the AL. The axons of the OSNs together with neurites from LNs and PNs form spheroidal neuropil units, the so-called glomeruli. OSN axons from the four AL input tracts (T1-T4) project into four glomerular clusters. LNs interconnect the AL glomeruli, whereas PNs relay the information to the next brain centers, the mushroom body (MB) - associated with sensory integration, learning and memory - and the lateral horn (LH). In honeybees, PNs project to the MBs and the LH via two separate tracts, the medial and the lateral antennal-lobe tract (m/lALT) which run in parallel in opposing directions. The mALT runs first to the MB and then to the LH, the lALT runs first to the LH and then to the MB. This dual olfactory pathway represents a feature unique to Hymenoptera. Interestingly, both tracts were shown to process information about similar sets of odorants by extracting different features. Individual mALT PNs are more odor specific than lALT PNs. On the other hand, lALT PNs have higher spontaneous and higher odor response action potential (AP) frequencies than mALT PNs. In the MBs, PNs form synapses with ~184.000 Kenyon cells (KC), which are the MB intrinsic neurons. KCs, in contrast to PNs, show almost no spontaneous activity and employ a spatially and temporally sparse code for odor coding.
In manuscript I of my thesis, I investigated whether the differences in specificity of odor responses between m- and lALT are due to differences in the synaptic input. Therefore, I investigated the axonal projection patterns of OSNs housed in S. basiconica in honeybee workers and compared them with S. trichoidea and S. placodea using selective anterograde labeling with fluorescent tracers and confocal- microscopy analyses of axonal projections in AL glomeruli. Axons of S. basiconica-associated OSNs preferentially projected into the T3 input-tract cluster in the AL, whereas the two other types of sensilla did not show a preference for a specific glomerular cluster. T3- associated glomeruli had previously been shown to be innervated by mALT PNs. Interestingly, S. basiconica as well as a number of T3 glomeruli lack in drones. Therefore I set out to determine whether this was associated with the reduction of glomeruli innervated by mALT PNs. Retrograde tracing of mALT PNs in drones and counting of innervated glomeruli showed that the number of mALT-associated glomeruli was strongly reduced in drones compared to workers. The preferential projections of S. basiconica-associated OSNs into T3 glomeruli in female workers together with the reduction of mALT-associated glomeruli in drones support the presence of a female-specific olfactory subsystem that is partly innervated by OSNs from S. basiconica and is associated with mALT projection neurons. As mALT PNs were shown to be more odor specific, I suppose that already the OSNs in this subsystem are more odor specific than lALT associated OSNs. I conclude that this female-specific subsystem allows the worker honeybees to respond adequately to the enormous variety of odorants they experience during their lifetime.
In manuscript II, I investigated the ion channel composition of mALT and lALT PNs and KCs in situ. This approach represents the first study dealing with the honeybee PN and KC ion channel composition under standard conditions in an intact brain preparation. With these recordings I set out to investigate the potential impact of intrinsic neuronal properties on the differences between m- and lALT PNs and on the sparse odor coding properties of KCs. In PNs, I identified a set of Na+ currents and diverse K+ currents depending on voltage and Na+ or Ca2+ that support relatively high spontaneous and odor response AP frequencies. This set of currents did not significantly differ between mALT and lALT PNs, but targets for potential modulation of currents leading to differences in AP frequencies were found between both types of PNs. In contrast to PNs, KCs have very prominent K+ currents, which are likely to contribute to the sparse response fashion observed in KCs. Furthermore, Ca2+ dependent K+ currents were found, which may be of importance for coincidence detection, learning and memory formation.
Finally, I conclude that the differences in odor specificity between m- and lALT PNs are due to their synaptic input from different sets of OSNs and potential processing by LNs. The differences in spontaneous activity between the two tracts may be caused by different neuronal modulation or, in addition, also by interaction with LNs. The temporally sparse representation of odors in KCs is very likely based on the intrinsic KC properties, whereas general excitability and spatial sparseness are likely to be regulated through GABAergic feedback neurons.
BD is a severe and highly prevalent psychiatric illness characterized by oscillating mood episodes, where patients express either depressed mood, anhedonia, decreased activation along with concentration difficulties and sleep disturbances, or elevated mood with hyperactivity and loss of inhibitions. Between mood episodes, patients return to a relatively normal state of functioning without mood symptoms. Previous research on underlying neuronal mechanisms has led to a model of neuronal dysfunction in BD which states that BD arises from disruption in early development within brain networks that modulate emotional behavior. These abnormalities in the structure and function of key emotional control networks then lead to decreased connectivity among ventral prefrontal networks and limbic brain regions. This in turn creates a loss of emotional homeostasis, putting bipolar patients at risk for developing extreme mood states and switching among mood states. Two core components for BD have been identified, a hyperactive emotion processing system and a hypoactive cognitive functions system. It is controversial whether these deficits are still detectable in euthymia, so it is unclear if hyper- and hypoactivations represent state or trait-like characteristics. The aim of this study was to research both core components of BD with a paradigm eliciting differential activations in both cognitive and emotion processing networks. For this, an emotional word working memory paradigm was constructed to test for differences between manic, depressive, and remitted patients as well as a healthy control group. Differences were assessed in behavior, brain activation (as a correlate for the hypoactive cognitive functions system), measured with near-infrared spectroscopy (fNIRS), and electrophysiological changes in the late positive potential (as a correlate for the hyperactive emotion processing system), an event-related potential (ERP) measured with electroencephalography. 47 patients in the acutely ill phase and 45 healthy controls were measured. Of the 47 patients, 18 returned to the clinic for a second testing while in remission for at least 3 months. Acutely ill patients were classified into 4 groups according to their disorder status: a mildly depressed group, a depressed group, a manic group, and a mixed group along DSM-IV criteria. Analyses were calculated for 3 load conditions (1-back, 2-back and 3-back) and 3 valence conditions (negative, neutral, positive) for behavioral measures reaction time and omission errors, for brain activation and event related potential changes.
Results indicate that ill patients differed from controls in their behavioral performance, but the difference in performance was modulated by the mood state they were in. Depressed patients showed the most severe differences in all behavioral measures, while manic and mixed patients differed from controls only upon different valence conditions. Brain activation changes were most pronounced in mildly depressed and manic patients, depressed patients and mixed patients did not differ as much from controls. ERP changes showed a significant difference only between mixed patients and controls, where mixed patients had an overall much higher ERP amplitude. When remitted patients were compared to controls, no differences in behavior, brain activation or ERP amplitude could be found. However, the same was true for differences in patients between acutely ill and remitted state. When looking at the overall data, the following conclusion can be drawn: assuming that the brain activation seen in the prefrontal cortex is part of the dorsal cognitive system, then this is the predominantly disturbed system in depressed patients who show only small changes in the ERP. In contrast, the predominantly disturbed system in manic and mixed patients is the ventral emotion processing system, which can be seen in a hyper-activation of ERP related neural correlates in mixed and hypo-activated neural correlates of the LPP in manic patients. When patients are remitted, the cognitive system regains temporary stability, and can be compared to that of healthy controls, while the emotion processing system remains dysfunctional and underlies still detectable performance deficits.
Flux distribution is an important tool to understand the variability processes in activegalactic nuclei. We now have available a great deal of observational evidences pointing towards thepresence of log-normal components in the high energy light curves, and different models have beenproposed to explain these data. Here, we collect some of the recent developments on this topic usingthe well-known blazar Mrk 501 as example of complex and interesting aspects coming from its fluxdistribution in different energy ranges and at different timescales. The observational data we refer toare those collected in a complementary manner by Fermi-LAT over multiple years, and by the FirstG-APD Cherenkov Telescope (FACT) telescope and the H.E.S.S. array in correspondence of the brightflare of June 2014
The abilities to comprehend and critically evaluate scientific texts and the various arguments stated in these texts are an important aspect of scientific literacy, but these competences are usually not formally taught to students. Previous research indicates that, although undergraduate students evaluate the claims and evidence they find in scientific
documents to some extent, these evaluations usually fail to meet normative standards. In addition, students’ use of source information for evaluation is often insufficient. The rise of the internet and the increased accessibility of information have yielded some additional challenges that highlight the importance of adequate training and instruction.The aim of the present work was to further examine introductory students’ competences to systematically and heuristically evaluate scientific information, to identify relevant strategies that are involved in a successful evaluation, and to use this knowledge to design appropriate interventions for fostering epistemic competences in university students.To this end, a number of computer-based studies, including both quantitative and qualitative data as well as experimental designs, were developed. The first two studies were designed to specify educational needs and to reveal helpful processing strategies that are required in different tasks and situations. Two expert-novice comparisons were developed, whereby the performance of German students of psychology (novices) was compared to the performance of scientists from the domain of psychology (experts) in a number of different tasks, such as systematic plausibility evaluations of informal arguments (Study 1) or heuristic evaluations of the credibility of multiple scientific documents (Study 2). A think-aloud procedure was used
to identify specific strategies that were applied in both groups during task completion, and that possibly mediated performance differences between students and scientists. In addition, relationships between different strategies and between strategy use and relevant conceptual knowledge was examined. Based on the results of the expert-novice comparisons, an intervention study, consisting of two training experiments, was constructed to foster some
competences that proved to be particularly deficient in the comparisons (Study 3). Study 1 examined introductory students’ abilities to accurately judge the plausibility of informal arguments according to normative standards, to recognise common argumentation fallacies, and to identify different structural components of arguments. The results from Study 1 indicate that many students, compared to scientists, lack relevant knowledge about the structure of arguments, and that normatively accurate evaluations of their plausibility seem to be challenging in this group. Often, common argumentation fallacies were not identified correctly. Importantly, these deficits were partly mediated by differences in strategy use: It was especially difficult for students to pay sufficient attention to the relationship between argument components when forming their judgements. Moreover, they frequently relied on their intuition or opinion as a criterion for evaluation, whereas scientists predominantly determined quality of arguments based on their internal consistency.
In addition to students’ evaluation of the plausibility of informal arguments, Study 2 examined introductory students’ competences to evaluate the credibility of multiple scientific texts, and to use source characteristics for evaluation. The results show that students struggled not only to judge the plausibility of arguments correctly, but also to heuristically judge the credibility of science texts, and these deficits were fully mediated by their insufficient use of source information. In contrast, scientists were able to apply different strategies in a flexible manner. When the conditions for evaluation did not allow systematic processing (i.e. time limit), they primarily used source characteristics for their evaluations. However, when
systematic evaluations were possible (i.e. no time limit), they used more sophisticated normative criteria for their evaluations, such as paying attention to the internal consistency of arguments (cf. Study 1). Results also showed that students, in contrast to experts, lacked relevant knowledge about different publication types, and this was related to their ability to correctly determine document credibility. The results from the expert-novice comparisons also suggest that the competences assessed in both tasks might develop as a result of a more fundamental form of scientific literacy and discipline expertise. Performances in all tasks were positively related. On the basis of these results, two training experiments were developed that aimed at fostering university students’ competences to understand and evaluate informal arguments (Study 3). Experiment 1 describes an intervention approach in which students were familiarised with the formal structure of arguments based on Toulmin’s (1958) argumentation model. The performance of the experimental group to identify the structural components of this model was compared to the performance of a control group in which speed reading skills were practiced, using a pre-post-follow-up design. Results show that the training was successful for improving the comprehension of more complex arguments and relational aspects between key components in the posttest, compared to the control group. Moreover, an interaction effect was found with study performance. High achieving students with above average grades profited the most from the training intervention. Experiment 2 showed that
training in plausibility, normative criteria of argument evaluation, and argumentation fallacies improved students’ abilities to evaluate the plausibility of arguments and, in addition, their competences to recognise structural components of arguments, compared to a speed-reading control group. These results have important implications for education and practice, which will be discussed in detail in this dissertation.
Objective Refractory coeliac disease (RCD) is a potentially hazardous complication of coeliac disease (CD). In contrast to RCD type I, RCD type II is a precursor entity of enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL. Using high-throughput sequencing (HTS), we aimed to establish the small-intestinal T-cell repertoire (TCR) in CD and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis. Design DNA extracted from duodenal mucosa specimens of controls (n=9), active coeliacs (n=10), coeliacs on a gluten-free diet (n=9), RCD type I (n= 8), RCD type II (n= 8) and unclassified Marsh I cases (n= 3) collected from 2002 to 2013 was examined by TCR beta-complementarity- determining regions 3 (CDR3) multiplex PCR followed by HTS of the amplicons. Results On average, 106 sequence reads per sample were generated consisting of up to 900 individual TCR beta rearrangements. In RCD type II, the most frequent clonotypes (ie, sequence reads with identical CDR3) represent in average 42.6% of all TCR beta rearrangements, which was significantly higher than in controls (6.8%; p<0.01) or RCD type I (6.7%; p<0.01). Repeat endoscopies in individual patients revealed stability of clonotypes for up to several years without clinical symptoms of EATL. Dominant clonotypes identified in individual patients with RCD type II were unique and not related between patients. CD-associated, gliad-independent CDR3 motifs were only detectable at low frequencies. Conclusions TCR beta-HTS analysis unravels the TCR in CD and allows detailed analysis of individual TCR beta rearrangements. Dominant TCR beta sequences identified in patients with RCD type II are unique and not homologous to known gliadin-specific TCR sequences, supporting the assumption that these clonal T-cells expand independent of gluten stimulation.
Background
Wilms’ tumor 1-associating protein (WTAP) is a nuclear protein, which is ubiquitously expressed in many tissues. Furthermore, in various types of malignancies WTAP is overexpressed and plays a role as an oncogene. The function of WTAP in diffuse large B-cell lymphoma (DLBCL), however, remains unclear.
Methods
Immunohistochemistry was applied to evaluate the levels of WTAP expression in DLBCL tissues and normal lymphoid tissues. Overexpression and knock-down of WTAP in DLBCL cell lines, verified on mRNA and protein level served to analyze cell proliferation and apoptosis in DLBCL cell lines by flow cytometry. Finally, co-immunoprecipitation (Co-IP), IP, and GST-pull down assessed the interaction of WTAP with Heat shock protein 90 (Hsp90) and B-cell lymphoma 6 (BCL6) as well as determined the extend of its ubiquitinylation.
Results
WTAP protein levels were consistently upregulated in DLBCL tissues. WTAP promoted DLBCL cell proliferation and improved the ability to confront apoptosis, while knockdown of WTAP in DLBCL cell lines allowed a significant higher apoptosis rate after treatment with Etoposide, an anti-tumor drug. The stable expression of WTAP was depended on Hsp90. In line, we demonstrated that WTAP could form a complex with BCL6 via Hsp90 in vivo and in vitro.
Conclusion
WTAP is highly expressed in DLBCL, promoting growth and anti-apoptosis in DLBCL cell lines. WTAP is a client protein of Hsp90 and can appear in a complex with BCL6 and Hsp90 in DLBCL. Down-regulation of WTAP could improve the chemotherapeutic treatments in DLBCL.
Background:
Drug induced immune hemolytic anemia (DIIHA) is a rare complication and often underdiagnosed. DIIHA is frequently associated with a bad outcome, including organ failure and even death. For the last decades, ceftriaxone has been one of the most common drugs causing DIIHA, and ceftriaxone-induced immune hemolytic anemia (IHA) has especially been reported to cause severe complications and fatal outcomes.
Case Presentation:
A 76-year-old male patient was treated with ceftriaxone for cholangitis. Short time after antibiotic exposure the patient was referred to intensive care unit due to cardiopulmonary instability. Hemolysis was observed on laboratory testing and the patient developed severe renal failure with a need for hemodialysis for 2 weeks. Medical history revealed that the patient had been previously exposed to ceftriaxone less than 3 weeks before with subsequent hemolytic reaction. Further causes for hemolytic anemia were excluded and drug-induced immune hemolytic (DIIHA) anemia to ceftriaxone could be confirmed.
Conclusions:
The case demonstrates the severity of ceftriaxone-induced immune hemolytic anemia, a rare, but immediately life-threatening condition of a frequently used antibiotic in clinical practice. Early and correct diagnosis of DIIHA is crucial, as immediate withdrawal of the causative drug is essential for the patient prognosis. Thus, awareness for this complication must be raised among treating physicians.
Highly invasive animal based test procedures for risk assessment such as the Draize eye test are under increasing criticism due to poor transferability for the human organism and animal-welfare concerns. However, besides all efforts, the Draize eye test is still not completely replaced by alternative animal-free methods. To develop an in vitro test to identify all categories of eye irritation, we combined organotypic cornea models based on primary human cells with an electrical readout system that measures the impedance of the test models. First, we showed that employing a primary human cornea epithelial cell based model is advantageous in native marker expression to the primary human epidermal keratinocytes derived models. Secondly, by employing a non-destructive measuring system based on impedance spectroscopy, we could increase the sensitivity of the test system. Thereby, all globally harmonized systems categories of eye irritation could be identified by repeated measurements over a period of 7 days. Based on a novel prediction model we achieved an accuracy of 78% with a reproducibility of 88.9% to determine all three categories of eye irritation in one single test. This could pave the way according to the 3R principle to replace the Draize eye test.
Results from a search for supersymmetry in events with four or more charged leptons (electrons, muons and taus) are presented. The analysis uses a data sample corresponding to 36.1 fb(-1) of proton-proton collisions delivered by the Large Hadron Collider at root s = 13 TeV and recorded by the ATLAS detector. Four-lepton signal regions with up to two hadronically decaying taus are designed to target a range of supersymmetric scenarios that can be either enriched in or depleted of events involving the production and decay of a Z boson. Data yields are consistent with Standard Model expectations and results are used to set upper limits on the event yields from processes beyond the Standard Model. Exclusion limits are set at the 95% confidence level in simplified models of general gauge mediated supersymmetry, where Higgsino masses are excluded up to 295 GeV. In R-parity-violating simplified models with decays of the lightest supersymmetric particle to charged leptons, lower limits of 1.46, 1.06, and 2.25 TeV are placed on wino, slepton and gluino masses, respectively.
A detailed study of multiparticle azimuthal correlations is presented using pp data at root s = 5.02 and 13 TeV, and p+Pb data at root s(NN) = 5.02 TeV, recorded with the ATLAS detector at the CERN Large Hadron Collider. The azimuthal correlations are probed using four-particle cumulants c(n){4} and flow coefficients v(n){4} = (-c(n){4})(1/4) for n = 2 and 3, with the goal of extracting long-range multiparticle azimuthal correlation signals and suppressing the short-range correlations. The values of c(n){4} are obtained as a function of the average number of charged particles per event, < N-ch >, using the recently proposed two-subevent and three-subevent cumulant methods, and compared with results obtained with the standard cumulant method. The standard method is found to be strongly biased by short-range correlations, which originate mostly from jetswith a positive contribution to c(n){4}. The threesubevent method, on the other hand, is found to be least sensitive to short-range correlations. The three-subevent method gives a negative c(2){4}, and therefore a well-defined v(2){4}, nearly independent of < N-ch >, which implies that the long-range multiparticle azimuthal correlations persist to events with low multiplicity. Furthermore, v(2){4} is found to be smaller than the v(2){2} measured using the two-particle correlation method, as expected for long-range collective behavior. Finally, the measured values of v(2){4} and v(2){2} are used to estimate the number of sources relevant for the initial eccentricity in the collision geometry. The results based on the subevent cumulant technique provide direct evidence, in small collision systems, for a long-range collectivity involving many particles distributed across a broad rapidity interval.
I. Timing is a crucial feature in organisms that live within a variable and changing environment. Complex mechanisms to measure time are wide-spread and were shown to exist in many taxa. These mechanisms are expected to provide fitness benefits by enabling organisms to anticipate environmental changes and adapt accordingly. However, very few studies have addressed the adaptive value of proper timing. The objective of this PhD-project was to investigate mechanisms and fitness consequences of timing decisions concerning colony phenology and foraging activity in the honey bee (Apis mellifera), a social insect species with a high degree of social organization and one of the most important pollinators of wild plants and crops. In chapter II, a study is presented that aimed to identify the consequences of disrupted synchrony between colony phenology and the local environment by manipulating the timing of brood onset after hibernation. In a follow-up experiment, the importance of environmental factors for the timing of brood onset was investigated to assess the potential of climate change to disrupt synchronization of colony phenology (Chapter III). Chapter IV aimed to prove for the first time that honey bees can use interval time-place learning to improve foraging activity in a variable environment. Chapter V investigates the fitness benefits of information exchange between nest mates via waggle dance communication about a resource environment that is heterogeneous in space and time.
II. In the study presented in chapter II, the importance of the timing of brood onset after hibernation as critical point in honey bee colony phenology in temperate zones was investigated. Honey bee colonies were overwintered at two climatically different sites. By translocating colonies from each site to the other in late winter, timing of brood onset was manipulated and consequently colony phenology was desynchronized with the local environment. Delaying colony phenology in respect to the local environment decreased the capability of colonies to exploit the abundant spring bloom. Early brood onset, on the other hand, increased the loads of the brood parasite Varroa destructor later in the season with negative impact on colony worker population size. This indicates a timing related trade-off and illustrates the importance of investigating effects of climate change on complex multi-trophic systems. It can be concluded that timing of brood onset in honey bees is an important fitness relevant step for colony phenology that is highly sensitive to climatic conditions in late winter. Further, phenology shifts and mismatches driven by climate change can have severe fitness consequences.
III. In chapter III, I assess the importance of the environmental factors ambient temperature and photoperiod as well as elapsed time on the timing of brood onset. Twenty-four hibernating honey bee colonies were placed into environmental chambers and allocated to different combinations of two temperature regimes and three different light regimes. Brood onset was identified non-invasively by tracking comb temperature within the winter cluster. The experiment revealed that ambient temperature plays a major role in the timing of brood onset, but the response of honey bee colonies to temperature increases is modified by photoperiod. Further, the data indicate the involvement of an internal clock. I conclude that the timing of brood onset is complex but probably highly susceptible to climate change and especially spells of warm weather in winter.
IV. In chapter IV, it was examined if honey bees are capable of interval time-place learning and if this ability improves foraging efficiency in a dynamic resource environment. In a field experiment with artificial feeders, foragers were able to learn time intervals and use this ability to anticipate time periods during which feeders were active. Further, interval time-place learning enabled foragers to increase nectar uptake rates. It was concluded that interval time-place learning can help honey bee foragers to adapt to the complex and variable temporal patterns of floral resource environments.
V. The study presented in chapter V identified the importance of the honey bee waggle dance communication for the spatiotemporal coordination of honey bee foraging activity in resource environments that can vary from day to day. Consequences of disrupting the instructional component of honey bee dance communication were investigated in eight temperate zone landscapes with different levels of spatiotemporal complexity. While nectar uptake of colonies was not affected, waggle dance communication significantly benefitted pollen harvest irrespective of landscape complexity. I suggest that this is explained by the fact that honey bees prefer to forage pollen in semi-natural habitats, which provide diverse resource species but are sparse and presumably hard to find in intensively managed agricultural landscapes. I conclude that waggle dance communication helps to ensure a sufficient and diverse pollen diet which is crucial for honey bee colony health.
VI. In my PhD-project, I could show that honey bee colonies are able to adapt their activities to a seasonally and daily changing environment, which affects resource uptake, colony development, colony health and ultimately colony fitness. Ongoing global change, however, puts timing in honey bee colonies at risk. Climate change has the potential to cause mismatches with the local resource environment. Intensivation of agricultural management with decreased resource diversity and short resource peaks in spring followed by distinctive gaps increases the probability of mismatches. Even the highly efficient foraging system of honey bees might not ensure a sufficiently diverse and healthy diet in such an environment. The global introduction of the parasitic mite V. destructor and the increased exposure to pesticides in intensively managed landscapes further degrades honey bee colony health. This might lead to reduced cognitive capabilities in workers and impact the communication and social organization in colonies, thereby undermining the ability of honey bee colonies to adapt to their environment.
Speckle tracking-derived bi-atrial strain before and after eleven weeks of training in elite rowers
(2018)
The left (LA) and right (RA) atria undergo adaptive remodeling in response to hemodynamic stress not only induced by endurance exercise but also as part of several cardiovascular diseases thereby confounding differential diagnosis. Echocardiographic assessment of the atria with novel speckle tracking (STE)-derived variables broadens the diagnostic spectrum compared to conventional analyses and has the potential to differentiate physiologic from pathologic changes. The purpose of this study was to assess and categorize baseline values of bi-atrial structure and function in elite rowers according to recommended cutoffs, and to assess the cardiac changes occurring with endurance training. Therefore, fifteen elite rowers underwent 2D-echocardiographic analysis of established variables of cardiac structure and function as well as STE-derived variables of bi-atrial function. Measurements were performed at baseline and after eleven weeks of extensive training. 40% of athletes displayed mildly enlarged LA and 47% mildly enlarged RA at baseline, whereas no athlete fell below the lower reference values of LA and RA reservoir strain. Average power during a 2000 m ergometer rowing test (P2000 m) improved from 426 +/- 39 W to 442 +/- 34 W (p = 0.010) but there were no changes of echocardiographic variables following training. In elite rowers, longitudinal bi-atrial strain assessment indicates normal resting function of structurally enlarged atria and thereby may assist to differentiate between exercise-induced versus disease-associated structural cardiac changes in which function is commonly impaired.
Neuroanatomy of the equine brain as revealed by high-field (3Tesla) magnetic-resonance-imaging
(2018)
In this study, the morphology of the horse brain (Equus caballus) is decribed in detail using high field MRI. The study includes sagittal, dorsal, and transverse T2-weighted images at 0.25 mm resolution at 3 Tesla and 3D models of the brain presenting the external morphology of the brain. Representative gallocyanin stained histological slides of the same brain are presented. The images represent a useful tool for MR image interpretation in horses and may serve as a starting point for further research aiming at in vivo analysis in this species.
This paper presents a measurement of the W boson production cross section and the W+/W- cross-section ratio, both in association with jets, in proton-proton collisions at root s = 8 TeV with the ATLAS experiment at the Large Hadron Collider. The measurement is performed in final states containing one electron and missing transverse momentum using data corresponding to an integrated luminosity of 20.2 fb(-1). Differential cross sections for events with at least one or two jets are presented for a range of observables, including jet transverse momenta and rapidities, the scalar sum of transverse momenta of the visible particles and the missing transverse momentum in the event, and the transverse momentum of the W boson. For a subset of the observables, the differential cross sections of positively and negatively charged W bosons are measured separately. In the cross-section ratio of W+/W- the dominant systematic uncertainties cancel out, improving the measurement precision by up to a factor of nine. The observables and ratios selected for this paper provide valuable input for the up quark, down quark, and gluon parton distribution functions of the proton.
Peripheral neuropathy is accompanied by changes in the neuronal environment. The blood-nerve barrier (BNB) is crucial in protecting the neural homeostasis: Tight junctions (TJ) seal paracellular spaces and thus prevent external stimuli from entering. In different models of neuropathic pain, the BNB is impaired, thus contributing to local damage, immune cell invasion and, ultimately, the development of neuropathy with its symptoms. In this study, we examined changes in expression and microstructural localization of two key tight junction proteins (TJP), claudin-1 and the cytoplasmic anchoring ZO-1, in the sciatic nerve of mice subjected to chronic constriction injury (CCI). Via qPCR and analysis of fluorescence immunohistochemistry, a marked downregulation of mRNA as well as decreased fluorescence intensity were observed in the nerve for both proteins. Moreover, a distinct zig-zag structure for both proteins located at cell-cell contacts, indicative of the localization of TJs, was observed in the perineurial compartment of sham-operated animals. This microstructural location in cell-cell-contacts was lost in neuropathy as semiquantified via computational analysis, based on a novel algorithm. In summary, we provide evidence that peripheral neuropathy is not only associated with decrease in relevant TJPs but also exhibits alterations in TJP arrangement and loss in barrier tightness, presumably due to internalization. Specifically, semiquantification of TJP in cell-cell-contacts of microcompartments could be used in the future for routine clinical samples of patients with neuropathy.
In social groups, infections have the potential to spread rapidly and cause disease outbreaks. Here, we show that in a social insect, the ant Lasius neglectus, the negative consequences of fungal infections (Metarhizium brunneum) can be mitigated by employing an efficient multicomponent behaviour, termed destructive disinfection, which prevents further spread of the disease through the colony. Ants specifically target infected pupae during the pathogens non-contagious incubation period, utilising chemical 'sickness cues' emitted by pupae. They then remove the pupal cocoon, perforate its cuticle and administer antimicrobial poison, which enters the body and prevents pathogen replication from the inside out. Like the immune system of a metazoan body that specifically targets and eliminates infected cells, ants destroy infected brood to stop the pathogen completing its lifecycle, thus protecting the rest of the colony. Hence, in an analogous fashion, the same principles of disease defence apply at different levels of biological organisation.
Background:
In previous studies, the gram-positive firmicute genus Paenibacillus was found with significant abundances in nests of wild solitary bees. Paenibacillus larvae is well-known for beekeepers as a severe pathogen causing the fatal honey bee disease American foulbrood, and other members of the genus are either secondary invaders of European foulbrood or considered a threat to honey bees. We thus investigated whether Paenibacillus is a common bacterium associated with various wild bees and hence poses a latent threat to honey bees visiting the same flowers.
Results:
We collected 202 samples from 82 individuals or nests of 13 bee species at the same location and screened each for Paenibacillus using high-throughput sequencing-based 16S metabarcoding. We then isolated the identified strain Paenibacillus MBD-MB06 from a solitary bee nest and sequenced its genome. We did find conserved toxin genes and such encoding for chitin-binding proteins, yet none specifically related to foulbrood virulence or chitinases. Phylogenomic analysis revealed a closer relationship to strains of root-associated Paenibacillus rather than strains causing foulbrood or other accompanying diseases. We found anti-microbial evidence within the genome, confirmed by experimental bioassays with strong growth inhibition of selected fungi as well as gram-positive and gram-negative bacteria.
Conclusions:
The isolated wild bee associate Paenibacillus MBD-MB06 is a common, but irregularly occurring part of wild bee microbiomes, present on adult body surfaces and guts and within nests especially in megachilids. It was phylogenetically and functionally distinct from harmful members causing honey bee colony diseases, although it shared few conserved proteins putatively toxic to insects that might indicate ancestral predisposition for the evolution of insect pathogens within the group. By contrast, our strain showed anti-microbial capabilities and the genome further indicates abilities for chitin-binding and biofilm-forming, suggesting it is likely a useful associate to avoid fungal penetration of the bee cuticula and a beneficial inhabitant of nests to repress fungal threats in humid and nutrient-rich environments of wild bee nests.
The electric and nonvolatile control of the spin texture in semiconductors would represent a fundamental step toward novel electronic devices combining memory and computing functionalities. Recently, GeTe has been theoretically proposed as the father compound of a new class of materials, namely ferroelectric Rashba semiconductors. They display bulk bands with giant Rashba-like splitting due to the inversion symmetry breaking arising from the ferroelectric polarization, thus allowing for the ferroelectric control of the spin. Here, we provide the experimental demonstration of the correlation between ferroelectricity and spin texture. A surface-engineering strategy is used to set two opposite predefined uniform ferroelectric polarizations, inward and outward, as monitored by piezoresponse force microscopy. Spin and angular resolved photoemission experiments show that these GeTe(111) surfaces display opposite sense of circulation of spin in bulk Rashba bands. Furthermore, we demonstrate the crafting of nonvolatile ferroelectric patterns in GeTe films at the nanoscale by using the conductive tip of an atomic force microscope. Based on the intimate link between ferroelectric polarization and spin in GeTe, ferroelectric patterning paves the way to the investigation of devices with engineered spin configurations.
Compared to naive T cells, differentiated T cells are thought to be less dependent on CD28 costimulation for full activation. To revisit the role of CD28 costimulation in mouse T cell recall responses, we adoptively transferred in vitro generated OT-II T helper (Th) 1 cells into C57BL/6 mice (Thy1.2\(^{+}\)) and then either blocked CD28–ligand interactions with Fab fragments of the anti-CD28 monoclonal antibody (mAb) E18 or deleted CD28 expression using inducible CD28 knock-out OT-II mice as T cell donors. After injection of ovalbumin protein in adjuvant into the recipient mice we observed that systemic interferon (IFN)γ release strongly depended on CD28 costimulation of the Th1 cells, while secondary clonal expansion was not reduced in the absence of CD28 costimulation. For human memory CD4\(^{+}\) T cell responses we also noted that cytokine release was reduced upon inhibition of CD28 costimulation. Together, our data highlight the so far underestimated role of CD28 costimulation for the reactivation of fully differentiated CD4\(^{+}\) T cells.
New experimental methods have drastically accelerated the pace and quantity at which biological data is generated. High-throughput DNA sequencing is one of the pivotal new technologies. It offers a number of novel applications in various fields of biology, including ecology, evolution, and genomics. However, together with those opportunities many new challenges arise. Specialized algorithms and software are required to cope with the amount of data, often requiring substantial training in bioinformatic methods. Another way to make those data accessible to non-bioinformaticians is the development of programs with intuitive user interfaces.
In my thesis I developed analyses and programs to tackle current problems with high-throughput data in biology. In the field of ecology this covers the establishment of the bioinformatic workflow for pollen DNA meta-barcoding. Furthermore, I developed an application that facilitates the analysis of ecological communities in the context of their traits. Information from multiple public databases have been aggregated and can now be mapped automatically to existing community tables for interactive inspection. In evolution the new data are used to reconstruct phylogenetic trees from multiple genes. I developed the tool bcgTree to automate this process for bacteria. Many plant genomes have been sequenced in current years. Sequencing reads of those projects also contain data from the chloroplasts. The tool chloroExtractor supports the targeted extraction and analysis of the chloroplast genome. To compare the structure of multiple genomes specialized software is required for calculation and visualization of the relationships. I developed AliTV to address this. In contrast to existing programs for this task it allows interactive adjustments of produced graphics. Thus, facilitating the discovery of biologically relevant information. Another application I developed helps to analyze transcriptomes even if no reference genome is present. This is achieved by aggregating the different pieces of information, like functional annotation and expression level, for each transcript in a web platform. Scientists can then search, filter, subset, and visualize the transcriptome.
Together the methods and tools expedite insights into biological systems that were not possible before.
Molecules containing multiple bonds between atoms—most often in the form of olefins—are ubiquitous in nature, commerce, and science, and as such have a huge impact on everyday life. Given their prominence, over the last few decades, frequent attempts have been made to perturb the structure and reactivity of multiply-bound species through bending and twisting. However, only modest success has been achieved in the quest to completely twist double bonds in order to homolytically cleave the associated π bond. Here, we present the isolation of double-bond-containing species based on boron, as well as their fully twisted diradical congeners, by the incorporation of attached groups with different electronic properties. The compounds comprise a structurally authenticated set of diamagnetic multiply-bound and diradical singly-bound congeners of the same class of compound.
Regulatory focus (RF) theory (Higgins, 1997) states that individuals follow different strategic concerns when focusing on gains (promotion) rather than losses (prevention). Applying the Reflective-Impulsive Model (RIM, Strack & Deutsch, 2004), this dissertation investigates RF’s influence on basic information processing, specifically semantic processing (Study 1), semantic (Study 2) and affective (Study 3) associative priming, and basic reflective operations (Studies 4-7). Study 1 showed no effect of RF on pre-activation of RF-related semantic concepts in a lexical decision task (LDT). Study 2 indicated that primes fitting a promotion focus improve performance in a LDT for chronically promotion-focused individuals, but not chronically prevention-focused individuals. However, the latter performed better when targets fit their focus. Stronger affect and arousal after processing valent words fitting an RF may explain this pattern. Study 3 showed some evidence for stronger priming effects for negative primes in a bona-fide pipeline task (Fazio et al., 1995) for chronically prevention-focused participants, while also providing evidence that situational prevention focus insulates individuals from misattributing the valence of simple primes. Studies 4-7 showed that a strong chronic prevention focus leads to greater negation effects for valent primes in an Affect Misattribution Procedure (Payne et al., 2005), especially when it fits the situation. Furthermore, Study 6 showed that these effects result from stronger weighting of negated valence rather than greater ease in negation. Study 7 showed that the increased negation effect is independent of time pressure. Broad implications are discussed, including how RF effects on basic processing may explain higher-order RF effects.
Aims: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-\(^{18}\)F-fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis.
Methods and results: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund’s adjuvant. Time course of disease was assessed by longitudinal \(^{18}\)F-FDG PET imaging. A correlative analysis between in- and ex vivo \(^{18}\)F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal \(^{18}\)F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo \(^{18}\)F-FDG PET signalling (R\(^2\) = 0.92) as well as with ex vivo 18F-FDG autoradiography (R\(^2\) = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at \(^{18}\)F-FDG decrease).
Conclusion: \(^{18}\)F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis.
We aimed to explore the impact of ageing on 11C-Hydroxyephedrine (11C-HED) uptake in the healthy rat heart in a longitudinal setting. To investigate a potential cold mass effect, the influence of specific activity on cardiac 11C-HED uptake was evaluated: 11C-HED was synthesized by N-methylation of (−)-metaraminol as the free base (radiochemical purity >95%) and a wide range of specific activities (0.2–141.9 GBq/μmol) were prepared. \(^{11}\)C-HED (48.7±9.7MBq, ranged 0.2–60.4μg/kg cold mass) was injected in healthy Wistar Rats. Dynamic 23-frame PET images were obtained over 30 min. Time activity curves were generated for the blood input function and myocardial tissue. Cardiac 11C-HED retention index (%/min) was calculated as myocardial tissue activity at 20-30 min divided by the integral of the blood activity curves. Additionally, the impact of ageing on myocardial 11CHED uptake was investigated longitudinally by PET studies at different ages of healthy Wistar Rats. A dose-dependent reduction of cardiac 11C-HED uptake was observed: The estimated retention index as a marker of norepinephrine function decreased at a lower specific activity (higher amount of cold mass). This observed high affinity of 11C-HED to the neural norepinephrine transporter triggered a subsequent study: In a longitudinal setting, the 11C-HED retention index decreased with increasing age. An age-related decline of cardiac sympathetic innervation could be demonstrated. The herein observed cold mass effect might increase in succeeding scans and therefore, 11C-HED microPET studies should be planned with extreme caution if one single radiosynthesis is scheduled for multiple animals.
The heart failure (HF) epidemic continues to rise with coronary artery disease (CAD) as one of its main causes. Novel concepts for risk stratification to guide the referring cardiologist towards revascularization procedures are of significant value. Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) agents has demonstrated high accuracy for the detection of clinically relevant stenoses. With positron emission tomography (PET) becoming more widely available, mainly due to its diagnostic performance in oncology, perfusion imaging with that modality is more practical than in the past and overcomes existing limitations of SPECT MPI. Advantages of PET include more reliable quantification of absolute myocardial blood flow, the routine use of computed tomography for attenuation correction, a higher spatiotemporal resolution and a higher count sensitivity. Current PET radiotracers such as rubidium-82 (half-life, 76 sec), oxygen-15 water (2 min) or nitrogen-13 ammonia (10 min) are labeled with radionuclides with very short half-lives, necessitating that stress imaging is performed under pharmacological vasodilator stress instead of exercise testing. However, with the introduction of novel 18F-labeled MPI PET radiotracers (half-life, 110 min), the intrinsic advantages of PET can be combined with exercise testing. Additional advantages of those radiotracers include, but are not limited to: potentially improved cost-effectiveness due to the use of pre-existing delivery systems and superior imaging qualities, mainly due to the shortest positron range among available PET MPI probes. In the present review, widely used PET MPI radiotracers will be reviewed and potential novel 18F-labeled perfusion radiotracers will be discussed.
Purpose: Early identification of aggressive disease could improve decision-support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR)-PET before PRRT was analyzed.
Procedures: 31 patients with G1/G2 pNET were enrolled (G2, n=23/31). Prior to PRRT with [\(^{177}\)Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET/CT was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUV\(_{mean/max}\)), imaging-based TF as well as clinical parameters (Ki67, CgA) for prediction of both progression-free (PFS) and overall survival (OS) after PRRT was evaluated.
Results: Within a median follow-up of 3.7y, tumor progression was detected in 21 patients (median, 1.5y) and 13/31 deceased (median, 1.9y). In ROC analysis, the TF Entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff=6.7, AUC=0.71, p=0.02). Of note, increasing Entropy could predict a longer survival (>6.7, OS=2.5y, 17/31), whereas less voxel-based derangement portended inferior outcome (<6.7, OS=1.9y, 14/31). These findings were supported in a G2 subanalysis (>6.9, OS=2.8y, 9/23 vs. <6.9, OS=1.9y, 14/23). Kaplan-Meier analysis revealed a significant distinction between high- and low-risk groups using Entropy (n=31, p<0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n=31, p=0.04). Ki67 was negatively associated with PFS (p=0.002); however, SUVmean/max failed in prognostication (n.s.).
Conclusions: In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification.
Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET) imaging agents for staging and restaging of prostate carcinoma or neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Both framework systems may contribute to increase the level of a reader’s confidence and to navigate the imaging interpreter through indeterminate lesions, so that appropriate workup for equivocal findings can be pursued. Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e. if the reader is familiar with one system, the other system can readily be applied as well. In the present review we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a future role of the umbrella framework MI-RADS compared to other harmonization systems.
Purpose: The metabolically most active lesion in 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) PET/CT can predict progression-free survival (PFS) in patients with medullary thyroid carcinoma (MTC) starting treatment with the tyrosine kinase inhibitor (TKI) vandetanib. However, this metric failed in overall survival (OS) prediction. In the present proof of concept study, we aimed to explore the prognostic value of intratumoral textural features (TF) as well as volumetric parameters (total lesion glycolysis, TLG) derived by pre-therapeutic \(^{18}\)F-FDG PET.
Methods: Eighteen patients with progressive MTC underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after vandetanib initiation. By manual segmentation of the tumor burden at baseline and follow-up PET, intratumoral TF and TLG were computed. The ability of TLG, imaging-based TF, and clinical parameters (including age, tumor marker doubling times, prior therapies and RET (rearranged during transfection) mutational status) for prediction of both PFS and OS were evaluated.
Results: The TF Complexity and the volumetric parameter TLG obtained at baseline prior to TKI initiation successfully differentiated between low- and high-risk patients. Complexity allocated 10/18 patients to the high-risk group with an OS of 3.3y (vs. low-risk group, OS=5.3y, 8/18, AUC=0.78, P=0.03). Baseline TLG designated 11/18 patients to the high-risk group (OS=3.5y vs. low-risk group, OS=5y, 7/18, AUC=0.83, P=0.005). The Hazard Ratio for cancer-related death was 6.1 for Complexity (TLG, 9.5). Among investigated clinical parameters, the age at initiation of TKI treatment reached significance for PFS prediction (P=0.02, OS, n.s.).
Conclusions: The TF Complexity and the volumetric parameter TLG are both independent parameters for OS prediction.
In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated \(^{18}\)F-fluorodeoxyglucose positron emission tomography (\(^{18}\)F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated \(^{18}\)F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n=6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, \(^{18}\)F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5±4.2 vs. 59.4±4.5%; HR: 331±35 vs. 309±24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1±0.8 vs. 10.2±1 Enddiastolic Volume/sec, P<0.01). Investigating a diabetic rat model, ECG-gated \(^{18}\)F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.
Ionotropic glycine receptors (GlyRs) enable fast synaptic neurotransmission in the adult spinal cord and brainstem. The inhibitory GlyR is a transmembrane glycinegated chloride channel. The immature GlyR protein undergoes various processing steps, e.g., folding, assembly, and maturation while traveling from the endoplasmic reticulum to and through the Golgi apparatus, where post-translational modifications, e.g., glycosylation occur. The mature receptors are forward transported via microtubules to the cellular surface and inserted into neuronal membranes followed by synaptic clustering. The normal life cycle of a receptor protein includes further processes like internalization, recycling, and degradation. Defects in GlyR life cycle, e.g., impaired protein maturation and degradation have been demonstrated to underlie pathological mechanisms of various neurological diseases. The neurological disorder startle disease is caused by glycinergic dysfunction mainly due to missense mutations in genes encoding GlyR subunits (GLRA1 and GLRB). In vitro studies have shown that most recessive forms of startle disease are associated with impaired receptor biogenesis. Another neurological disease with a phenotype similar to startle disease is a special form of stiff-person syndrome (SPS), which is most probably due to the development of GlyR autoantibodies. Binding of GlyR autoantibodies leads to enhanced receptor internalization. Here we focus on the normal life cycle of GlyRs concentrating on assembly and maturation, receptor trafficking, post-synaptic integration and clustering, and GlyR internalization/recycling/degradation. Furthermore, this review highlights findings on impairment of these processes under disease conditions such as disturbed neuronal ER-Golgi trafficking as the major pathomechanism for recessive forms of human startle disease. In SPS, enhanced receptor internalization upon autoantibody binding to the GlyR has been shown to underlie the human pathology. In addition, we discuss how the existing mouse models of startle disease increased our current knowledge of GlyR trafficking routes and function. This review further illuminates receptor trafficking of GlyR variants originally identified in startle disease patients and explains changes in the life cycle of GlyRs in patients with SPS with respect to structural and functional consequences at the receptor level.
More than 25 years after the first peptide receptor radionuclide therapy (PRRT), the concept of somatostatin receptor (SSTR)-directed imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly increasing use. To maximize the full potential of its theranostic promise, efforts in recent years have expanded recommendations in current guidelines and included the evaluation of novel theranostic radiotracers for imaging and treatment of NET. Moreover, the introduction of standardized reporting framework systems may harmonize PET reading, address pitfalls in interpreting SSTR-PET/CT scans and guide the treating physician in selecting PRRT candidates. Notably, the concept of PRRT has also been applied beyond oncology, e.g. for treatment of inflammatory conditions like sarcoidosis. Future perspectives may include the efficacy evaluation of PRRT compared to other common treatment options for NET, novel strategies for closer monitoring of potential side effects, the introduction of novel radiotracers with beneficial pharmacodynamic and kinetic properties or the use of supervised machine learning approaches for outcome prediction. This article reviews how the SSTR-directed theranostic concept is currently applied and also reflects on recent developments that hold promise for the future of theranostics in this context.
Animal-microbe mutualisms are typically maintained by vertical symbiont transmission or partner choice. A third mechanism, screening of high-quality symbionts, has been predicted in theory, but empirical examples are rare. Here we demonstrate that ambrosia beetles rely on ethanol within host trees for promoting gardens of their fungal symbiont and producing offspring. Ethanol has long been known as the main attractant for many of these fungus-farming beetles as they select host trees in which they excavate tunnels and cultivate fungal gardens. More than 300 attacks by Xylosandrus germanus and other species were triggered by baiting trees with ethanol lures, but none of the foundresses established fungal gardens or produced broods unless tree tissues contained in vivo ethanol resulting from irrigation with ethanol solutions. More X. germanus brood were also produced in a rearing substrate containing ethanol. These benefits are a result of increased food supply via the positive effects of ethanol on food-fungus biomass. Selected Ambrosiella and Raffaelea fungal isolates from ethanol-responsive ambrosia beetles profited directly and indirectly by (i) a higher biomass on medium containing ethanol, (ii) strong alcohol dehydrogenase enzymatic activity, and (iii) a competitive advantage over weedy fungal garden competitors (Aspergillus, Penicillium) that are inhibited by ethanol. As ambrosia fungi both detoxify and produce ethanol, they may maintain the selectivity of their alcohol-rich habitat for their own purpose and that of other ethanol-resistant/producing microbes. This resembles biological screening of beneficial symbionts and a potentially widespread, unstudied benefit of alcohol-producing symbionts (e.g., yeasts) in other microbial symbioses.
Galectin-1 (Gal-1) has been described to promote tumour growth by inducing angiogenesis and to contribute to the tumour immune escape. We had previously identified up-regulation of Gal-1 in preclinical models of aggressive neuroblastoma (NB), the most common extracranial tumour of childhood. While Gal-1 did not confer a survival advantage in the absence of exogenous stressors, Gal-1 contributed to enhanced cell migratory and invasive properties. Here, we review these findings and extend them by analyzing Gal-1 mediated effects on immune cell regulation and radiation resistance. In line with previous results, cell autonomous effects as well as paracrine functions contribute to Gal-1 mediated pro-tumourigenic functions. Interfering with Gal-1 functions in vivo will add to a better understanding of the role of the Gal-1 axis in the complex tumour-host interaction during immune-, chemo- and radiotherapy of neuroblastoma.
A search for the supersymmetric partners of quarks and gluons (squarks and gluinos) in final states containing hadronic jets and missing transverse momentum, but no electrons or muons, is presented. The data used in this search were recorded in 2015 and 2016 by the ATLAS experiment in root s = 13 TeV proton-proton collisions at the Large Hadron Collider, corresponding to an integrated luminosity of 36.1 fb(-1). The results are interpreted in the context of various models where squarks and gluinos are pair produced and the neutralino is the lightest supersymmetric particle. An exclusion limit at the 95% confidence level on the mass of the gluino is set at 2.03 TeV for a simplified model incorporating only a gluino and the lightest neutralino, assuming the lightest neutralino is massless. For a simplified model involving the strong production of mass-degenerate first-and second-generation squarks, squark masses below 1.55 TeVare excluded if the lightest neutralino is massless. These limits substantially extend the region of supersymmetric parameter space previously excluded by searches with the ATLAS detector.
Measurements of ZZ production in the l(+)l(-)l'(+)l'(-) channel in proton-proton collisions at 13 TeV center-of-mass energy at the Large Hadron Collider are presented. The data correspond to 36.1 fb(-1) of collisions collected by the ATLAS experiment in 2015 and 2016. Here l and l ' stand for electrons or muons. Integrated and differential ZZ -> l(+)l(-)l'(+)l'(-) cross sections with Z -> l(+)l(-) candidate masses in the range of 66 GeV to 116 GeV are measured in a fiducial phase space corresponding to the detector acceptance and corrected for detector effects. The differential cross sections are presented in bins of twenty observables, including several that describe the jet activity. The integrated cross section is also extrapolated to a total phase space and to all standard model decays of Z bosons with mass between 66 GeV and 116 GeV, resulting in a value of 17.3 +/- 0.9 [+/- 0.6(start) +/- 0.5 (syst) +/- 0.6 (lumi)] pb. The measurements are found to be in good agreement with the standard model. A search for neutral triple gauge couplings is performed using the transverse momentum distribution of the leading Z boson candidate. No evidence for such couplings is found and exclusion limits are set on their parameters.
A search is presented for the direct pair production of the stop, the supersymmetric partner of the top quark, that decays through an R-parity-violating coupling to a final state with two leptons and two jets, at least one of which is identified as a b-jet. The data set corresponds to an integrated luminosity of 36.1 fb(-1) of proton-proton collisions at a center-of-mass energy of root s = 13 TeV, collected in 2015 and 2016 by the ATLAS detector at the LHC. No significant excess is observed over the Standard Model background, and exclusion limits are set on stop pair production at a 95% confidence level. Lower limits on the stop mass are set between 600 GeV and 1.5 TeV for branching ratios above 10% for decays to an electron or muon and a b-quark.
G-protein-coupled receptors (GPCRs) represent one of the most important classes of drug targets. The discovery of new GCPR therapeutics would greatly benefit from the development of a generalizable high-throughput assay to directly monitor their activation or de-activation. Here we screened a variety of labels inserted into the third intracellular loop and the C-terminus of the alpha(2 Lambda)-adrenergic receptor and used fluorescence (FRET) and bioluminescence resonance energy transfer (BRET) to monitor ligand-binding and activation dynamics. We then developed a universal intramolecular BRET receptor sensor design to quantify efficacy and potency of GPCR ligands in intact cells and real time. We demonstrate the transferability of the sensor design by cloning beta(2)-adrenergic and PTH1-receptor BRET sensors and monitored their efficacy and potency. For all biosensors, the Z factors were well above 0.5 showing the suitability of such design for microtiter plate assays. This technology will aid the identification of novel types of GPCR ligands.
The dynamics of isolated-photon production in association with a jet in proton-proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb(-1). Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti-k(t) algorithm with radius parameter R = 0.4 and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon-jet invariant mass and the scattering angle in the photon-jet centre-of-mass system. Tree-level plus parton-shower predictions from SHERPA and PYTHIA as well as next-to-leading-order QCD predictions from JETPHOX and SHERPA are compared to the measurements. (C) 2018 The Author. Published by Elsevier B.V.
The production of exclusive gamma gamma -> mu(+)mu(-) events in proton-proton collisions at a centre-of-mass energy of 13 TeV is measured with the ATLAS detector at the LHC, using data corresponding to an integrated luminosity of 3.2 fb(-1). The measurement is performed for a dimuon invariant mass of 12 GeV < m(mu+mu-) < 70 GeV. The integrated cross-section is determined within a fiducial acceptance region of the ATLAS detector and differential cross-sections are measured as a function of the dimuon invariant mass. The results are compared to theoretical predictions both with and without corrections for absorptive effects. (c) 2017 The Author(s). Published by Elsevier B.V.
An angular analysis of the decay B-d(0) -> K*mu(+)mu(-) is presented, based on proton-proton collision data recorded by the ATLAS experiment at the LHC. The study is using 20.3 fb(-1) of integrated luminosity collected during 2012 at centre-of-mass energy of root s = 8TeV. Measurements of the K* longitudinal polarisation fraction and a set of angular parameters obtained for this decay are presented. The results are compatible with the Standard Model predictions.
Search for exclusive Higgs and Z boson decays to phi gamma and rho gamma with the ATLAS detector
(2018)
A search for the exclusive decays of the Higgs and Z bosons to a phi or rho meson and a photon is performed with a pp collision data sample corresponding to an integrated luminosity of up to 35.6 fb(-1) collected at root s = 13 TeV with the ATLAS detector at the CERN Large Hadron Collider. These decays have been suggested as a probe of the Higgs boson couplings to light quarks. No significant excess of events is observed above the background, as expected from the Standard Model. Upper limits at 95% confidence level were obtained on the branching fractions of the Higgs boson decays to phi gamma and rho gamma of 4.8 x 10(-4) and 8.8 x 10(-4), respectively. The corresponding 95% confidence level upper limits for the Z boson decays are 0.9 x 10(-6) and 25 x 10(-6) for phi gamma and rho gamma, respectively.
The transcription factor Myc interacts with several co-factors to regulate growth and proliferationand thereby enables normal animal development. Deregulation of Myc is associated witha wide range of human tumors. Myc binds to DNA together with its dimerization partner Max, preferentially to canonical E-box motifs, but this sequence-specific interaction is probably not sufficient for Myc’s binding to target genes.
In this work, the PAF1 complex was characterized as a novel co-factor of Myc in Drosophila melanogaster. All components of the complex are required for Myc’s recruitment to chromatin, but the subunit Atu has the strongest effect on Myc's binding to target genes through ist direct physical interaction with Myc. Unexpectedly, the impact of Atu depletion on the Expression of Myc target genes was weak compared to its effect on Myc binding. However, the influence of Atu becomes more prominent in situations of elevated Myc levels in vivo . Mycrepressed as well as Myc-activated targets are affected, consistent with the notion that Myc
recruitment is impaired.
An independent set of analyses revealed that Myc retains substantial activity even in the complete absence of Max. The overexpression of Myc in Max0 mutants specifically blocks their pupariation without affecting their survival, which raised the possibility that Myc might
affect ecdysone biosynthesis. This connection was studied in the second part of this Thesis which showed that Myc inhibits the expression of ecdysteroidogenic genes and thereby the production of ecdysone. Myc most likely affects the signaling pathways (PTTH and insulin
signaling) upstream of the PG, the organ where ecdysone is produced. By combining existing ChIPseq, RNAseq and electronic annotation data, we identified five potential Maxindependent Myc targets and provided experimental data that they might be involved in Myc's effect on Max mutant animals. Together our data confirm that some Myc functions are Max-independent and they raise the possibility that this effect might play a role during replication.
This dissertation contributes to the empirical analysis of economic development. The continuing poverty in many Sub-Saharan-African countries as well as the declining trend in growth in the advanced economies that was initiated around the turn of the millennium raises a number of new questions which have received little attention in recent empirical studies. Is culture a decisive factor for economic development? Do larger financial markets trigger positive stimuli with regard to incomes, or is the recent increase in their size in advanced economies detrimental to economic growth? What causes secular stagnation, i.e. the reduction in growth rates of the advanced economies observable over the past 20 years? What is the role of inequality in the growth process, and how do governmental attempts to equalize the income distribution affect economic development? And finally: Is the process of democratization accompanied by an increase in living standards? These are the central questions of this doctoral thesis.
To facilitate the empirical analysis of the determinants of economic growth, this dissertation introduces a new method to compute classifications in the field of social sciences. The approach is based on mathematical algorithms of machine learning and pattern recognition. Whereas the construction of indices typically relies on arbitrary assumptions regarding the aggregation strategy of the underlying attributes, utilization of Support Vector Machines transfers the question of how to aggregate the individual components into a non-linear optimization problem.
Following a brief overview of the theoretical models of economic growth provided in the first chapter, the second chapter illustrates the importance of culture in explaining the differences in incomes across the globe. In particular, if inhabitants have a lower average degree of risk-aversion, the implementation of new technology proceeds much faster compared with countries with a lower tendency towards risk. However, this effect depends on the legal and political framework of the countries, their average level of education, and their stage of development.
The initial wealth of individuals is often not sufficient to cover the cost of investments in both education and new technologies. By providing loans, a developed financial sector may help to overcome this shortage. However, the investigations in the third chapter show that this mechanism is dependent on the development levels of the economies. In poor countries, growth of the financial sector leads to better education and higher investment levels. This effect diminishes along the development process, as intermediary activity is increasingly replaced by speculative transactions. Particularly in times of low technological innovation, an increasing financial sector has a negative impact on economic development. In fact, the world economy is currently in a phase of this kind. Since the turn of the millennium, growth rates in the advanced economies have experienced a multi-national decline, leading to an intense debate about "secular stagnation" initiated at the beginning of 2015. The fourth chapter deals with this phenomenon and shows that the growth potentials of new technologies have been gradually declining since the beginning of the 2000s.
If incomes are unequally distributed, some individuals can invest less in education and technological innovations, which is why the fifth chapter identifies an overall negative effect of inequality on growth. This influence, however, depends on the development level of countries. While the negative effect is strongly pronounced in poor economies with a low degree of equality of opportunity, this influence disappears during the development process. Accordingly, redistributive polices of governments exert a growth-promoting effect in developing countries, while in advanced economies, the fostering of equal opportunities is much more decisive.
The sixth chapter analyzes the growth effect of the political environment and shows that the ambiguity of earlier studies is mainly due to unsophisticated measurement of the degree of democratization. To solve this problem, the chapter introduces a new method based on mathematical algorithms of machine learning and pattern recognition. While the approach can be used for various classification problems in the field of social sciences, in this dissertation it is applied for the problem of democracy measurement. Based on different country examples, the chapter shows that the resulting SVMDI is superior to other indices in modeling the level of democracy. The subsequent empirical analysis emphasizes a significantly positive growth effect of democracy measured via SVMDI.
This dissertation focuses on the performance evaluation of all components of Software Defined Networking (SDN) networks and covers whole their architecture. First, the isolation between virtual networks sharing the same physical resources is investigated with SDN switches of several vendors. Then, influence factors on the isolation are identified and evaluated. Second, the impact of control mechanisms on the performance of the data plane is examined through the flow rule installation time of SDN switches with different controllers. It is shown that both hardware-specific and controller instance have a specific influence on the installation time. Finally, several traffic flow monitoring methods of an SDN controller are investigated and a new monitoring approach is developed and evaluated. It is confirmed that the proposed method allows monitoring of particular flows as well as consumes fewer resources than the standard approach. Based on findings in this thesis, on the one hand, controller developers can refer to the work related to the control plane, such as flow monitoring or flow rule installation, to improve the performance of their applications. On the other hand, network administrators can apply the presented methods to select a suitable combination of controller and switches in their SDN networks, based on their performance requirements
Forest ecosystems fulfill a whole host of ecosystem functions that are essential for life on our planet. However, an unprecedented level of anthropogenic influences is reducing the resilience and stability of our forest ecosystems as well as their ecosystem functions. The relationships between drivers, stress, and ecosystem functions in forest ecosystems are complex, multi-faceted, and often non-linear, and yet forest managers, decision makers, and politicians need to be able to make rapid decisions that are data-driven and based on short and long-term monitoring information, complex modeling, and analysis approaches. A huge number of long-standing and standardized forest health inventory approaches already exist, and are increasingly integrating remote-sensing based monitoring approaches. Unfortunately, these approaches in monitoring, data storage, analysis, prognosis, and assessment still do not satisfy the future requirements of information and digital knowledge processing of the 21st century. Therefore, this paper discusses and presents in detail five sets of requirements, including their relevance, necessity, and the possible solutions that would be necessary for establishing a feasible multi-source forest health monitoring network for the 21st century. Namely, these requirements are: (1) understanding the effects of multiple stressors on forest health; (2) using remote sensing (RS) approaches to monitor forest health; (3) coupling different monitoring approaches; (4) using data science as a bridge between complex and multidimensional big forest health (FH) data; and (5) a future multi-source forest health monitoring network. It became apparent that no existing monitoring approach, technique, model, or platform is sufficient on its own to monitor, model, forecast, or assess forest health and its resilience. In order to advance the development of a multi-source forest health monitoring network, we argue that in order to gain a better understanding of forest health in our complex world, it would be conducive to implement the concepts of data science with the components: (i) digitalization; (ii) standardization with metadata management after the FAIR (Findability, Accessibility, Interoperability, and Reusability) principles; (iii) Semantic Web; (iv) proof, trust, and uncertainties; (v) tools for data science analysis; and (vi) easy tools for scientists, data managers, and stakeholders for decision-making support.
The high infection rates and recent emergence of extremely drug resistant forms of
Mycobacterium tuberculosis pose a significant challenge for global health. The NADH-
dependent enoyl-ACP-reductase InhA of the type II mycobacterial fatty acid biosynthesis
pathway is a well-validated target for inhibiting mycobacterial growth. InhA has been
shown to be inhibited by a variety of compound series. Prominent classes of InhA
inhibitors from literature include diaryl ethers, pyrrolidine carboxamides and arylamides
which can be subjected to further development. Despite the progress in this area, very
few compounds are in clinical development phase. The present work involves a detailed
computational investigation of the binding modes and structure-based optimisation of
pyrrolidine carboxamides as InhA inhibitors.
With substituents of widely varying bulkiness, the pyrrolidine carboxamide dataset
presented a challenge for prediction of binding mode as well as affinity. Using advanced
docking protocols and in-house developed pose selection procedures, the binding modes
of 44 compounds were predicted. The poses from docking were used in short molecular
dynamics (MD) simulations to ascertain the dominant binding conformations for the
bulkier members of the series. Subsequently, an activity-based classification strategy
could be developed to circumvent the affinity prediction problems observed with this
dataset. The prominent motions of the bound ligand and the active site residues were
then ascertained using Essential Dynamics (ED). The information from ED and literature
was subsequently used to design a total of 20 compounds that were subjected to extensive
in-silico evaluations. Finally, the molecular determinants of rapid-reversible binding of
pyrrolidine carboxamides were investigated using long MD simulations.
A search for long-lived, massive particles predicted by many theories beyond the Standard Model is presented. The search targets final states with large missing transverse momentum and at least one highmass displaced vertex with five or more tracks, and uses 32.8 fb(-1) of root s = 13 TeV pp collision data collected by the ATLAS detector at the LHC. The observed yield is consistent with the expected background. The results are used to extract 95% C.L. exclusion limits on the production of long-lived gluinos with masses up to 2.37 TeV and lifetimes of O(10(-2)) - O(10) ns in a simplified model inspired by split supersymmetry.
Understanding human navigation behavior has implications for a wide range of application scenarios. For example, insights into geo-spatial navigation in urban areas can impact city planning or public transport. Similarly, knowledge about navigation on the web can help to improve web site structures or service experience.
In this work, we focus on a hypothesis-driven approach to address the task of understanding human navigation: We aim to formulate and compare ideas — for example stemming from existing theory, literature, intuition, or previous experiments — based on a given set of navigational observations. For example, we may compare whether tourists exploring a city walk “short distances” before taking their next photo vs. they tend to "travel long distances between points of interest", or whether users browsing Wikipedia "navigate semantically" vs. "click randomly".
For this, the Bayesian method HypTrails has recently been proposed. However, while HypTrails is a straightforward and flexible approach, several major challenges remain:
i) HypTrails does not account for heterogeneity (e.g., incorporating differently behaving user groups such as tourists and locals is not possible), ii) HypTrails does not support the user in conceiving novel hypotheses when confronted with a large set of possibly relevant background information or influence factors, e.g., points of interest, popularity of locations, time of the day, or user properties, and finally iii) formulating hypotheses can be technically challenging depending on the application scenario (e.g., due to continuous observations or temporal constraints). In this thesis, we address these limitations by introducing various novel methods and tools and explore a wide range of case studies.
In particular, our main contributions are the methods MixedTrails and SubTrails which specifically address the first two limitations: MixedTrails is an approach for hypothesis comparison that extends the previously proposed HypTrails method to allow formulating and comparing heterogeneous hypotheses (e.g., incorporating differently behaving user groups). SubTrails is a method that supports hypothesis conception by automatically discovering interpretable subgroups with exceptional navigation behavior. In addition, our methodological contributions also include several tools consisting of a distributed implementation of HypTrails, a web application for visualizing geo-spatial human navigation in the context of background information, as well as a system for collecting, analyzing, and visualizing mobile participatory sensing data.
Furthermore, we conduct case studies in many application domains, which encompass — among others — geo-spatial navigation based on photos from the photo-sharing platform Flickr, browsing behavior on the social tagging system BibSonomy, and task choosing behavior on a commercial crowdsourcing platform. In the process, we develop approaches to cope with application specific subtleties (like continuous observations and temporal constraints). The corresponding studies illustrate the variety of domains and facets in which navigation behavior can be studied and, thus, showcase the expressiveness, applicability, and flexibility of our methods. Using these methods, we present new aspects of navigational phenomena which ultimately help to better understand the multi-faceted characteristics of human navigation behavior.
Among external stimuli used to trigger release of a drug from a polymeric carrier, ultrasound has gained increasing attention due to its non-invasive nature, safety and low cost. Despite this attention, there is only limited knowledge about how materials available for the preparation of drug carriers respond to ultrasound. This study investigates the effect of ultrasound on the release of a hydrophobic drug, dexamethasone, from poly(2-oxazoline)-based micelles. Spontaneous and ultrasound-mediated release of dexamethasone from five types of micelles made of poly(2-oxazoline) block copolymers, composed of hydrophilic poly(2-methyl-2-oxazoline) and hydrophobic poly(2-n-propyl-2-oxazoline) or poly(2-butyl-2-oxazoline-co-2-(3-butenyl)-2-oxazoline), was studied. The release profiles were fitted by zeroorder and Ritger-Peppas models. The ultrasound increased the amount of released dexamethasone by 6% to 105% depending on the type of copolymer, the amount of loaded dexamethasone, and the stimulation time point. This study investigates for the first time the interaction between different poly(2-oxazoline)-based micelle formulations and ultrasound waves, quantifying the efficacy of such stimulation in modulating dexamethasone release from these nanocarriers.
This paper presents a search for direct electroweak gaugino or gluino pair production with a chargino nearly mass-degenerate with a stable neutralino. It is based on an integrated luminosity of 36.1 fb(-1) of pp collisions at root s = 13 TeV collected by the ATLAS experiment at the LHC. The final state of interest is a disappearing track accompanied by at least one jet with high transverse momentum from initial-state radiation or by four jets from the gluino decay chain. The use of short track segments reconstructed from the innermost tracking layers significantly improves the sensitivity to short chargino lifetimes. The results are found to be consistent with Standard Model predictions. Exclusion limits are set at 95% confidence level on the mass of charginos and gluinos for different chargino lifetimes. For a pure wino with a lifetime of about 0.2 ns, chargino masses up to 460 GeV are excluded. For the strong production channel, gluino masses up to 1.65 TeV are excluded assuming a chargino mass of 460 GeV and lifetime of 0.2 ns.
Mutations in GlyR α1 or β subunit genes in humans and rodents lead to severe startle disease characterized by rigidity, massive stiffness and excessive startle responses upon unexpected tactile or acoustic stimuli. The recently characterized startle disease mouse mutant shaky carries a missense mutation (Q177K) in the β8-β9 loop within the large extracellular N-terminal domain of the GlyR α1 subunit. This results in a disrupted hydrogen bond network around K177 and faster GlyR decay times. Symptoms in mice start at postnatal day 14 and increase until premature death of homozygous shaky mice around 4–6 weeks after birth. Here we investigate the in vivo functional effects of the Q177K mutation using behavioral analysis coupled to protein biochemistry and functional assays. Western blot analysis revealed GlyR α1 subunit expression in wild-type and shaky animals around postnatal day 7, a week before symptoms in mutant mice become obvious. Before 2 weeks of age, homozygous shaky mice appeared healthy and showed no changes in body weight. However, analysis of gait and hind-limb clasping revealed that motor coordination was already impaired. Motor coordination and the activity pattern at P28 improved significantly upon diazepam treatment, a pharmacotherapy used in human startle disease. To investigate whether functional deficits in glycinergic neurotransmission are present prior to phenotypic onset, we performed whole-cell recordings from hypoglossal motoneurons (HMs) in brain stem slices from wild-type and shaky mice at different postnatal stages. Shaky homozygotes showed a decline in mIPSC amplitude and frequency at P9-P13, progressing to significant reductions in mIPSC amplitude and decay time at P18-24 compared to wild-type littermates. Extrasynaptic GlyRs recorded by bath-application of glycine also revealed reduced current amplitudes in shaky mice compared to wild-type neurons, suggesting that presynaptic GlyR function is also impaired. Thus, a distinct, but behaviorally ineffective impairment of glycinergic synapses precedes the symptoms onset in shaky mice. These findings extend our current knowledge on startle disease in the shaky mouse model in that they demonstrate how the progression of GlyR dysfunction causes, with a delay of about 1 week, the appearance of disease symptoms.