Refine
Year of publication
- 2019 (696) (remove)
Document Type
- Journal article (487)
- Doctoral Thesis (163)
- Book article / Book chapter (23)
- Preprint (19)
- Conference Proceeding (1)
- Other (1)
- Report (1)
- Working Paper (1)
Language
- English (696) (remove)
Keywords
- Animal Studies (24)
- Cultural Animal Studies (24)
- Cultural Studies (24)
- Ecocriticism (24)
- Environmental Humanities (24)
- Human-Animal Studies (24)
- Literary Studies (24)
- boron (11)
- apoptosis (8)
- inflammation (7)
- Tissue Engineering (6)
- cancer (6)
- ischemic stroke (6)
- children (5)
- measles virus (5)
- tissue engineering (5)
- DNA methylation (4)
- Drosophila melanogaster (4)
- Hydrogel (4)
- Maschinelles Lernen (4)
- Neisseria meningitidis (4)
- Spektroskopie (4)
- Taufliege (4)
- cancer therapy (4)
- deep brain stimulation (4)
- infection (4)
- microbiome (4)
- multiple myeloma (4)
- sphingolipids (4)
- stroke (4)
- virtual reality (4)
- Übergangsmetalloxide (4)
- 3D tissue model (3)
- 3D-Druck (3)
- Ancistrocladaceae (3)
- Candida albicans (3)
- Chronobiologie (3)
- Elektrophysiologie (3)
- Exziton (3)
- Fluoreszenzmikroskopie (3)
- GABA (3)
- Genexpression (3)
- Leistungsbewertung (3)
- Maus (3)
- Megakaryozyt (3)
- Meningitis (3)
- Monte-Carlo (3)
- Physics (3)
- Raman-Spektroskopie (3)
- Schlaganfall (3)
- Serotonin (3)
- Soziale Wahrnehmung (3)
- Staphylococcus aureus (3)
- Survival (3)
- Ureaplasma parvum (3)
- Ureaplasma urealyticum (3)
- aging (3)
- blood–brain barrier (3)
- boranes (3)
- climate change (3)
- colorectal cancer (3)
- cytokines (3)
- cytotoxicity (3)
- death receptors (3)
- depression (3)
- epigenetics (3)
- genetics (3)
- gephyrin (3)
- in vitro (3)
- length of stenosis (3)
- leukemic cells (3)
- lysosome (3)
- machine learning (3)
- magnetic resonance imaging (3)
- metagenomics (3)
- migration (3)
- p53 (3)
- platelets (3)
- presence (3)
- psychiatric disorders (3)
- remote sensing (3)
- risk factors (3)
- stem cells (3)
- ubiquitin (3)
- 2Dimensionale Spektroskopie (2)
- 3D (2)
- 3D printing (2)
- AdS/CFT (2)
- Aggregation (2)
- Angst (2)
- Annotation (2)
- Anxiety (2)
- Aufmerksamkeit (2)
- B-MYB (2)
- Bees (2)
- Bilanzpolitik (2)
- Bildverarbeitung (2)
- Bioinformatik (2)
- Biomaterial (2)
- Biomedical engineering (2)
- Blutgerinnung (2)
- C-reactive protein (2)
- CXCR4 (2)
- Cancer (2)
- Channelrhodopsin (2)
- Chlamydia trachomatis (2)
- Colonization (2)
- Constraints (2)
- Cross-Section (2)
- Cryo-EM (2)
- DNA damage (2)
- Decay (2)
- Deutschland (2)
- Drosophila (2)
- EEA (2)
- Ecology (2)
- Exercise capacity (2)
- Expression (2)
- FKBP5 (2)
- GABAA receptors (2)
- Gedächtnis (2)
- HBMEC (2)
- HBV (2)
- HIV (2)
- Hadron colliders (2)
- Halbleiter (2)
- HeLa cells (2)
- Imaging techniques (2)
- Impact (2)
- Implantat (2)
- In vitro (2)
- Inhibitor (2)
- KDELR2 (2)
- Kernspintomografie (2)
- Knochenzement (2)
- Kognition (2)
- Lungenkrebs (2)
- MLST (2)
- MSC (2)
- Machine Learning (2)
- Melanoma (2)
- Merocyanine (2)
- Metabolomics (2)
- Metadynamics (2)
- Methylation (2)
- Mitose (2)
- Molekulargenetik (2)
- Muscarinrezeptor (2)
- NHC (2)
- Naphthylisochinolinalkaloide (2)
- Neurons (2)
- Optimierung (2)
- Optogenetik (2)
- PIP2 (2)
- Pair Production (2)
- Parton Distributions (2)
- Parton distributions (2)
- Perylenderivate (2)
- Pontryagin maximum principle (2)
- Positronen-Emissions-Tomografie (2)
- Quanten-Vielteilchensysteme (2)
- Quantum Information (2)
- Quantum many-body systems (2)
- RNA-seq (2)
- Radiative-corrections (2)
- Reduction (2)
- Regenerative Medizin (2)
- Röntgen-Photoelektronenspektroskopie (2)
- S-ADAPT (2)
- SQH method (2)
- Screening (2)
- Selbstorganisation (2)
- Sentinel-1 (2)
- Signaltransduktion (2)
- Simulation (2)
- Solution-state NMR (2)
- Stem cells (2)
- Supramolekulare Chemie (2)
- TNF receptor superfamily (2)
- TNF superfamily (2)
- TNFR1 (2)
- TRAIL (2)
- Tanzania (2)
- Telekommunikationsnetz (2)
- Thrombozyt (2)
- Top-Quark (2)
- VEGF (2)
- Vaskularisierung (2)
- Verhalten (2)
- Zellteilung (2)
- actin (2)
- adolescents (2)
- agriculture (2)
- allometric scaling (2)
- antibiotics (2)
- antibody (2)
- antibody fusion proteins (2)
- artemisinin (2)
- autophagy (2)
- bacteria (2)
- biofabrication (2)
- blood-brain barrier (2)
- body composition (2)
- body size (2)
- bone (2)
- bone adhesive (2)
- cAArC (2)
- calcium phosphate cement (2)
- cancer genomics (2)
- cancer immunotherapy (2)
- cancer metabolism (2)
- cardiomyopathy (2)
- carotid atherosclerosis (2)
- carotid stenosis (2)
- carotid ultrasound (2)
- caspase-8 (2)
- cell death (2)
- cell imaging (2)
- cell therapy (2)
- chemistry (2)
- complexes (2)
- copper (2)
- cystic fibrosis patients (2)
- dSTORM (2)
- degree of stenosis (2)
- dendritic cells (2)
- density functional calculations (2)
- diagnostic markers (2)
- diazepam (2)
- dopamine (2)
- drug delivery (2)
- ecology (2)
- endothelium (2)
- evolution (2)
- exciton-exciton (2)
- fatigue (2)
- fluorescence (2)
- genome annotation (2)
- genome assembly (2)
- geomorphology (2)
- glioblastoma multiforme (2)
- glucocorticoid receptor (2)
- glycoprotein VI (2)
- healthy volunteers (2)
- human behaviour (2)
- hydroboration (2)
- hydrogel (2)
- imaging (2)
- immunotherapy (2)
- information extraction (2)
- inhibitory neurotransmission (2)
- interleukin-8 (2)
- irradiation (2)
- knockout (2)
- lymphocytes (2)
- macrophages (2)
- magnetic properties and materials (2)
- measurement (2)
- megakaryopoiesis (2)
- melt electrospinning writing (2)
- meningitis (2)
- mental health (2)
- mesencephalic locomotor region (2)
- metabolic adaptation (2)
- microRNA (2)
- microtubules (2)
- mitochondria (2)
- molecular biology (2)
- mouse (2)
- multiple bonding (2)
- multiple sclerosis (2)
- natural language processing (2)
- neuroinflammation (2)
- neurology (2)
- neuroprotection (2)
- next generation sequencing (2)
- oncology (2)
- oncolytic virus (2)
- optimal drug combination (2)
- optogenetics (2)
- outcome (2)
- pathogens (2)
- performance (2)
- personalized medicine (2)
- photothrombotic stroke (2)
- platelet (2)
- polycyclic aromatic hydrocarbons (2)
- polymers (2)
- population pharmacokinetics (2)
- prognosis (2)
- prognostic marker (2)
- prostate cancer (2)
- quantum optics (2)
- radicals (2)
- reactive oxygen species (2)
- recurrence (2)
- relapse (2)
- rheumatoid arthritis (2)
- ring-expansion reaction (2)
- screening (2)
- secondary prevention (2)
- semiconductor lasers (2)
- smartphone app (2)
- social attention (2)
- software (2)
- structure (2)
- subthalamic nucleus (2)
- surgery (2)
- survival (2)
- synthesis (2)
- targeted therapy (2)
- tight junction (2)
- trade-offs (2)
- two-photon excited fluorescence (2)
- vascularization (2)
- wound healing (2)
- (classical and atypical) Werner syndrome (1)
- (hem)ITAM signaling (1)
- + (1)
- ++ (1)
- 1,2-additions (1)
- 18F-FDS (1)
- 2 Jets (1)
- 2-deoxy-2-18F-fluoro-D-sorbitol (1)
- 25-hydroxycholesterol 7 alpha-hydroxylase (1)
- 2D material (1)
- 3-coordinate organoboron compounds (1)
- 3D Bioprinting (1)
- 3D Modell (1)
- 3D Point Cloud Processing (1)
- 3D Tumormodell (1)
- 3D cultures (1)
- 3D model (1)
- 3D remote sensing (1)
- 3D tumour model (1)
- 3D-Modell (1)
- 3 T (1)
- 4-HNE (1)
- 4D flow (1)
- 68Ga-DOTANOC (1)
- 68Ga-DOTATATE (1)
- 68Ga-DOTATOC (1)
- A-D-A dyes (1)
- A-priori-Wissen (1)
- A. abbreviatus (1)
- A. likoko (1)
- ABP1 (1)
- ADHD (1)
- AHRR (1)
- ALAN (1)
- AMP-activated kinases (1)
- AMP‐activated protein kinase (1)
- APOBEC3G (1)
- APRI (1)
- ARCI (1)
- ARCI EM type III (1)
- ATP generation (1)
- AUX1 (1)
- Abfallbehandlung (1)
- Abfallwirtschaft (1)
- Absorbed Doses (1)
- Abszision (1)
- Accurate (1)
- Acids (1)
- Acinetobacter baumannii (1)
- Ackerschmalwand (1)
- Actin (1)
- Actin-bindende Proteine (1)
- Activation (1)
- Active Galactic Nuclei (1)
- Active disease (1)
- Acute myeloid leukemia (AML) (1)
- AdS-CFT Correspondence (1)
- AdS-CFT-Korrespondenz (1)
- AdS/CFT correspondence (1)
- Adaptation (1)
- Adherens junction (1)
- Adhesion GPCR (1)
- Adipositas (1)
- Administered Activities (1)
- Adolescent (1)
- Adult (1)
- Advanced Analytics (1)
- Affekt (1)
- African Trypanosomiasis (1)
- Akt (1)
- Akt/PKB (1)
- Aktionsforschung (1)
- Alcohol dependence (1)
- Algorithm (1)
- Alien limb syndrome (1)
- Alkaloid (1)
- Allogeneic transplantation (1)
- Alpine habitats (1)
- Alzheimer's disease (1)
- Aminerge Nervenzelle (1)
- Amygdala (1)
- Anarchic limb syndrome (1)
- Andalusian varieties (1)
- Angiogenese (1)
- Angstverarbeitung (1)
- Animales Nervensystem (1)
- Anisotropic Magnetoresistance (1)
- Anomalous magnetic-moment (1)
- Anreize (1)
- Antarctica (1)
- Anthropocene (1)
- Anti-infective (1)
- Antibiotikum (1)
- Antigen CD19 (1)
- Antigen CD28 (1)
- Antigenrezeptor (1)
- Antikörper (1)
- Antimalariamittel (1)
- Antioxidants (1)
- Antizipation (1)
- Aortic arch (1)
- Apidae (1)
- Apis mellifera (1)
- Aplastic anemia (1)
- Apoptosis (1)
- Applied physics (1)
- Arabidopsis thaliana (1)
- Arbeitsmobilität (1)
- Archaeology (1)
- Aromatically annulated triquinacenes (1)
- Aromatisch anellierte Triquinacene (1)
- Arylborylene Complexes (1)
- Arzneimittel (1)
- Ascaris lumbricoides (1)
- Aspergillus (1)
- Aspergillus fumigalus (1)
- Assistenzbedarf (1)
- Associative learning (1)
- Astronomie (1)
- Astrophysical neutrino sources (1)
- Astroteilchenphysik (1)
- Atacama (1)
- Atmospheric muons (1)
- Atomic and molecular interactions with photons (1)
- Atrial fibrillation (1)
- Attitude Determination and Control (1)
- Attitude Dynamics (1)
- Audit Quality (1)
- Audit sampling (1)
- Aufsichtsrat (1)
- Autoaggressionskrankheit (1)
- Autologous hematopoietic stem cell transplantation (1)
- Autoproteolysis (1)
- Auxine (1)
- Außenhandel (1)
- B cell (1)
- B cell malignancies (1)
- B cells (1)
- B,N-heterocylcles (1)
- B-B bond activation (1)
- B7-H1 (1)
- BAL (1)
- BCG (1)
- BMI (1)
- BRAF mutation (1)
- BRAF-mutant (1)
- BRAF-mutiert (1)
- BRCA1 (1)
- BaBiO3 (1)
- Bank (1)
- Banking (1)
- Barrier (1)
- Behaviour (1)
- Behavioural ecology (1)
- Benchmarking (1)
- Benutzeroberfläche (1)
- Benzimidazole (1)
- Berberine (1)
- Berechnung (1)
- Berufsbildung (1)
- Bevacizumab (1)
- Bhabha Scattering (1)
- Big Data (1)
- Bildbearbeitung (1)
- Bildgebung intakten Knochens (1)
- Bildungswesen (1)
- Binge drinking (1)
- Biofabrication (1)
- Biofabrikation (1)
- Biofilm (1)
- Biofilmarchitektur (1)
- Bioink (1)
- Biokinetics (1)
- Biologika (1)
- Biomarke (1)
- Biomedicine (1)
- Biophysics (1)
- Bioreaktor (1)
- Biotinten (1)
- Bioverfügbarkeit (1)
- Bipolar disorder (1)
- Biradikal (1)
- Bistability (1)
- Black Holes in String Theory (1)
- Black holes (1)
- Black-hole (1)
- Blazar (1)
- Blood (1)
- Body schema (1)
- Boson (1)
- Bosons (1)
- Brain cancer (1)
- Brain diseases (1)
- Brain endothelial cells (1)
- Branching fractions (1)
- Bronchopulmonary dysplasia (1)
- Brustkrebs (1)
- Business Process Management (1)
- Business Process Modeling (1)
- By-Light Scattering (1)
- B−H activation (1)
- C-60 fullerene (1)
- C-C coupling (1)
- C-terminal HSP90 inhibitors (1)
- C/EBP (1)
- C3a (1)
- C3aR (1)
- C5a (1)
- C5aR1 (1)
- C5aR2 (1)
- C60 fullerene (1)
- CAR T cells (1)
- CCI (1)
- CD274 (1)
- CD4+ T cells (1)
- CD8+ T cells (1)
- CD95 (1)
- CDC42 (1)
- CERN (1)
- CIDP (1)
- CMV (1)
- CO sensing (1)
- CO‐releasing molecules (CORMs) (1)
- CRH1 (1)
- CRISPR-Cas systems (1)
- CRM (1)
- CRMO (1)
- CVID (1)
- CXCL5 (1)
- CXCL8 (1)
- CXCR2 (1)
- CYP1B1 (1)
- C\(_{60}\) fullerene (1)
- Cadherine (1)
- Caenorhabditis elegans (1)
- Calcium (1)
- Calciumphosphat (1)
- Calciumphosphate (1)
- Calciumphosphatzemente (1)
- Callyspongia siphonella (1)
- Cancer Cell (1)
- Cancer genetics (1)
- Candida (1)
- Capicua transcriptional repressor (1)
- Capillary Electrophoresis (1)
- Cardiac ventricles (1)
- Cardiovascular diseases (1)
- Cardiovascular risk factors (1)
- Cardiovascular risk prediction (1)
- Carotid intima-media thickness (CIMT) (1)
- Carotid segment (1)
- Carotid ultrasound (1)
- Carotisstenose (1)
- Caspase (1)
- Cataglyphis (1)
- Cdh13 (1)
- Cell migration (1)
- Cell stainin (1)
- Central Asia (1)
- Central nervous system (1)
- Ceramic polymer composite (1)
- Chambers (1)
- Channelrhodopsin-2 (1)
- Characterization and analytical techniques (1)
- Charge carrier recombination (1)
- Charge-transfer-Komplexe (1)
- Chelatbildner (1)
- Chemical Structure (1)
- Chemical composition (1)
- Chemical stability (1)
- Chemische Synthese (1)
- Cherenkov underwater neutrino telescope (1)
- Children (1)
- Chile (1)
- Chili RNA Aptamer (1)
- Chimeric Antigen Receptor (1)
- Chimärer Antigenrezeptor (1)
- China (1)
- Chiral spin liquids (1)
- Chirale Spinflússigkeiten (1)
- Choice Behavior/physiology (1)
- Chondrogenesis (1)
- Chromatographie (1)
- Chronische Nierenerkrankung (1)
- Chronobiology (1)
- Circinella (1)
- Circular dichroism (1)
- Click Chemie (1)
- Clinical Data Warehouse (1)
- Clinically silent stroke (1)
- CoQ10 (1)
- Code Examples (1)
- Codon (1)
- Cognitive behavior (1)
- Cognitive neuroscience (1)
- Coherent Multidimensional Spectroscopy (1)
- Community-acquired methicillin-resistant Staphylococcus aureus (1)
- Commuting (1)
- Complexity (1)
- Computational Chemistry (1)
- Computational and Systems Biology (1)
- Computed axial tomography (1)
- Computer modelling (1)
- Computersimulation (1)
- Conditioning regimen (1)
- Confidence intervals (1)
- Confocal microscopy (1)
- Conformal Metrics (1)
- Congolese Ancistrocladus plants (1)
- Conical Intersections (1)
- Conifers (1)
- Conservation (1)
- Consistent partial least squares (1)
- Construct Modeling (1)
- Controlling (1)
- Corporate Governance (1)
- Corporate Social Responsibility (1)
- Correlated Electron Materials (1)
- Correlated Fermions (1)
- Corticobasal syndrome (1)
- Corticosteroids (1)
- Cosmic-rays (1)
- Couplings (1)
- CpG (1)
- Cranial sutures (1)
- Cross-section (1)
- Curvature Equation (1)
- Cushing-Syndrom (1)
- Cushing’s disease (1)
- Cutaneous lymphoma (1)
- Cysteinproteasen (1)
- Cystic fibrosis (1)
- Cytochrome P 450 pathway (1)
- Cytokine (1)
- Cytologie (1)
- Cytosol (1)
- DC gate (1)
- DCAF17 (1)
- DEM (1)
- DFT mechanism (1)
- DLS and AFM measurements (1)
- DNA electronic transport (1)
- DNA methyltransferases (1)
- DNA repair (1)
- DNA sequencing (1)
- DNA weight (1)
- DNA-Schäden (1)
- DNA-repair (1)
- DNA-repair genes (1)
- DPP IV (1)
- DRG (1)
- DROSHA (1)
- DSB focus substructure (1)
- DSM (1)
- Dark-Matter (1)
- Dark-matter (1)
- Data Analytics (1)
- Data Warehouse (1)
- Data acquisition (1)
- Data-Warehouse-Konzept (1)
- Decision Support (1)
- Declarative Performance Engineering (1)
- Deep Inelastic-scattering (1)
- Delbruck Scattering (1)
- Demokratische Republik Kongo (1)
- Dendritic cell (1)
- Dendritische Zelle (1)
- Densovirus (1)
- Dental Phobia (1)
- Depression (1)
- Design (1)
- Development (1)
- Developmental biology (1)
- Dezellularisierung (1)
- Diabetes mellitus (1)
- Diagnosis prediction (1)
- Diagnostic Imaging Exams (1)
- Diagnostic medicine (1)
- Dickdarmtumor (1)
- Diffusion tensor imaging (1)
- Dihydroboranes (1)
- Disease severity (1)
- Dopamin (1)
- Dopamine (1)
- Dosimetry (1)
- Dosis (1)
- Dotierung (1)
- Double-Beta Decay (1)
- Doxorubicin (1)
- Drug delivery platforms (1)
- Drug discovery (1)
- Drug resistance (1)
- Drug testing (1)
- Dual setting system (1)
- Dynamical Systems (1)
- Dynamical system (1)
- Dynamics (1)
- Dünne Schicht (1)
- Dünnschichten (1)
- E(+)E(-) collicions (1)
- E-Learning (1)
- E2 conjugating enzyme (1)
- E3 ligating enzyme (1)
- E8 symmetry (1)
- EBF1 (1)
- EQ5D-5L (1)
- ER-Stress (1)
- ERK (1)
- ERK signaling (1)
- ERK1/2 (1)
- ESAT‐6‐like secretion system (1)
- ESKAPE (1)
- ESS (1)
- EUROASPIRE (1)
- EWAS (1)
- Earnings Management (1)
- Earnings Quality (1)
- Earnings management (1)
- Earth observation (1)
- Echinococcosis (1)
- Echinococcus (1)
- Efficiency (1)
- Efficiency Gains (1)
- Effizienzsteigerung (1)
- Efflux transport (1)
- Eierstockkrebs (1)
- Eigenvectors (1)
- Einkommensverteilung (1)
- Einwandige Kohlenstoff-Nanoröhre (1)
- Einzelmolekülmikroskopie (1)
- Elderly (1)
- Electrical impedance tomography (1)
- Electromagnetic signals (1)
- Electromagnon (1)
- Electron (1)
- Electrophysiology (1)
- Electrospinning (1)
- Electroweak Measurements (1)
- Electroweak Phase-Transition (1)
- Electroweak interaction (1)
- Elektrizitätsverbrauch (1)
- Elektromagnon (1)
- Elektron-Phonon-Wechselwirkung (1)
- Elektronentransfer (1)
- Elektrospinnen (1)
- Elissen-Palm flux (1)
- Embryonic induction (1)
- Embryos (1)
- Emergence (1)
- Emotionales Verhalten (1)
- Empirical Analysis (1)
- Enantiomerentrennung (1)
- Endogene Rhythmik (1)
- Endoplasmic-Reticulum Stress (1)
- Endothel (1)
- Energieeffizienz (1)
- Energy (1)
- Energy Efficiency (1)
- Enhancer elements (1)
- Entanglement (1)
- Entscheidungsunterstützung (1)
- Entscheidungsunterstützungssystem (1)
- Entwicklung (1)
- Entzündung (1)
- Environmental impact (1)
- Epidemiology (1)
- Epigenetic (1)
- Epigenetic regulation (1)
- Epitaxy (1)
- Epstein-Barr virus-induced gene 2 (1)
- Equipment (1)
- Erfolgsplanung (1)
- EsaA (1)
- Escherichia coli (1)
- European Organization for Nuclear Research. ATLAS Collaboration (1)
- European Society for Immunodeficiencies (ESID) (1)
- European Spanish (1)
- European group (1)
- Event builder (1)
- Events GW150914 (1)
- Evolutionary developmental biology (1)
- Evolutionary emergence (1)
- Excited state dynamics (1)
- Exciton (1)
- Exciton coupling (1)
- Exciton localization dynamics (1)
- Exercise testing (1)
- Experimental Studies (1)
- Experimentelle Psychologie (1)
- Expiry date (1)
- Explosives (1)
- Explosivstoff (1)
- Extensions of gauge sector (1)
- Extracellular matrix (1)
- Extracellular volume (1)
- Extramedullary disease (1)
- Extrazelluläre Matrix (1)
- Extreme flows (1)
- Exziton-Polariton (1)
- Exzitonenkopplung (1)
- Eye Movements/physiology (1)
- Eye development (1)
- FIB-4 (1)
- Face Voice Matching (1)
- Fahrerassistenzsystem (1)
- Fak regulation (1)
- Familial Beckwith-Wiedemann syndrome (1)
- Farbstoff (1)
- FasL (1)
- Fatigue (1)
- Fats (1)
- Fear Generalization (1)
- Fear Learning (1)
- Fear conditioning (1)
- Female (1)
- Fertigarzneimittel (1)
- Festkörperphysik (1)
- Fgf-signalling (1)
- Fibroblastenwachstumsfaktor (1)
- Finite support distributions (1)
- Flavor Violation (1)
- Fliegenkippen (1)
- Flowering plants (1)
- Flowers (1)
- Fludarabine (1)
- Fludarabine-treosulfan (FT) (1)
- Fluorescence spectroscopy (1)
- Fluoreszenzspektroskopie (1)
- Fluorine (1)
- Fluorverbindungen (1)
- Flüssigkristall (1)
- Forces (1)
- Forests (1)
- Fotochemie (1)
- Fotophysik (1)
- Fourier-Spektroskopie (1)
- Fractional cover analysis (1)
- Fractional quantum Hall effect (1)
- Fraktionaler Quanten-Hall-Effekt (1)
- Full body ownership illusion (1)
- Functional Connectivity (1)
- Funktionalisierung <Chemie> (1)
- Funktionalisierung von elektrogesponnenen Fasern (1)
- Funktionelle Konnektivität (1)
- Furchkonditionierung (1)
- Furcht (1)
- Furchtgeneralisierung (1)
- Fusarium (1)
- G Protein-coupled receptor (1)
- G-2 (1)
- G-Protein gekoppelte Rezeptor (1)
- G-quadruplex (1)
- GABAA (1)
- GAD1 (1)
- GRP78 (1)
- GSV (1)
- GVHD (1)
- Ga-68-labelled Peptides (1)
- Galactic sources (1)
- Gallensalze (1)
- Gas chromatography (1)
- Gaseous detectors (1)
- Gauge bosons (1)
- Gauge-gravity correspondence (1)
- Gauge/Gravity Duality (1)
- Gaussian approximation (1)
- Gelatine (1)
- Gen-Umwelt Interaktion (1)
- Gene by Environment (1)
- Gene expression analysis (1)
- Gene silencing (1)
- General anaesthesia (1)
- Generalisierung (1)
- Generalisierung <Kartografie> (1)
- Generation (1)
- Genetik (1)
- Genmutation (1)
- Genom (1)
- Genome (1)
- Genome Annotation (1)
- Genomics (1)
- Genotype (1)
- Geriatric care (1)
- Geriatrics (1)
- German PID-NET registry (1)
- Germany (1)
- Germline (1)
- Gesicht (1)
- Gestational diabetes (1)
- Gestationsdiabetes (1)
- Getz Ice Shelf (1)
- Gitterdynamik (1)
- Gliazelle (1)
- Glioblastoma (1)
- Glutathione (1)
- Glycidol (1)
- Glycoengineering (1)
- Glykane (1)
- Glykosylierung (1)
- Go/NoGo task (1)
- Google Earth Engine (1)
- Governance (1)
- Graft versus host disease (1)
- Gram-positive bacteria (1)
- Graph (1)
- Gravitons (1)
- Greenland ice sheet (1)
- Grenzfläche (1)
- Grenzflächenleitfähigkeit (1)
- Group B Streptococcus (1)
- Grundlagenforschung (1)
- Gruppo-italiano (1)
- GvHD (1)
- Gyrasehemmer (1)
- H-infinity (1)
- HARPES (1)
- HCV (1)
- HDAC (1)
- HEMA (1)
- HIV-associated candidiasis (1)
- HNE (1)
- HNSCC (1)
- HPA axis (1)
- HPLC (1)
- HRQOL (1)
- Hadron-Hadron scattering (experiments) (1)
- Hadron-hadron interactions (1)
- Haemophilus influenzae (1)
- Hard X-ray Angle Resolved Photoemission (1)
- Haut (1)
- Health (1)
- Heart (1)
- Heart failure (1)
- Helicasen (1)
- Hematopoietic Stem (1)
- Hematopoietic cell transplant (1)
- Heme-regulated inhibitor (1)
- Hemipelvectomy (1)
- Herzmuskelzelle (1)
- Heterosolarzelle (1)
- Heterostruktur (1)
- Hfq (1)
- Higgy-Boson (1)
- High grade glioma (1)
- High-Energies (1)
- High-Z Oxides (1)
- High-energy astrophysics (1)
- Hindbrain (1)
- Hippo pathway (1)
- Hippocampus (1)
- Histone deacetylase (1)
- Hochauflösende Fluoreszenzmikroskopie (1)
- Hodgkin lymphoma (1)
- Holstein model (1)
- Holstein-Modell (1)
- Honey bees (1)
- Hordeum vulgare (1)
- Hormontransport (1)
- Host Genome Integrity (1)
- Host-parasite interaction (1)
- Human Body Weight (1)
- Human Herpesvirus 6 (1)
- Human Muse Cells (1)
- Human behaviour (1)
- Human-Computer Interaction (1)
- Humanes Herpesvirus 6 (1)
- Humangenetik (1)
- Humans (1)
- Hunsrueck (1)
- Hurwitz theorem (1)
- Hyaluronic Acid (1)
- Hyaluronsäure (1)
- Hybrid Dynamical Systems (1)
- Hybridsystem (1)
- Hydrocarbon radicals (1)
- Hydrocarbons (1)
- Hydrogen (1)
- Hyperosmotic Stress (1)
- Hypothalamus (1)
- Hypothetical gauge bosons (1)
- Hypoxia (1)
- Hypoxie (1)
- IFN (1)
- IL-10 (1)
- IP3 (1)
- Icecube (1)
- Ideomotor Theory (1)
- Ideomotorik (1)
- IgG substitution therapy (1)
- Image Processing (1)
- Imatinib (1)
- Immune system (1)
- Immune-related adverse event (1)
- Immunologe (1)
- Immunology (1)
- Immunoprecipitation (1)
- Immuntherapie (1)
- Imo Bundesstaat (1)
- Imo State - Nigeria (1)
- Impella (1)
- Implicit and explicit reward learning (1)
- InSAR (1)
- InSAR height (1)
- Incontinentia pigmenti (1)
- Individualität (1)
- Induced apoptosis (1)
- Inducible Clindamycin Resistance (1)
- Induzierte pluripotente Stammzelle (1)
- Infectious disease (1)
- Inflammatio (1)
- Inflammatory Pain (1)
- Inflammatory diseases (1)
- Inflammatory pain (1)
- Information (1)
- Information Extraction (1)
- Information System (1)
- Information seeking and sharing (1)
- Information system (1)
- Informationsverarbeitung (1)
- Inhibition (1)
- Innovation (1)
- Input-Output-Tabelle (1)
- Insect flight (1)
- Insulin (1)
- Insulin-like Growth Factor I (1)
- Insulin-like growth factor-I (1)
- Integrine (1)
- Intention (1)
- Intentional Nonaction (1)
- Intentionale Nichthandlung (1)
- Interaction Design (1)
- Interactions (1)
- Interconnection (1)
- Interface Conductivity (1)
- Interfaces (1)
- Intergenerational income mobility (1)
- Intergenerationenmobilität (1)
- Intergenerative Einkommensmobilität (1)
- Interleukin-10 (1)
- Interleukin-6 (1)
- Invasion (1)
- Inverse Gaschromatographie (1)
- Invertebrate herbivory (1)
- Ionenkanal (1)
- Ionenleitfähigkeit (1)
- Ionic Liquid (1)
- Ionische Flüssigkeit (1)
- Ipilimumab (1)
- Iridate (1)
- Ischemic stroke (1)
- Isocyanate (1)
- Isolation (1)
- J-Aggregate (1)
- JAK2 (1)
- K-RAS (1)
- KIF (1)
- KIF11 (1)
- KM3NeT (1)
- KTaO3 (1)
- Kapillarelektrophorese (1)
- Kilombero (1)
- Kinect (1)
- Kinetic Self-assembly (1)
- Kleinsatellit (1)
- Klinisches Experiment (1)
- Knee (1)
- Knochenimplantat (1)
- Knochenkleber (1)
- Knochenregeneration (1)
- Knochenwachs (1)
- Knorpelbildung (1)
- Kohärente Multidimensionale Spektroskopie (1)
- Kokristallisation (1)
- Kollektive Invasion (1)
- Komplexität (1)
- Komponentenanalyse (1)
- Konditionierung (1)
- Konfidenzintervall (1)
- Konfokale Mikroskopie (1)
- Konforme Metrik (1)
- Kongo (1)
- Konische Durchschneidung (1)
- Korrelierte Fermionen (1)
- Krebs (1)
- Krebs <Medizin> (1)
- Kreditgenossenschaft (1)
- Kristallfeld (1)
- Körpergewicht (1)
- L1 reading comprehension (1)
- L2 reading comprehension (1)
- L2 reading motivation (1)
- LATE DEATHS (1)
- LC-HRESIMS (1)
- LC3-associated phagocytosis (1)
- LCD Pulse Shaper (1)
- LCD Pulsformer (1)
- LHC (1)
- LMICS (1)
- LSD1 (1)
- LST (1)
- La gestion des déchets (1)
- LaAlO3/SrTiO3 (1)
- Ladungstrennung (1)
- Ladungsträger (1)
- Ladungsträgerlokalisation (1)
- Lageregelung (1)
- Land Change Modeler (1)
- Landnutzungskartierung (1)
- Landsat time series (1)
- Lantana camara (1)
- Lanthantitanate (1)
- Laparoscopy (1)
- Large Hadron Collider (1)
- Laser Pulse Shaping (1)
- Laserpulsformung (1)
- Late mortality (1)
- Latin America (1)
- Latrophilin (1)
- Leaf traits (1)
- Learning and memory (1)
- Learning walk (1)
- Learning/physiology (1)
- Lebende Polymerisation (1)
- Lee Smolin (1)
- Leptonic (1)
- Lernen (1)
- Lernverhalten (1)
- Leseverstehen (1)
- Lewis-base adducts (1)
- Library Screening (1)
- Lichtabsorption (1)
- Lichtblattmikroskopie (1)
- Lichtheimia (1)
- Lichtscheibenmikroskopie (1)
- Lichtstreuung (1)
- Lidschlag (1)
- Lifetime spectroscopy (1)
- Ligand <Biochemie> (1)
- Light sheet microscopy (1)
- Limb development (1)
- Limb salvage (1)
- Limestone (1)
- Liquid Crystal (1)
- Liquid Crystals (1)
- Living Polymerisation (1)
- Llullaillaco Volcano (1)
- Lokalisation (1)
- Low energy electron microscopy LEEM (1)
- Low risk alcohol use (1)
- Low-income Countries (1)
- Lung (1)
- Lung disease, (1)
- Lunge (1)
- Lyapunov Stability (1)
- Lymph nodes (1)
- Lysine-specific methylase (1)
- Löslichkeit (1)
- M14 carboxypeptidasses (1)
- MASS (1)
- MCP1 (1)
- MDSC (1)
- MGMT promoter methylation (1)
- MI-RADS (1)
- MIBG (1)
- MMB (1)
- MMB complex (1)
- MODIS (1)
- MOF (1)
- MOLLI (1)
- MRI (1)
- MRI spectroscopy (1)
- MRSA (1)
- Maculinea butterfly (1)
- Magnesiumphosphate (1)
- Magnetic Resonance Imaging (1)
- Magnetic resonance imaging (1)
- Magnetische Eigenschaft (1)
- Magnetismus (1)
- Magnetit (1)
- Magnetometry (1)
- Magnetoresistance (1)
- Magnetowiderstand (1)
- Magnon (1)
- Makrokolonie (1)
- Male (1)
- Mamma carcinoma (1)
- Mammakarzinom (1)
- Management (1)
- Managementinformationssystem (1)
- Manganese Carbonyl ligands (1)
- Mangansilicide (1)
- Manöverintention (1)
- Masern-Virus (1)
- Masticatory mucosa (1)
- Mastoid process (1)
- Mathematik (1)
- Matter (1)
- Mc4r (1)
- Measles virus (1)
- Measurement error correlation (1)
- Measurement-based Analysis (1)
- Meat (1)
- Mechanisms (1)
- Mechanisms of Social Attention (1)
- Mechanismus (1)
- Mechanosensation (1)
- Media Psychology (1)
- Medical research (1)
- Medienkonsum (1)
- Megakaryopoese (1)
- Megakaryozytopoese (1)
- Melanom (1)
- Melt Electrowriting (1)
- Memory B cells (1)
- Meniskus (1)
- Meniskusimplantat (1)
- Mensch-Maschine-Kommunikation (1)
- Merger-specific Efficiency Gains (1)
- Mergers (1)
- Mergers and Acquisitions (1)
- Merkel cell carcinoma (MCC) (1)
- Merocyanine dyes (1)
- Mesenchymal stem/stromal cells (1)
- Messenger-RNAs (1)
- Messung (1)
- Metadynamik (1)
- Metal clusters (1)
- Metall-Isolator-Phasenumwandlung (1)
- Metallorganisches Netzwerk (1)
- Methicillin-resistant Staphylococcus aureus (1)
- Methodology (1)
- Metrics (1)
- Metrologie (1)
- Mfn2 KO mice (1)
- Microbiology and Infectious Disease (1)
- Midollo-Osseo (1)
- Migration (1)
- Mikroskopie (1)
- Mikrotubulus (1)
- Minimal change disease (1)
- Minimally invasive surgery (1)
- Missing Energy (1)
- Mitochondria (1)
- MnSi (1)
- Mobile genetic element (1)
- Model specification (1)
- Model-based Performance Prediction (1)
- Modell (1)
- Modifikation von Biokeramiken (1)
- Modular Hamiltonian (1)
- Modularer Hamiltonoperator (1)
- Molekulardynamik (1)
- Molekularstrahlepitaxie (1)
- Molekülsystem (1)
- Monoschicht (1)
- Monte Carlo simulation (1)
- Monte-Carlo-Simulation (1)
- Moral Hazard (1)
- Motivation (1)
- Motor behaviour (1)
- Mott Transistion (1)
- Mott-Isolator (1)
- Mott-Übergang (1)
- Mouse (1)
- Movement behavior (1)
- Mucor (1)
- Mucorales (1)
- Multi-Messenger (1)
- Multiferroics (1)
- Multiferroika (1)
- Multiphotonenmikroskopie (1)
- Multiple (1)
- Multiple myeloma (1)
- Multiple-Scattering (1)
- Multiplex PCR (1)
- Multiwavelength Astronomy (1)
- Muon spectrometers (1)
- Muscle function (1)
- Muscle power (1)
- Muster (1)
- Mutation (1)
- Myb-MuvB (1)
- Myrmecology (1)
- Myrmica ant non-equilibrium dynamics (1)
- N-heterocyclic olefins (1)
- N-terminal HSP90 inhibitors (1)
- NAFLD (1)
- NASH (1)
- NCH93 (1)
- NCI-H295R (1)
- NCO-sP(EO-stat-PO) (1)
- NF-Kappa-B (1)
- NF-κB/NFAT reporter cells (1)
- NFATc1 (1)
- NFκB (1)
- NHCs (1)
- NH\(_{3}\) (1)
- NIPAL4 (1)
- NIQs (1)
- NIR OLED (1)
- NLO Computations (1)
- NMR spectroscopy (1)
- NMR-Spektroskopie (1)
- NPY (1)
- Nachhaltigkeit (1)
- Nahfeldoptik (1)
- Nahrungserwerb (1)
- Nanoparticles (1)
- Nanostruktur (1)
- Naphthylisoquinoline (1)
- Naphthylisoquinoline alkaloids (1)
- Nasal Carriage (1)
- Necrotizing enterocolitis (1)
- Nectin‐2 (1)
- Neisseria gonorrhoeae (1)
- Neolithic period (1)
- Nephroblastom (1)
- Nephrogenese (1)
- Netherlands (1)
- Netzwerk (1)
- Neural Differentiation (1)
- Neural circuits (1)
- Neuroanatomie (1)
- Neurodevelopmental Disorder (1)
- Neuroimaging (1)
- Neuroinflammation (1)
- Neuroscience (1)
- Neutrino Detectors and Telescopes (experiments) (1)
- Neutrino Mass (1)
- Neutrinos (1)
- Nfatc1 (1)
- Nicht-kleinzelliges Bronchialkarzinom (1)
- Nigeria (1)
- Nivolumab (1)
- Nociceptor (1)
- Non-coding RNA (1)
- Non-smooth optimal control (1)
- Nonlinear Dynamics (1)
- Non‐ischaemic cardiogenic shock (1)
- Nuclear Medicine (1)
- Nucleus subthalamicus (1)
- Numerical Cognition (1)
- Nursing homes (1)
- OSCC (1)
- OSI (1)
- Oberflächenfunktionalisierung (1)
- Oberflächenphonon (1)
- Oberflächenphysik (1)
- Oberflächenplasmon (1)
- Object recognition (1)
- Oculomotor Muscles/physiology (1)
- Oncology (1)
- Operations Management (1)
- Optical spectroscopy (1)
- Optik (1)
- Optimal foraging (1)
- Optimale Kontrolle (1)
- Optogenetics (1)
- Oral anticoagulation (1)
- Ordered metal adsorbates on semiconductor surfaces (1)
- Ordinal Categorical Indictators (1)
- Organic and hybrid semiconductors (1)
- Organische Chemie (1)
- Oscillation (1)
- Outer membrane proteins (1)
- Overstatement models (1)
- OxPL (1)
- Oxide Heterostructure (1)
- Oxidized Phospholipids (1)
- Oxidized phospholipids (1)
- P(P) over-bar collisions (1)
- P-glycoprotein (1)
- P-gp (1)
- PA-flexed view (1)
- PALS (1)
- PCR (1)
- PD-1 (1)
- PD-L1 (1)
- PDF neurons (1)
- PET/CT (1)
- PID prevalence (1)
- PKD1 (1)
- PP collisions (1)
- PRKACA (1)
- PROMISE (1)
- PSMA (1)
- PSMA-RADS (1)
- PTEN (1)
- Parametric inference (1)
- Parkinson’s disease (1)
- Partial Least Squares Path Modeling (1)
- Particle accelerators (1)
- Particle tracking detectors (Gaseous detectors) (1)
- Particle-acceleration (1)
- Parvovirus (1)
- Paternal age and BMI effects (1)
- Pathogenesis (1)
- Pathogens (1)
- Patterns and drivers of invertebrate herbivory (1)
- Patterns and drivers of species diversity of phytophagous beetles (1)
- Patterns and drivers of species richness and community biomass of large mammals (1)
- Pavlovian-to-instrumental transfer (1)
- Pediatric Nuclear Medicine (1)
- Pediatric Patients (1)
- Peierls-Übergang (1)
- Pendeln (1)
- Pentixafor (1)
- Perception (1)
- Perowskit (1)
- Personalized medicine (1)
- Perturbative/Functional Renormalization Group (1)
- Perturbative/Funktionale Renormierungsgruppe (1)
- Perylenbisdicarboximide <Perylen-3,4:9,10-bis(dicarboximide)> (1)
- Perylenbisimide (1)
- Perylenbisimides (1)
- Perylene Bisimide (1)
- Perylene Bisimides (1)
- Pfadintegral (1)
- Pflanzen (1)
- Pflanzenhormone (1)
- Phagozytose (1)
- Pharmakokinetik (1)
- Pharmakotherapie (1)
- Phase- (1)
- Phenols (1)
- Phobie (1)
- Phosphatasen (1)
- Phosphoglykolat-Phosphatase (1)
- Phosphoglykolatphosphatase (1)
- Phospholipide (1)
- Phosphorylation (1)
- Photic (1)
- Photoelectron Spectroscopy (1)
- Photoelektronenspektroskopie (1)
- Photoemission electron microscopy PEEM (1)
- Photoluminescence (1)
- Photolumineszenz (1)
- Photoreceptor (1)
- Physical activity (1)
- Physiologie (1)
- Phytochemical investigations of a Congolese Ancistrocladus Liana (1)
- Phytochemie (1)
- Pigmentdispergierender Faktor (1)
- Plant signalling (1)
- Plants (1)
- Plasmaantrieb (1)
- Plasmamembranorganisation (1)
- Plasmon (1)
- Platzierungsalgorithmen (1)
- Poly(2-oxazolin)e (1)
- Polyethylenglykole (1)
- Polygonum cuspidatum (1)
- Polymer-drug interaction (1)
- Polymere (1)
- Polymers (1)
- Polynomial Factor Models (1)
- Polyphenole (1)
- Polysaccharide (1)
- Poplars (1)
- Positron annihilation spectroscopy (1)
- Positron-Emission Tomography (1)
- Postoperative complications (1)
- Preconcentration (1)
- Predictive Analytics (1)
- Prefrontal cortex (1)
- Premna (1)
- Prescriptive Analytics (1)
- Preterm birth (1)
- Prevalence (1)
- Prior information (1)
- Privatsphäre (1)
- ProQ (1)
- Probability theory (1)
- Prognostic markers (1)
- Prognostic scoring system (1)
- Prospektives Gedächtnis (1)
- Protease-sensitive release (1)
- Protein (1)
- Protein Kinase D (1)
- Protein Kinase D 1 (1)
- Protein folding (1)
- Protein kinase D3 (PKD3) (1)
- Proteinkinase A (1)
- Proteinkinase D (1)
- Proteomics Analysis of Complexes (1)
- Proteotype (1)
- Proteus vulgaris (1)
- Proton-Proton Collisions (1)
- Präsenz (1)
- Präzisionsmessung (1)
- Psychiatric disorders (1)
- Psychiatrie (1)
- Psychologie (1)
- Psychology (1)
- Psychometrie (1)
- Psychomotor Performance/physiology (1)
- Pulmonary function tests (1)
- Pulsed laser deposition (1)
- Punktwolke (1)
- Quality assessment of antimalarial medicines from the Congo (1)
- Quality ccontrol (1)
- Quality-control (1)
- Qualität der Abschlussprüfung (1)
- Qualität der Rechnungslegung (1)
- Qualitätskontrolle (1)
- Quanten-Hall-Effekt (1)
- Quanten-Monte-Carlo (1)
- Quanteninformation (1)
- Quantenpunkt (1)
- Quantifizierung (1)
- Quantitative Mikroskopie (1)
- Quantum Hall effect (1)
- Quantum electrodynamics (1)
- Quinolone amides (1)
- R package (1)
- RADS (1)
- RAS Evaluation (1)
- RCT (1)
- REDD1 (1)
- RFID (1)
- RNA Sequencing (1)
- RNA expression (1)
- RNA metabolism (1)
- RNA protein interactions (1)
- RNA secondary structures (1)
- RNA sequencing (1)
- RNA-Seq (1)
- RNA-seq transcriptome (1)
- RNAi (1)
- RNAlater (1)
- RNS (1)
- ROR1 (1)
- ROS (1)
- RSV-A ON1 (1)
- RT-qPCR (1)
- Radiation (1)
- Radiation Protection (1)
- Radiation exposure (1)
- Radiation-associated Cancer Risk (1)
- Radiographs (1)
- Radiotherapy (1)
- Raphe (1)
- RapidEye (1)
- Raumwahrnehmung (1)
- Regelbasiertes Modell (1)
- Regimes (1)
- Regional trade (1)
- Regionaler Arbeitsmarkt (1)
- Regionaler Handel (1)
- Regionalpolitik (1)
- Regionalwirtschaft (1)
- Regulierung (1)
- Reiz (1)
- Relativistic heavy-ion collisions (1)
- Reminder e-mails (1)
- Remnant RX J1713.7-3946 (1)
- Remote Sensing (1)
- Reporter Cells (1)
- Reporterzellen (1)
- Rescue behaviour (1)
- Research Article (1)
- Respiratory tract infection (1)
- Retinopathy (1)
- Rhizomucor (1)
- Rhizopus (1)
- RhoA (1)
- Rhodopsin (1)
- Ribozyme-catalyzed RNA labeling (1)
- Ringöffnungspolymerisation (1)
- Risk (1)
- Risk Assessment (1)
- Roboter (1)
- Robotics (1)
- Runge-type Theorems (1)
- Ruthenium (1)
- Ruxolitinib (1)
- Röntgenastronomie (1)
- Röntgendiffraktometrie (1)
- S. aureus (1)
- SASHA (1)
- SB332235 (1)
- SIX1 (1)
- SPOT-6 (1)
- SR/mitochondria metabolic feedback (1)
- SREBP (1)
- SSR42 (1)
- SSTR (1)
- SSTR-RADS (1)
- ST 772 (1)
- ST18 (1)
- SWAT (1)
- SWAT model (1)
- Saccades/physiology (1)
- Salmo trutta fario (1)
- Satellit (1)
- Scarabaeidae (1)
- Scattering (1)
- Scenario analysis (1)
- Scheme for solving optimal control problems (1)
- Schlichte Funktion (1)
- Schmerzforschung (1)
- Schmerztherapie (1)
- Secondary stroke prevention (1)
- Sediment (1)
- Segmentation (1)
- Sekundärprävention (1)
- Selbstassemblierung (1)
- Self-assembly (1)
- Self-navigation (1)
- Self-renewal (1)
- Semantics (1)
- Semantik (1)
- Sense of Agency (1)
- Sensor Fusion (1)
- Sentinel-2 (1)
- Septine (1)
- Sequential quadratic Hamiltonian scheme (1)
- Serine proteases (1)
- Server (1)
- Sex chromosome (1)
- Sex determination (1)
- Sexual development and function (1)
- ShMOLLI (1)
- Shelf-life (1)
- Shell (1)
- Sibling donor (MSD) (1)
- Silver (1)
- Single Molecule Localization Microscopy (SMLM) (1)
- Single-Photon (1)
- Situationsbewusstsein (1)
- Skin (1)
- Skull (1)
- Small RNA (1)
- Small interfering RNAs (1)
- Small-Gain Theorem (1)
- Smoking (1)
- Social Cognition (1)
- Social Cueing (1)
- Social Web (1)
- Societe Francaise (1)
- Soft tissues (1)
- Software (1)
- Software Defined Networking (1)
- Software Performance Engineering (1)
- Software-defined Networking (1)
- Softwarisierte Netze (1)
- Solid tumors (1)
- Somites (1)
- Soziale Aufmerksamkeit (1)
- Soziale Mobilität (1)
- Soziale Software (1)
- Spatial Cognition (1)
- Spatially resolved 2D spectroscopy (1)
- Species delimitation (1)
- Species richness (1)
- Specific Phobia (1)
- Specimen grinding (1)
- Speckle tracking (1)
- Spezifische Phobien (1)
- Spezifische Wärme (1)
- Sphingosine-1-phosphate (1)
- Sphingosine-1-phosphats (1)
- Spin flip (1)
- Spin-Bahn-Kopplung (1)
- Spin-Orbit interaction (1)
- Spin-Phonon Kopplung (1)
- Spin-chemistry (1)
- Spin-phonon coupling (1)
- Spinflüssigkeit (1)
- Stability (1)
- Stabilität (1)
- Stammzelle (1)
- Standardmodell <Elementarteilchenphysik> (1)
- Staphylococcus (1)
- Staphylococcus aureus USA300 (1)
- Starke Kopplung (1)
- Stechameisen (1)
- Stem cell (1)
- Stem-cell biotechnology (1)
- Stenosis degree (1)
- Stenosis length (1)
- Stereochemistry (1)
- Sternpolymere (1)
- Stigmatisierung (1)
- Stimme (1)
- Stimmverarbeitung (1)
- Stimulation (1)
- Stoffwechsel (1)
- Stokes-shifted fluorescence emission (1)
- Strains (1)
- Strange Baryon Production (1)
- Strategisches Management (1)
- Stratigraphy (1)
- Streptococcus agalactiae (1)
- Stroke (1)
- Stroke unit (1)
- Stromal cells (1)
- Strontiumtitanat (1)
- Strontiumvanadate (1)
- Structural Equation Modeling (1)
- Structural elucidation (1)
- Structural equation modelling (1)
- Structure elucidation (1)
- Struktur-Aktivitäts-Beziehung (1)
- Strukturgleichungsmodell (1)
- Sub-Saharan Africa (1)
- Subject (1)
- Subtercola vilae (1)
- Success Factors (1)
- Supernova (1)
- Support vector machine (1)
- Supportive therapy (1)
- Supramolecular Block Copolymers (1)
- Supramolecular aggregates (1)
- Supramolekulare Aggregate (1)
- Supramolekulare Struktur (1)
- Surface Plasmon (1)
- Surface Raman spectroscopy (1)
- Surgical and invasive medical procedures (1)
- Surgical oncology (1)
- Survey (1)
- Suspensionskultur (1)
- Swine (1)
- Syap1 knockout (1)
- Symmetry (1)
- Systemic sclerosis (1)
- T cell (1)
- T cell receptor (1)
- T cell suppression (1)
- T cells (1)
- T-cell lymphoma (1)
- T1 mapping (1)
- TDDFT (1)
- TDMT (1)
- TEV (1)
- TFP (1)
- TGFβ/BMP signaling (1)
- TLR2 (1)
- TLR3 (1)
- TLR4 (1)
- TMEM16F (1)
- TNF (1)
- TNF-alpha (1)
- TNFR family costimulatory receptors (1)
- TNFR2 (1)
- TNFR2 agonists (1)
- TNFR2 antagonism (1)
- TNFα (1)
- TNNI3 (1)
- TP53 (1)
- TPCA1 (1)
- TRAF1 (1)
- TRAF2 (1)
- TRAILR1 (1)
- TRAILR2 (1)
- TRPA1 channel (1)
- TWEAK (1)
- Tagesrhythmus (1)
- Tamoxifen (1)
- TanDEM-X (1)
- Tc-99m-MAG3 Scans (1)
- TeV energies (1)
- Telemedizin (1)
- Temozolomide (1)
- Terramechanics (1)
- Theoretische Chemie (1)
- Therapeutisches System (1)
- Therapie (1)
- Therapiesimulation (1)
- Thermodynamik (1)
- Thin Films (1)
- Thin intermetallic films (1)
- Thiotepa-busulfan-fludarabine (TBF) (1)
- Thrombo-inflammation (1)
- Thrombosis (1)
- Thrombozytopenie (1)
- Thrust Vector Control (1)
- Tiermodell (1)
- Time resolved measurements (1)
- Time-resolved photoemission electron microscopy (1)
- Time-resolved photoluminescence (1)
- Tissue engineering (1)
- Toddler (1)
- Top quark (1)
- Topological insulators (1)
- Topologische Isolatoren (1)
- Topologischer Isolator (1)
- Torque (1)
- Total Factor Productivity (1)
- Tourenplanung (1)
- Tractography (1)
- Transcription (1)
- Transcription factor NRF1 (1)
- Transcriptomic (1)
- Translation (1)
- Translation Initiation (1)
- Translational research (1)
- Transplantat-Wirt-Reaktion (1)
- Transposable element (1)
- Transverse-Momentum (1)
- Trees (1)
- Tregs (regulatory T cells) (1)
- Triquinacenderivate (1)
- Triticeae (1)
- Triticum aestivum (1)
- Trousseau's syndrome (1)
- Trypanosomiase (1)
- Tryptophan hydroxylase (1)
- Tubulin (1)
- Tumor (1)
- Tumorzelle (1)
- Twin Domains (1)
- Twin Suppression (1)
- Two-color pump-probe spectroscopy (1)
- U-Net (1)
- USA (1)
- UV-VIS-Spektroskopie (1)
- UV/Vis spectroscopy (1)
- UV–Vis (1)
- Ultrakurzzeitspektroskopie (1)
- Ultrarelativistic Heavy-Ion (1)
- Ultrashort echo time - UTE (1)
- Umwelt (1)
- Unconventional/Topological superconductivity (1)
- Universal Functions (1)
- Unkonventionelle/Topologische Supraleitung (1)
- Unnötige Warnung (1)
- Unrelated donor (UD) (1)
- Unternehmensverfassung (1)
- User Behavior (1)
- User-Guidelines (1)
- Ustilago maydis (1)
- V-ATPase (1)
- VLBW (1)
- VMAT (1)
- Vakuole (1)
- Valentine Leukocidin Genes (1)
- Valgus osteoarthritis (1)
- Value at Risk (1)
- Vascularized (1)
- Vaskularisation (1)
- Vcsels (1)
- Verarbeitende Industrie (1)
- Verbundwerkstoff (1)
- Verkehrspsychologie (1)
- View (1)
- Virtuelle Realität (1)
- Visuelle Aufmerksamkeit (1)
- Visuo-tactile congruency (1)
- Voice Processing (1)
- W & Z bosons (1)
- W-Boson (1)
- WSS (1)
- Wahrscheinlichkeitstheorie (1)
- Warnung (1)
- Waste management (1)
- Weak-Interactions (1)
- WebGIS (1)
- Wechselwirkungen (1)
- Wheel (1)
- White matter lesions (1)
- Wide-gap-Halbleiter (1)
- Wilms tumor (1)
- Wilms-Tumor (1)
- Winkelaufgelöste Photoemission mit harten Röntgenstrahlen (1)
- Wire chambers (MWPC, Thin-gap chambers, drift chambers, drift tubes, proportional chambers etc) (1)
- Wirkstoff (1)
- Wirkstofftestung (1)
- Wirtschaftliche Integration (1)
- Wirtschaftsinformatik (1)
- Woodhouse-Sakati Syndrom (1)
- Woodhouse-Sakati sydrome (1)
- Wundheilung (1)
- X-ray radiography (1)
- XRD (1)
- YAP (1)
- Yoga (1)
- Young Adult (1)
- ZF1 degradation assay (1)
- ZFAND1 (1)
- Zahnbehandlungsphobie (1)
- Zebrafish (1)
- Zell Migration (1)
- Zelloberfläche (1)
- Zentralasien (1)
- Zinc (1)
- Zinkselenid (1)
- ZnO-NP (1)
- Zusammenstoß (1)
- Zwillingsbildung (1)
- [68Ga]Pentixafor (1)
- \(^{177}\)Lu-OPS201 (1)
- abdominal surgery (1)
- absolute bioavailability (1)
- accessory medulla (1)
- accidents (1)
- accumulation (1)
- accuracy (1)
- acetate (1)
- acid ceramidase (1)
- acid ceramidase inhibitor ceranib-2 (1)
- acoustic radiation force impulse imaging (1)
- acrophobia (1)
- actin cytoskeleton (1)
- actin-binding proteins (1)
- action control (1)
- activated delayes flourescence (1)
- activation (1)
- active galactic nuclei (1)
- active ingredients (1)
- acute kidney injury (1)
- acute lymphoblastic leukemia (1)
- adalimumab (1)
- adaptive choice-based conjoint (1)
- additive manufacturing (1)
- adenoma (1)
- adenotonsillectromy (1)
- adipocyte (1)
- adipose (1)
- adiposity (1)
- administrative boundary (1)
- adrenal gland (1)
- adrenocortical carcinoma (1)
- adult attention deficit/hyperactivity disorder (adult ADHD) (1)
- advanced breast cancer (1)
- aerobic fitness (1)
- affect bursts (1)
- age at onset (1)
- age groups (1)
- age-related macular degeneration (1)
- agroecology (1)
- airway management (1)
- alcohol use disorder (1)
- alkaloids-Quinoid (1)
- alkynes (1)
- alternative splicing (1)
- altitudinal gradients (1)
- alveolar epithelium (1)
- amine borane dehydrocoupling (1)
- aminergic neurons (1)
- amodiaquine (1)
- amorphous solid dispersion (1)
- amphiphilic block copolymer (1)
- amsacrine (1)
- amyloidoma (1)
- amyotrophic lateral sclerosis (1)
- amyotrophic lateral sclerosis (ALS) (1)
- anakinra (1)
- analysis of variance (1)
- animal behaviour (1)
- animal physiology (1)
- animal research (1)
- anime (1)
- anomaly detection (1)
- anorexia nervosa (1)
- anti-contactin-1 (1)
- anti-depressant drug (1)
- antibacterial (1)
- antibacterial activity (1)
- antibiofilm (1)
- antibiotic (1)
- antibiotic resistance (1)
- anticancer (1)
- anticipation (1)
- antifungal (1)
- antifungal susceptibility (1)
- antimicrobial compounds (1)
- antimicrobial susceptibility (1)
- antitrypanosomal (1)
- anti‐aging (1)
- anxiety (1)
- anxiety generalization (1)
- anxiolytics (1)
- aortocaval fistula model (1)
- appraisal theory of emotion expression (1)
- arctic greening (1)
- arenes (1)
- artemether - lumefantrine (1)
- arterial thrombus formation (1)
- artifacts (1)
- artificial intelligence (1)
- artificial light at night (1)
- aspergillosis (1)
- asylum seekers (1)
- asylum status (1)
- atmospheric waves (1)
- atrial fibrillation (1)
- attention (1)
- auto-planning (1)
- autoantibody (1)
- autobiography (1)
- autoimmune disease (1)
- autoimmune encephalitis (1)
- autonomic nervous system (1)
- autosomal recessive (1)
- auxin (1)
- axillary dissection (1)
- back reaction (1)
- bacterial pathogen (1)
- bacterial physiology (1)
- bacteriology (1)
- baghdadite (1)
- balancing trade-offs (1)
- bank mergers (1)
- bariatric surgery (1)
- behavior (1)
- behavioral plasticity (1)
- beige adipocytes (1)
- bench press (1)
- bending strength (1)
- benige tumor (1)
- beta-lactam antibiotics (1)
- biceps tendinitis (1)
- biceps tendon (1)
- big earth data (1)
- bilateral internal carotid artery stenosis (1)
- binary species (1)
- bioavailability (1)
- bioceramics (1)
- biofabricated vascular graft (1)
- biofilm architecture (1)
- bioinformatics (1)
- bioinformatics tool (1)
- bioink (1)
- bioinks (1)
- biokinetics (1)
- biological rhythm (1)
- biological scaffolds (1)
- biological techniques (1)
- biologics (1)
- biomarker (1)
- biomarker signature (1)
- biomaterial ink (1)
- biomaterials (1)
- biomaterials – cells (1)
- biomechanics (1)
- biomolecular processes (1)
- biophysics (1)
- bioreactor (1)
- biotechnology (1)
- biotic interaction (1)
- bispecific antobodies (1)
- bisulfite pyrosequencing (1)
- black trout syndrome (1)
- bladder (1)
- blazars (1)
- bleeding (1)
- blinatumoman (1)
- blinking (1)
- blocking phagocytosis (1)
- blood (1)
- blood brain barrier (1)
- blood cerebrospinal fluid barrier (1)
- blood-cerebrospinal fluid barrier (1)
- bohrbar (1)
- bone critical size defect (1)
- bone graft substitutes (1)
- bone marrow stromal cells (1)
- bone metastases (1)
- bone microenvironment (1)
- bone tissue engineering (1)
- bone wax (1)
- boolean modeling (1)
- boreholes (1)
- borohydrides (1)
- boronate (1)
- boronic acid (1)
- borylenes (1)
- bottom-up processing (1)
- brain (1)
- brain activity (1)
- brain development (1)
- brain disorders (1)
- brain endothelial cell (1)
- brain endothelial cells (1)
- brain networks (1)
- brain plasticity (1)
- brain tumor (1)
- breast cancer (1)
- bridge-to-transplant (1)
- bronchoalveolar lavage fluid (1)
- bronchopulmonary dysplasia (1)
- broth microdilution (1)
- brown trout (1)
- building (1)
- bullae (1)
- burn severity (1)
- burnt-wood (1)
- calcium (1)
- calcium phosphate (1)
- calnexin (1)
- calving front (1)
- cancer imaging (1)
- capillary zone electrophoresis (1)
- carabid beetles (1)
- carbenes (1)
- carbon (1)
- carbon monoxide (1)
- cardiac autonomic nervous system (1)
- cardiac metabolism (1)
- cardiac remodelling (1)
- cardiac surgery (1)
- cardiac tissue (1)
- cardiolipin (1)
- cardiomyocytes (1)
- cardiopulmonary bypass (1)
- cardiovascular genetics (1)
- cardiovascular risk factors (1)
- care (1)
- cartilage repair (1)
- catalysis (1)
- catchment (1)
- catheterization (1)
- catheters (1)
- cattle (1)
- caveolin-1 (Cav-1) (1)
- cefotiam (1)
- cell biology (1)
- cell death and immune response (1)
- cell death in the nervous system (1)
- cell differentiation (1)
- cell growth (1)
- cell migration (1)
- cell signalling (1)
- cell therapy and immunotherapy (1)
- cellular model (1)
- cellular neuroscience (1)
- ceramide (1)
- cerebral microbleeds (1)
- cerebrospinal fluid (1)
- cervical dystonia (1)
- channelrhodopsins (1)
- chaperones (1)
- charge carrier localization (1)
- charge recombination (1)
- charge separation (1)
- chemical crosslinking (1)
- chemical engineering (1)
- chemokine (1)
- chemokine receptor (1)
- child behavior (1)
- chimeric antigen receptor (1)
- chirality (1)
- chirality-induced spin selectivity (1)
- chlamydia (1)
- chlorophyll fluorescence imaging (1)
- cholesterol (1)
- cholesterol 25 hydroxylase (1)
- cholesteryl ester (1)
- chondrocyte (1)
- chondrogenesis (1)
- chronic kidney disease (1)
- chronic kidney disease (CKD) (1)
- chronic non-bacterial osteomyelitis (1)
- circRNA (1)
- circadian clock (1)
- circadian rhythm (1)
- circadian rhythms (1)
- circular transcriptome sequencing (1)
- cisplatin (1)
- claudin-5 (1)
- click chemistry (1)
- climate extremes (1)
- clinical characteristics (1)
- clinical imaging (1)
- clinical outcome (1)
- clinical pharmacy (1)
- clinical trial (1)
- closed-loop systems (1)
- cluster analysis (1)
- co-culture (1)
- coagulation system (1)
- coastline (1)
- cocrystal (1)
- cognitive control (1)
- coherence (1)
- coherent risk measures (1)
- cold adaptation (1)
- collagen (1)
- collagen sponge (1)
- collective invasion (1)
- collimator (1)
- collodion baby (1)
- collybistin (1)
- colonization (1)
- commission error (1)
- common diseases (1)
- comparative genomics (1)
- comparison (1)
- competition (1)
- complement deposition (1)
- complement factor H (1)
- complex DNA damage (1)
- composite material (1)
- composition (1)
- computational science (1)
- computer-mediated communication (1)
- computerized tomography (1)
- concealed information test (1)
- conditioning (1)
- congruency sequences (1)
- conjugation (1)
- consensus (1)
- conservation (1)
- constructed trade-offs (1)
- context-based teaching (1)
- contextual fear conditioning (1)
- continuous theta burst stimulation (cTBS) (1)
- continuum limit (1)
- control levels (1)
- convolutional neural network (1)
- copeptin (1)
- coping (1)
- copy number variation (1)
- coronary heart disease (1)
- correspondence (1)
- cortical excitability (1)
- cortical silent period (1)
- cortisol (1)
- cosmology (1)
- count time series (1)
- covalent and site-specific RNA labeling (1)
- cristal engeneering (1)
- crop statistics (1)
- cross-coupling (1)
- cross-sectional study (1)
- cryosphere (1)
- cryostructured scaffolds (1)
- crystal growth (1)
- crystallization (1)
- crystallography (1)
- curcumin (1)
- curvature (1)
- curved hydrocarbons (1)
- cuticular permeability (1)
- cyclase-associated protein (1)
- cyclase-associated protein 2 (1)
- cyclic compounds (1)
- cyclophosphamide (FLAMSA) (1)
- cytokinesis (1)
- cytoskeleton (1)
- cytotoxic (1)
- daratumumab (1)
- data structure (1)
- data warehouse (1)
- dead-wood enrichment (1)
- decay (1)
- decellularization (1)
- deception (1)
- deep learning (1)
- default-interventionist framework (1)
- definition (1)
- dehydrocoupling (1)
- dehydrogenaticve borylation (1)
- democracy (1)
- democracy profiles (1)
- dendritic cell (1)
- denosumab (1)
- depth dose curves (1)
- designer cell (1)
- desk-based (1)
- desmin (1)
- desmin-related myopathy (1)
- desminopathy (1)
- desmoglein (1)
- desmoplastic small round cell tumor (1)
- desmosome (1)
- detrended fluctuation analysis (1)
- deubiquitinases (1)
- developmental forms (1)
- dexamethasone (1)
- diabetes (1)
- diacylglycerol (1)
- diacylglycerol (DAG) (1)
- dialysis adequacy (1)
- diazadiborinines (1)
- diborane(6) (1)
- diboranes (1)
- diboration (1)
- diborene (1)
- diborenes (1)
- diborynes (1)
- differentiation (1)
- differentiation potential (1)
- diffuse large B-cell lymphoma (1)
- diffusion weighted mri (1)
- digital health (1)
- diluted magnetic Semiconductor (1)
- dimeric peptide (1)
- direct muss spectrometric profiling (1)
- discrete systems (1)
- disease genetics (1)
- disease modelling (1)
- dissolution rates (1)
- distractor-response binding (1)
- distributed control (1)
- distributed learning (1)
- distributions (1)
- diversity gradients (1)
- document analysis (1)
- domain-specific language (1)
- donor (1)
- donor-acceptor systems (1)
- dorsal root ganglion (1)
- dose individualization (1)
- dosimetry (1)
- double arc (1)
- doxorubicin (1)
- drillable (1)
- drivers and patterns of diversity and herbivory (1)
- driving simulation (1)
- drought (1)
- drug release (1)
- drug resistance evolution (1)
- dual abbindend (1)
- dual setting (1)
- dual setting system (1)
- dualsteric (1)
- duchenne muscular dystrophy (1)
- duplication-deficiency (1)
- dyads (1)
- dyes (1)
- dynamic facial emotion expression (1)
- dystonia (1)
- e(+)e(-) Collisions (1)
- e-learning (1)
- early brain injury (1)
- early-life stress (1)
- earlywood (1)
- eccentric hypertrophy (1)
- echocardiography (1)
- ecosystem service (1)
- ecosystem services (1)
- education system (1)
- effective point of measurement (1)
- efficient intervention points (1)
- eindimensionale Systeme (1)
- electrical resistivity tomography (1)
- electrochemistry (1)
- electron-precise diborates (1)
- electronic properties and materials (1)
- electrospun fibers (1)
- elementary body (1)
- eletrhydrodynamic (1)
- elite (1)
- emergency care (1)
- emission (1)
- emotion (1)
- emotion enactment (1)
- emotion processing (1)
- emotion recognition (1)
- emotional behavior (1)
- emotions (1)
- emulsions oil-in-water (1)
- en bloc transfer (1)
- enantiomers (1)
- enbrel (1)
- end-stage renal disease (1)
- endocytosis (1)
- endothelial cells (1)
- endothelin-1 (1)
- endurance (1)
- endurance exercise (1)
- endurance training (1)
- enercy-richness hypothesis (1)
- energy homeostasis (1)
- enhancer (1)
- environmental justice (1)
- environmental sciences (1)
- environmental sustainability (1)
- enzyme mechanism (1)
- enzymes (1)
- epidemiology (1)
- epidural block (1)
- epithelial (1)
- epithelial-mesenchymal transition (1)
- epithelial-to-mesenchymal transition (1)
- error estimation (1)
- estimation error (1)
- etanercept (1)
- ethics (1)
- eugenol (1)
- evapotranspiration (1)
- event-related potentials (1)
- evolutionary ecology (1)
- evolutionary genetics (1)
- exciton (1)
- exciton dynamics (1)
- exciton-polariton (1)
- exercise intervention (1)
- expansion microscopy (1)
- expected value of control (1)
- external stimuli (1)
- extinction (1)
- extinction dynamics (1)
- extracellular domain (1)
- extramedullary hematopoiesis (1)
- extreme phenotypes (1)
- eye movement (1)
- eye movements (1)
- eye-tracking (1)
- fMRI (1)
- fMRT (1)
- face (1)
- face-voice integration (1)
- faces (1)
- fan culture (1)
- fault detection (1)
- fear (1)
- fear conditioning (1)
- fear learning (1)
- febrile seizures (1)
- feminist rap (1)
- femoral head (1)
- fertility (1)
- fibre length (1)
- fibroblast (1)
- fibromyalgia (1)
- fibrotest (1)
- field-induced surface hopping (1)
- fission (1)
- flash freezing (1)
- fliegende Toilette (1)
- flora (1)
- flourescence quantum yield (1)
- flu-like symptoms (1)
- fluconazole (1)
- fluerescence (1)
- fluidics (1)
- fluorenscence (1)
- fluorescence microscopy (1)
- fluorescent probes (1)
- fluorine (1)
- fluoroarene (1)
- fluorogen-activating RNA aptamer (FLAP) (1)
- fluoroquinolone (1)
- fluxosome (1)
- fly-tipping (1)
- flying toilet (1)
- folda-dimer (1)
- follistatin 288 (FST288) (1)
- follistatin 315 (FST315) (1)
- food colorings (1)
- food resources (1)
- foraging patterns (1)
- forensic sample (1)
- forest ecology (1)
- forest fire (1)
- forest management (1)
- forest resources inventory (1)
- formation control (1)
- fractional variability (1)
- fracture (1)
- fragmentation functions (1)
- free choice (1)
- free movement (1)
- free radical polymerization (1)
- friut fly behaviour (1)
- full arc (1)
- fully convolutional neural networks (1)
- function (1)
- functional MRI (1)
- functional analysis (1)
- functional connectivity (1)
- functional training (1)
- fungal ecology (1)
- fungal evolution (1)
- fungal molecular diagnostics (1)
- fungal rhodopsins (1)
- funktionale Präpolymere (1)
- games (1)
- gangliosides and lipid rafts (1)
- gastric-bypass surgery (1)
- gastrointestinal cancer (1)
- gastrointestinal tract (1)
- gauge/gravity duality (1)
- gaze control (1)
- gekrümmte Kohlenwasserstoffe (1)
- gem-bisboronates (1)
- gene alleles (1)
- gene expression analysis (1)
- gene family evolution (1)
- gene network (1)
- gene regulation (1)
- gene regulation in immune cells (1)
- genetic codon expansion (1)
- genetic counselling (1)
- genetic engineering (1)
- genetic recombination (1)
- genetics of the nervous system (1)
- genome (1)
- genome analysis (1)
- genome-wide association studies (1)
- genomic imprinting (1)
- genomics (1)
- genotoxicity (1)
- glacier front (1)
- glacier terminus (1)
- glia cells (1)
- glioblastoma multiforme (GBM) (1)
- glioma (1)
- global (1)
- global change (1)
- glucose transporter (1)
- glycine transporter 2 (1)
- glycoprotein Ibα (1)
- glyvine uptake (1)
- graft vs. host disease (1)
- graft-versus host (1)
- graft-versus-host-disease (1)
- granules (1)
- gravitational waves (1)
- green fluorescence protein (GFP) (1)
- ground penetrating radar (1)
- ground-dwelling predators (1)
- growth (1)
- growth patterns (1)
- growth ring width (1)
- guanylyl cyclase (GC) (1)
- guided bone regeneration (1)
- guideline adherent treatment (1)
- guidelines (1)
- gustatory dysfunction (1)
- gut–liver axis (1)
- hA<sub>3</sub>AR (1)
- habit (1)
- habit strength (1)
- hadronic Recoil (1)
- hadronischer Rückstoß (1)
- haematopoietic stem cell (1)
- halogens (1)
- hard x-ray photoemission (1)
- head and neck squamous cell carcinoma (1)
- heart rate variability (1)
- heart-to-mediastinum ratio (1)
- heat wave (1)
- helical molecules (1)
- helicenes (1)
- hematopoietic stem cell transplantation (1)
- heme oxygenase-1 (1)
- hemicraniectomy (1)
- hemodiafiltration (1)
- hemodialysis (1)
- hemophagocytosis (1)
- hemorrhagic (1)
- hemostasis (1)
- henoch-schönlein purpura (1)
- hepatitis B virus (1)
- hereditary breast and ovarian cancer (1)
- heterocycles (1)
- heterotypic scaffold design (1)
- heuristics (1)
- hiPSC aggregation (1)
- high LET irradiation (1)
- high efficiency (1)
- high risk (1)
- high-intensity training (1)
- high-performance sports (1)
- high-resolution tandem mass spectrometry (1)
- hip fracture (1)
- hippocampus (1)
- histogenesis (1)
- histological subtype (1)
- histone H2AX (1)
- historical document analysis (1)
- historical printings (1)
- homogeneous catalysis (1)
- homogenization (1)
- honeybee (1)
- honeybees (1)
- hospital exemption (1)
- hospital-acquired methicillin-resistant Staphylococcus aureus (1)
- human adipose-derived stromal cells (1)
- human cerebral endothelial cells (1)
- human plasma (1)
- human xenografted mouse models (1)
- hybrid fabrication (1)
- hybrid materials (1)
- hydrogels (1)
- hydrological regime (1)
- hydroxyapatite (1)
- hydroxylation (1)
- hyperosmolality (1)
- hyperpersonal communication (1)
- hypertension (1)
- hypothermia (1)
- hypoxia (1)
- iGC (1)
- iPSC (1)
- ichthyology (1)
- ichthyosis (1)
- identification (1)
- iliac crest (1)
- illness-death model (1)
- image processing (1)
- imaging PAM (1)
- imiquimod (1)
- immediate-early gene (1)
- immune evasion (1)
- immunity (1)
- immunocompetent skin (1)
- immunotherapy of cancer (1)
- implant (1)
- impurity profiling (1)
- in situ microscopy (1)
- in vitro model (1)
- in vitro models (1)
- in vitro selection from a structured RNA library (1)
- incentive salience (1)
- incidence (1)
- individual response (1)
- individualization (1)
- indole-3-acetic acid (1)
- indolylpyrimidylpiperazines (1)
- induced pluripotent stem cells (1)
- infection biology (1)
- infections (1)
- infectious diseases (1)
- inflammatory gene (1)
- inflation (1)
- information retrieval (1)
- information sharing (1)
- inherited cardiomyopathies (1)
- inherited macrothrombocytopenia (1)
- inhibition (1)
- inhibitor (1)
- injectable in situ gelling slow release system (1)
- injection site reactions (1)
- injury (1)
- inmates (1)
- innate immune evasions (1)
- insect abundance (1)
- insect collection (1)
- insurance medicine (1)
- intact bone imaging (1)
- integrative management strategy (1)
- integrin α2 (1)
- integrins (1)
- interactions (1)
- intercomparison (1)
- interface (1)
- interface conductivity (1)
- interferon beta (1)
- interleukin (1)
- interleukin-6 (1)
- intermediate dose Ara-C (1)
- intermediate filaments (1)
- intermittent exercise (1)
- intermolecular applications of ribozymes (1)
- internal carotid artery stenosis (1)
- intersession experiences (1)
- intersession processes (1)
- interval training (1)
- intervention point analyzing (1)
- intestine (1)
- intracellular bacterial pathogens (1)
- intracerebral hemorrhage (1)
- intracranial bleeding (1)
- invasive aspergillosis (1)
- inventory (1)
- iodine (1)
- ionization chambers (1)
- ionization energy (1)
- ionization potential (1)
- iron metabolism (1)
- ischemia reperfusion injury (1)
- ischemia time (1)
- isotropic hyper fine coupling (1)
- jet shapes (1)
- jet stream (1)
- jets (1)
- keratinocytes (1)
- key structure - fluorescence activation relationships (SFARs) (1)
- kidney (1)
- kidney development (1)
- kinesin (1)
- kinesthesia (1)
- kolorektales Karzinom (1)
- koronare Herzerkrankung (1)
- la durabilité environnementale (1)
- labour market (1)
- lactate threshold training (1)
- lag effect (1)
- land sharing (1)
- land surface (1)
- land use (1)
- land-cover area (1)
- language development (1)
- language in media (1)
- language intervention (1)
- late onset sepsis (1)
- late positive potential (1)
- lateral process of the talus (1)
- latewood (1)
- lattice forces (1)
- leaf width (1)
- learner characteristics (1)
- learning (1)
- les toilettes volantes (1)
- library screening (1)
- lichen planus (1)
- lifestyle (1)
- ligand binding (1)
- ligand exchange (1)
- ligand-receptor promiscuity (1)
- light-emitting-diodes (1)
- light-matter interaction (1)
- lightsheet microscopy (1)
- lignan (1)
- lineage-specific genes (1)
- linear conversion (1)
- linguistic cues (1)
- linguistic politics (1)
- lipid metabolism (1)
- liponeurocytoma (1)
- liquid biopsy (1)
- liver (1)
- liver disease (1)
- liver metastases (1)
- local field potentials (1)
- localization microscopy (1)
- logical trade-offs (1)
- long head of biceps tendon (1)
- long-term potentiation (1)
- loss of function (1)
- low-cost photometer (1)
- low-valent compounds (1)
- low-valent main group chemistry (1)
- low-valent main-group species (1)
- lowland beech forests (1)
- luminescence (1)
- lung cancer (1)
- lung metastases (1)
- lying (1)
- lymph nodes (1)
- lymphohistiocytosis (1)
- lymphoid tissues (1)
- lyso-phospholipids (1)
- mAb engineering (1)
- mRNA (1)
- mTOR (1)
- macrocolony (1)
- macroecology (1)
- macrophage polarization (1)
- magnesium phosphate cement (1)
- magnetic field effect (1)
- maintenance therapy (1)
- major river basins (1)
- management (1)
- manga (1)
- manoeuvre intention (1)
- match load (1)
- materials for optics (1)
- maternal separation (1)
- mating (1)
- mating preference (1)
- mebendazole (1)
- mechanical performance (1)
- mechanisms of disease (1)
- mechanistic modelling (1)
- medaka (1)
- medical rehabilitation (1)
- medication extraction (1)
- medicinal plant (1)
- medicine (1)
- medieval manuscripts (1)
- medulloblastoma (1)
- megakaryocyte (1)
- melatonin (1)
- melt electrowriting (MEW) (1)
- membrane active (1)
- memory (1)
- meningioma (1)
- meningococcal disease (1)
- meningococcus (1)
- meniscus implant (1)
- merkel cell polyomavirus (MCPyV) (1)
- merocyanines (1)
- mesenchymal stem cell (1)
- mesenchymal stem cells (1)
- mesenchymal stromal cell (1)
- mesentery (1)
- meta-analysis (1)
- metabolic flux (1)
- metabolic modeling (1)
- metabolic modelling (1)
- metabolic switch (1)
- metabolism (1)
- metabolism of infected and uninfected host cells (1)
- metabolite profiling (1)
- metabolomic (1)
- metabolomic profiling (1)
- metacognition (1)
- metal complexenes (1)
- metallo-supramolecular polymer (1)
- metals (1)
- metaproteomics (1)
- metastasis (1)
- metastasis-associated in colon cancer 1 (MACC1) (1)
- methods (1)
- methylation array (1)
- methylprednisolone (1)
- miR-221-5p (1)
- micelles (1)
- micro processor complex (1)
- micro-chambers (1)
- micro-optics (1)
- microbial rhodopsins (1)
- microbial surface component recognising adhesive matrix molecules (1)
- microbiology (1)
- microbiota (1)
- microfilament (1)
- microfluidics (1)
- midbody remnant (1)
- migrant (1)
- minerals (1)
- minimal residual disease (1)
- minipig (1)
- minocycline (1)
- mitochondrial genome (1)
- mitochondrial mRyR1 (1)
- mitofusin 2 (1)
- mitosis (1)
- mitotic gene expression (1)
- mitotic genes (1)
- mixed methods (1)
- mobile app (1)
- mobile health intervention (1)
- model-based diagnosis (1)
- molecular imaging (1)
- molecular neuroscience (1)
- molecular signature (1)
- molecular structures (1)
- molecular subtypes (1)
- monitoring (1)
- monocyte-derived DC (1)
- monotoring (1)
- moonlighting (1)
- morphing (1)
- motility (1)
- motor aging (1)
- motor-evoked potentials (MEP) (1)
- mouse feeding model (1)
- movement (1)
- mucormycosis (1)
- multi-photon microscopy (1)
- multi-spectral (1)
- multiphoton microscopy (1)
- multiresistance (1)
- multivariate analysis (1)
- murine (1)
- muscarinic receptors (1)
- mutants (1)
- mycophenolic acid (1)
- myelination (1)
- myeloid-derived suppressor cell (MDSC) (1)
- n-Halbleiter (1)
- n-type semiconductors (1)
- nalmefene (1)
- nano-satellite (1)
- nanocomplex (1)
- nanoparticles (1)
- nanophotonics and plasmonics (1)
- nanoscale devices (1)
- naphthylisoquinoline alkaloids (1)
- nasal mucosal barrier function (1)
- native populations (1)
- natural pest control (1)
- naturalistic scenes (1)
- naïve B cells (1)
- near-IR chromophores (1)
- necroptosis (1)
- need for assistance (1)
- negation detection (1)
- neonatal outcome (1)
- neonates (1)
- nerve injury (1)
- nervous system (1)
- nest microbiota (1)
- neume notation (1)
- neural circuits (1)
- neurocytoma (1)
- neurodegenerative disease (1)
- neuroendocrine neoplasia (1)
- neuroendocrine neoplasms (1)
- neuroendocrine tumors (1)
- neuromuscular disease (1)
- neuronal (1)
- neuronal apoptosis (1)
- neurooncology (1)
- neuropathic pain (1)
- neuropeptide (1)
- neurotrophic factors (1)
- neurovascular unit (1)
- neutral sphingomyelinase-2 (1)
- neutrinos (1)
- neutrophil (1)
- next-generation sequencing (1)
- next-generation-sequencing (1)
- niche (1)
- nicknames (1)
- non-alcoholic fatty liver disease (NAFLD) (1)
- non-alcoholic steatohepatitis (NASH) (1)
- non-invasive fibrosis assessment (1)
- non-smooth optimization (1)
- nonalcoholic fatty liver disease (1)
- noncoding RNA (1)
- nonconvex optimization (1)
- noncovalent complex (1)
- noncovalent nanocomplex (1)
- normal distribution (1)
- nu SVR (1)
- nuclear envelope (1)
- nuclear export (1)
- null-aggregate (1)
- number of (1)
- obesity (1)
- object segmentation (1)
- obsessive-compulsive (1)
- obstructive sleep apnoea (1)
- office environment (1)
- office-workers (1)
- olfactory dysfunction (1)
- olfactory testing (1)
- oligodendrocyte (1)
- oncogenes (1)
- oncolysis (1)
- oncolytic vaccinia virus (1)
- one-dimensional systems (1)
- online dating (1)
- online survey (1)
- ontology (1)
- open waste burning (1)
- optical antenna (1)
- optical character recognition (1)
- optical materials and structures (1)
- optical music recognition (1)
- optimal drug targeting (1)
- optimal pharmacological modulation (1)
- optimal treatment strategies (1)
- optimization (1)
- organic solar cells (1)
- origin (1)
- orthoreovirus (1)
- orthostatic test (1)
- oscillations (1)
- osteochondral defect (1)
- osteogenesis (1)
- otakuism (1)
- outcome devaluation (1)
- outcomes research (1)
- ovarian cancer (1)
- overreaching (1)
- overuse injury (1)
- oxidative DNA damage (1)
- oxidative stress (1)
- oxide heterostructure (1)
- oxidische Heterostruktur (1)
- oxindole alkaloids (1)
- oxygen vacancies (1)
- p-block element (1)
- p21-activated kinase Mbt/PAK4 (1)
- paediatrics (1)
- pain generator (1)
- panel sequencing (1)
- panic disorder (1)
- panniculitis (1)
- paranodopathy (1)
- parasexual recombination (1)
- parasite biology (1)
- parent-child relationship (1)
- parental perception (1)
- partial agonists (1)
- partial arc (1)
- passive transfer (1)
- patch-clamp (1)
- pathogenesis (1)
- pathogenic bacteria (1)
- patient preference (1)
- patient-based evidence (1)
- patient-reported outcomes (1)
- peatland (1)
- pediatrics (1)
- peer review (1)
- pefloxacin (1)
- peginterferon bet-1a (1)
- pemphigus (1)
- penetration bias (1)
- penumbra (1)
- peptide inhibitor design (1)
- peptidomoics (1)
- performativity (1)
- pericytes (1)
- permeability (1)
- persistence (1)
- person identity processing (1)
- personality development (1)
- personality judgments (1)
- perylene bisimide (1)
- perylene bisimide dimers (1)
- perylene bisimides (1)
- pesicicles (1)
- pharmacokinetics (1)
- pharmacophore map (1)
- phase transitions and critical phenomena (1)
- phenolic compounds (1)
- phenotypic screening (1)
- phosphorescence (1)
- phosphorescene spectra (1)
- phosphorylation (1)
- photoconductive interlayer (1)
- photodynamic chemotherapy (1)
- photoelectron spectroscopy (1)
- photoluminescence spectroscopy (1)
- photolysis (1)
- photonic devices (1)
- photophysical prosperties (1)
- photophysics (1)
- physical activity (1)
- physical activity promotion (1)
- physical saliency (1)
- phytic acid (1)
- pi-conjugation (1)
- piRNA (1)
- piscine orthoreovirus (1)
- pit membrane diameter (1)
- pkd (1)
- placebo and nocebo effects (1)
- plan comparison (1)
- plant reproduction (1)
- plant-derived metabolites (1)
- plants (1)
- plant–microbe–pollinator triangle (1)
- plant–pathogen interaction (1)
- plaque cross-sectional area (1)
- plasma membrane (1)
- plasma membrane depolarization (1)
- plasma membrane organization (1)
- plasminogen (1)
- platelet degranulation (1)
- platelet-neutrophil complexes (PNCs) (1)
- podosome formation (1)
- point shear wave elastography (1)
- pointing task (1)
- pol(2-oxazoline) (1)
- polarimetery (1)
- polarization (1)
- pollination (1)
- pollination network (1)
- poly(2-oxazine) (1)
- poly(2-oxazoline) (1)
- poly(2-oxazoline)s (1)
- poly(glycidol) (1)
- polycaprolactone (1)
- polyglycerol sulfates (1)
- polynomials (1)
- polyphenols (1)
- population genetics (1)
- position estimation (1)
- positron (1)
- positron annihilation lifetime spectroscopy (1)
- post-fire management (1)
- post-translational modification (1)
- posttranscriptional control (1)
- powerlifting (1)
- pre-B (1)
- precision medicine (1)
- predictive markers (1)
- predictive performance (1)
- premature aging (1)
- premixed (1)
- preschool (1)
- presynaptic hyperekplexia (1)
- preterm infants (1)
- primary endpoint (1)
- primary healthcare (1)
- primary immunodeficiency (PID) (1)
- primary outcome (1)
- primary vascular smooth muscle‐like cells (vSMCs) (1)
- pro-B (1)
- probe-based real-time PCR (1)
- procedural learning (1)
- production machines (1)
- proliferation (1)
- proliferative darkening syndrome (1)
- prospective memory (1)
- prostate-specific membrane antigen (1)
- protected forests (1)
- protein binding (1)
- protein kinase D1 (1)
- protein processing (1)
- protein transport (1)
- protein-bound uremic toxins (1)
- protein-protein interaction (PPI) (1)
- proteins (1)
- proteomics (1)
- präfabriziert (1)
- psoriasis (1)
- psychological pain modulation (1)
- psychology (1)
- psychometrics (1)
- psychosocial adaptation (1)
- psychosocial stress (1)
- psychotherapy (1)
- puberty (1)
- pyrolysis (1)
- quality assurance (1)
- quality of democracy (1)
- quality of life (QoL) (1)
- quantile forecasts (1)
- quantitative analysis (1)
- quantum Monte Carlo (1)
- quantum dot (1)
- quantum dots (1)
- quantum gravity (1)
- quantum information (1)
- qubits (1)
- questionnaires (1)
- radiation (1)
- radiation sensitivity (1)
- radical (1)
- radical ion pair (1)
- radiopacity (1)
- radiotherapy (1)
- ray (1)
- reaction times (1)
- reactive intermediates (1)
- real life setting (1)
- real world evidence (1)
- reciprocal translocation (1)
- recombinant tissue-type plasminogen activator (1)
- reconstructive surgery (1)
- recording methods (1)
- recovery (1)
- rectum (1)
- refractory aGvHD (1)
- regenerative medicine (1)
- registry for primary immunodeficiency (1)
- regulatory T cells (1)
- regulatory T cells (Treg) (1)
- regulatory capital (1)
- regulatory dendritic cells (1)
- reinforcement learning (1)
- reliability (1)
- renal imaging (1)
- repeated sprint (1)
- reprogamming of host cell metabolism (1)
- required hydrophilic–lipophilic balance (1)
- rereading (1)
- resettlement refugees (1)
- resistance (1)
- resistance training (1)
- resonance theory (1)
- response inhibition (1)
- restriction factors (1)
- restrictive cardiomyopathy (1)
- resveratrol biosynthesis (1)
- retention interval (1)
- reticulate body (1)
- retinal pigment epithelium (1)
- retrospective (1)
- review (1)
- rhBMP–2 (1)
- rheumatic diseases (1)
- rheumatology (1)
- rhodomyrtone (1)
- ring-expansion reactions (1)
- ring-opening polymerization (1)
- ripk1 (1)
- ripk3 (1)
- risk society (1)
- risk stratification (1)
- robust control (1)
- rulebased analysis (1)
- ruthenium (1)
- sPEG (1)
- saccades (1)
- sacha inchi oil (1)
- sample storage (1)
- saproxylic organisms (1)
- sarcomere (1)
- satellite formation flying (1)
- satellite remote sensing (1)
- scaffold (1)
- search (1)
- seco-NIQs-Naphthylisoindolinone (1)
- secreted effectors (1)
- segmental progeria (1)
- self-determination theory (1)
- semantic segmentation (1)
- semileptonic & radiative decays (1)
- sensor data (1)
- sensor supports (1)
- sentinel (1)
- sentinel prey (1)
- sepsis (1)
- sequence analysis (1)
- sequential addition (1)
- serial reaction time task (1)
- serotonin (1)
- serotonin deficiency (1)
- setting reaction (1)
- sex robots (1)
- shared reading (1)
- short neuropeptide F (1)
- short-range JCT-coupling (1)
- short-range order (1)
- shoulder (1)
- shoulder pain (1)
- shyness (1)
- sigma boranes (1)
- signal specification (1)
- signal transduction (1)
- signalling (1)
- silica supraparticles (1)
- simple (1)
- simulation and modeling (1)
- simulation training (1)
- simultaneous presentation paradigm (1)
- single arc (1)
- single cell anatomy (1)
- single photon (1)
- single-molecule tracking (1)
- sirolimus (1)
- site-specific protein modification (1)
- situation awareness (1)
- skeletal progenitor cells (1)
- skeletal-related events (1)
- skewness (1)
- skin model (1)
- sleep (1)
- slope bogs (1)
- small RNA (1)
- small RNAs (1)
- small intestinal submucosa scaffold (1)
- small-cell lung cancer (1)
- small-molecule activation (1)
- smart surfaces (1)
- snowboarder's ankle (1)
- snowboarder's fracture (1)
- soccer (football) (1)
- social anxiety disorder (1)
- social behaviour (1)
- sociophonetics (1)
- sodium (1)
- soft tissue sarcoma (1)
- soft x-ray photoemission (1)
- soil fauna (1)
- solar cells (1)
- solid tumors (1)
- solid-state NMR spectroscopy (1)
- solid-state emitters (1)
- solitary bees (1)
- solubility (1)
- solubility enhancement (1)
- solvent-dependent fluorescence yield (1)
- somatic mutations (1)
- somatosensory evoked potential (1)
- somatosensory temporal discrimination (1)
- somatostatin receptor (1)
- spa typing (1)
- spacer-controlled self-assembly (1)
- spacing effect (1)
- spatial analyses (1)
- spatial heterogeneity (1)
- spatial scale (1)
- species richness (1)
- species‐area hypothesis (1)
- specific heat (1)
- sphingomyelinase (1)
- sphingosine kinase (1)
- sphingosine kinase inhibitor SKI-II (1)
- sphingosine-1-phosphate (1)
- spin polarization (1)
- spin relaxation (1)
- spin transport (1)
- spinal muscular atrophy (1)
- spleen (1)
- split renal function (1)
- sporidia (1)
- standardized reporting (1)
- standing (1)
- starPEG (1)
- starPEG hydrogel (1)
- startle response (1)
- static vs. dynamic faces (1)
- statistical distributions (1)
- statistical models (1)
- steering (1)
- stem Cells (1)
- stem cell transplantation (1)
- stereospecific sythesis (1)
- stereotactic body radiation therapy (1)
- stereotactic irradiation (1)
- steric effects (1)
- steroid-resistant aGvHD (1)
- stigma (1)
- storage-pool diseases (1)
- storytelling (1)
- strain rate (1)
- strength training (1)
- stress (1)
- stress fiber (1)
- stress tolerance (1)
- stroke management (1)
- stromal vascular fraction (1)
- strong coupling (1)
- strong light matter coupling (1)
- structural disruption (1)
- structural restriction (1)
- structure-activity (1)
- structure-activity relationship (1)
- structure-activity relationships (1)
- structured illumination microscopy (1)
- subadditivity (1)
- subarachnoid hemorrhage (1)
- submicroscopic chromosome rearrangement (1)
- subsarcolemmal mitochondria (1)
- substandard and falsified medicines from the Congo (1)
- substituent (1)
- subsurface hydrology (1)
- sulfoimines (1)
- sulfur (1)
- super resolution microscopy (1)
- super-resolution fluorescence microscopy (1)
- super-resolution microscopy (1)
- superresolution (1)
- suppressor cells (1)
- suppressor mutation (1)
- surface functionalization (1)
- surface plasmon (1)
- surface transport (1)
- surface water (1)
- surfaces, interfaces and thin films (1)
- surgical and invasive medical procedures (1)
- surgical site infection (1)
- survival analysis (1)
- synapses (1)
- synchrotron radiation (1)
- synchrotron radiatoren (1)
- synergistic effect (1)
- synthetic biology (1)
- systematic affiliation (1)
- systematic drug targeting (1)
- targeted bisulfite sequencing (1)
- targeted therapies (1)
- taxonomy (1)
- telemedicine (1)
- temozolomide (1)
- temperature‐mediated resource exploitation hypothesis (1)
- temperature‐richness hypothesis (1)
- temporal discrimination threshold (1)
- temporal lobe epilepsy (1)
- tendon-derived stem cell (1)
- terrestrial LiDAR (1)
- theranostics (1)
- therapy (1)
- therapy response (1)
- therapy simulation (1)
- thermal remote sensing (1)
- thiol-ene (1)
- threshold discrimination identification test (1)
- thrombo-inflammation (1)
- thrombolysis (1)
- thrombolysis (tPA) (1)
- thrombosis (1)
- tight junctions (1)
- time lag (1)
- time series (1)
- time-resolved photoelectron spectroscopy (1)
- time-resolved spectroscopy (1)
- tisindoline (1)
- top-down processing (1)
- topminnow (1)
- topological insulators (1)
- topological matter (1)
- total body irradiation/busulfan (1)
- toxicity (1)
- trans-acting 2'-5' adenylyl transferase ribozymes (1)
- transcranial magnetic simulation (TMS) (1)
- transcription (1)
- transcription deficiency (1)
- transcriptome (1)
- transcriptomics (1)
- transfer hydrogenation (1)
- transient absorption (1)
- transient dynamics (1)
- transient elastography (1)
- transient ischemic attack (1)
- transient middle cerebral artery occlusion (1)
- transition metal (1)
- transition metall dichalcogenide monolayer (1)
- transmission (1)
- transplantation (1)
- transposable elements (1)
- treatment (1)
- tree cavities (1)
- triacylglycerides (1)
- triarylboranes (1)
- triple bonds (1)
- triquinacene derivatives (1)
- trivalent boron (1)
- trypanosomes (1)
- tryptophan hydroxylase 2 (1)
- tumor burden (1)
- tumor control probability (1)
- tumor heterogeneity (1)
- tumor suppressor miRNA (1)
- tumour (1)
- tumour-necrosis factors (1)
- two-component (1)
- two-photon absorption (1)
- tyloses (1)
- type VII secretion system (1)
- ubiquitin ligase (1)
- ubiquitylation (ubiquitination) (1)
- uncanny valley (1)
- uncertainties (1)
- uncertainty (1)
- uneven-aged mountainous (1)
- unmanaged broadleaved forests (1)
- unnecessary alarm (1)
- unsaturated fatty acids (1)
- upconversion (1)
- uptake (1)
- urban environments (1)
- uremic toxins (1)
- urinary tract infections (1)
- vaccinia (1)
- variability (1)
- vasculitis (1)
- verdünnt magnetische Halbleiter (1)
- vertebral body (1)
- vertical and radial variation (1)
- very high energies (VHE) (1)
- very long-chain aliphatic compounds (1)
- vessel lumen diameter (1)
- vessel wall resident stem cells (1)
- vestibular schwannoma (1)
- viability (1)
- video laryngoscopy (1)
- virotherapy (1)
- virtual isocenter (1)
- virus (1)
- viruses (1)
- visual orientation (1)
- visual perception (1)
- visual realism (1)
- vitamin D (1)
- vitamins (1)
- vocational education (1)
- voice-face matching (1)
- volume overload (1)
- voluntary exhaustion (1)
- voxel-based morphometry (1)
- walking (1)
- waste sorting (1)
- water balance (1)
- watershed (1)
- weightlifting (1)
- well-being (1)
- white matter lesions (1)
- whole-genome duplication (1)
- whole-genome sequencing (1)
- wild bees (1)
- wood anatomy (1)
- work (1)
- work capacity evaluation (1)
- work engagement (1)
- work performance (1)
- youth (1)
- zeitaufgelöste Spektroskopie (1)
- zielgerichtete Behandlung (1)
- zinc oxide (1)
- zinc oxide nanoparticles (1)
- zonal construct (1)
- zooming (1)
- État d'Imo (1)
- β3 adrenergic receptor (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (97)
- Graduate School of Life Sciences (51)
- Physikalisches Institut (44)
- Medizinische Klinik und Poliklinik II (33)
- Institut für Psychologie (32)
- Institut für Anorganische Chemie (27)
- Institut für Organische Chemie (27)
- Neurologische Klinik und Poliklinik (27)
- Institut für deutsche Philologie (24)
- Neuphilologisches Institut - Moderne Fremdsprachen (24)
Schriftenreihe
Sonstige beteiligte Institutionen
- VolkswagenStiftung (24)
- Johns Hopkins School of Medicine (2)
- Bio-Imaging Center Würzburg (1)
- CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - the development agency of the Brazilian Federal Government (1)
- Center for Nanosystems Chemistry (CNC), Universität Würzburg (1)
- DAAD - Deutscher Akademischer Austauschdienst (1)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Ernst Strüngmann Institute for Neuroscience in Cooperation with Max Planck Society (ESI) (1)
ResearcherID
- B-4606-2017 (1)
Background
Medication trend studies show the changes of medication over the years and may be replicated using a clinical Data Warehouse (CDW). Even nowadays, a lot of the patient information, like medication data, in the EHR is stored in the format of free text. As the conventional approach of information extraction (IE) demands a high developmental effort, we used ad hoc IE instead. This technique queries information and extracts it on the fly from texts contained in the CDW.
Methods
We present a generalizable approach of ad hoc IE for pharmacotherapy (medications and their daily dosage) presented in hospital discharge letters. We added import and query features to the CDW system, like error tolerant queries to deal with misspellings and proximity search for the extraction of the daily dosage. During the data integration process in the CDW, negated, historical and non-patient context data are filtered. For the replication studies, we used a drug list grouped by ATC (Anatomical Therapeutic Chemical Classification System) codes as input for queries to the CDW.
Results
We achieve an F1 score of 0.983 (precision 0.997, recall 0.970) for extracting medication from discharge letters and an F1 score of 0.974 (precision 0.977, recall 0.972) for extracting the dosage. We replicated three published medical trend studies for hypertension, atrial fibrillation and chronic kidney disease. Overall, 93% of the main findings could be replicated, 68% of sub-findings, and 75% of all findings. One study could be completely replicated with all main and sub-findings.
Conclusion
A novel approach for ad hoc IE is presented. It is very suitable for basic medical texts like discharge letters and finding reports. Ad hoc IE is by definition more limited than conventional IE and does not claim to replace it, but it substantially exceeds the search capabilities of many CDWs and it is convenient to conduct replication studies fast and with high quality.
Human health is known to be affected by the physical environment. Various environmental influences have been identified to benefit or challenge people's physical condition. Their heterogeneous distribution in space results in unequal burdens depending on the place of living. In addition, since societal groups tend to also show patterns of segregation, this leads to unequal exposures depending on social status. In this context, environmental justice research examines how certain social groups are more affected by such exposures. Yet, analyses of this per se spatial phenomenon are oftentimes criticized for using “essentially aspatial” data or methods which neglect local spatial patterns by aggregating environmental conditions over large areas. Recent technological and methodological developments in satellite remote sensing have proven to provide highly detailed information on environmental conditions. This narrative review therefore discusses known influences of the urban environment on human health and presents spatial data and applications for analyzing these influences. Furthermore, it is discussed how geographic data are used in general and in the interdisciplinary research field of environmental justice in particular. These considerations include the modifiable areal unit problem and ecological fallacy. In this review we argue that modern earth observation data can represent an important data source for research on environmental justice and health. Especially due to their high level of spatial detail and the provided large-area coverage, they allow for spatially continuous description of environmental characteristics. As a future perspective, ongoing earth observation missions, as well as processing architectures, ensure data availability and applicability of ’big earth data’ for future environmental justice analyses.
Background and Purpose: Internal carotid artery stenosis ≥70% is a leading cause of ischemic cerebrovascular events. However, a considerable percentage of stroke survivors with symptomatic internal carotid artery stenosis have <70% stenosis with a vulnerable plaque. Whether the length of internal carotid artery stenosis is associated with high risk of ischemic cerebrovascular events or with white matter lesions is poorly investigated. Our main aim was to investigate the relation between the length of internal carotid artery stenosis and the development of ischemic cerebrovascular events as well as ipsi-, contralateral as well as mean white matter lesion load.
Methods: In a retrospective cross-sectional study, 168 patients with 208 internal carotid artery stenosis were identified. The degree and length of internal carotid artery stenosis as well as plaque morphology (hypoechoic, mixed or echogenic) were assessed on ultrasound scans. The white matter lesions were assessed in 4 areas separately, (periventricular and deep white matter lesions on each hemisphere), using the Fazekas scale. The mean white matter lesions load was calculated as the mean of these four values.
Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of internal carotid artery stenosis was detected for symptomatic internal carotid artery stenosis ≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for symptomatic internal carotid artery stenosis <70% (ρ = 0.15, p = 0.45, n = 27) nor for asymptomatic internal carotid artery stenosis (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for symptomatic internal carotid artery stenosis <70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for symptomatic internal carotid artery stenosis <90% and symptomatic internal carotid artery stenosis 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with internal carotid artery stenosis <70%, a cut-off length of ≥16 mm was found for symptomatic internal carotid artery stenosis rather than asymptomatic internal carotid artery stenosis with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the symptomatic internal carotid artery stenosis compared to asymptomatic internal carotid artery stenosis were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02). The length but not the degree of internal carotid artery stenosis showed a very slight trend toward association with ipsilateral white matter lesions and with mean white matter lesions load.
Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of symptomatic internal carotid artery stenosis <70% to be longer than that of symptomatic internal carotid artery stenosis ≥70%. Moreover, the ultrasound-measured length of symptomatic internal carotid artery stenosis <90% was significantly longer than that of symptomatic internal carotid artery stenosis 90%. Among patients with symptomatic internal carotid artery stenosis ≥70%, the degree and length of stenosis were inversely correlated. Furthermore, we have shown that a slight correlation exists between the length of stenosis and the presence of ipsilateral white matter lesions which might be due to microembolisation originating from the carotid plaque. Larger studies are needed before a clinical implication can be drawn from these results.
The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood–DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68\(^+\) macrophages had migrated into the NRR. In summary, NRR and FRR are different in naïve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy.
Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS).
Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women.
Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MDP: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05).
Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS.
Interleukin 10 is a central regulator of the antigen-presenting function of myeloid cells. It exerts immunomodulatory effects in vivo and induces a regulatory phenotype in monocyte-derived cells in vitro. We analyzed phenotype and function of monocytic cells in vitro in relation to the cytokine milieu and the timing of TLR-based activation. In GM-CSF/IL-4 cultured human monocytic cells, we identified two, mutually exclusive cell populations arising from undifferentiated cells: CD83\(^+\) fully activated dendritic cells and CD14\(^+\) macrophage like cells. Re-expression of CD14 occurs primarily after a sequential trigger with a TLR signal following IL-10 preincubation. This cell population with re-expressed CD14 greatly differs in phenotype and function from the CD83+ cells. Detailed analysis of individual subpopulations reveals that exogenous IL-10 is critical for inducing the shift toward the CD14\(^+\) population, but does not affect individual changes in marker expression or cell function in most cases. Thus, plasticity of CD14 expression, defining a subset of immunoregulatory cells, is highly relevant for the composition of cellular products (such as DC vaccines) as it affects the function of the total product.
Rapid multiple-quantum three-dimensional fluorescence spectroscopy disentangles quantum pathways
(2019)
Coherent two-dimensional spectroscopy is a powerful tool for probing ultrafast quantum dynamics in complex systems. Several variants offer different types of information but typically require distinct beam geometries. Here we introduce population-based three-dimensional (3D) electronic spectroscopy and demonstrate the extraction of all fourth- and multiple sixth-order nonlinear signal contributions by employing 125-fold (1⨯5⨯5⨯5) phase cycling of a four-pulse sequence. Utilizing fluorescence detection and shot-to-shot pulse shaping in single-beam geometry, we obtain various 3D spectra of the dianion of TIPS-tetraazapentacene, a fluorophore with limited stability at ambient conditions. From this, we recover previously unknown characteristics of its electronic two-photon state. Rephasing and nonrephasing sixth-order contributions are measured without additional phasing that hampered previous attempts using noncollinear geometries. We systematically resolve all nonlinear signals from the same dataset that can be acquired in 8 min. The approach is generalizable to other incoherent observables such as external photoelectrons, photocurrents, or photoions.
We investigate the mode-switching dynamics of an electrically driven bimodal quantum-dot micropillar laser when subject to delayed coherent optical feedback from a short external cavity. We experimentally characterize how the external cavity length, being on the same order than the microlaser’s coherence length, influences the spectral and dynamical properties of the micropillar laser. Moreover, we determine the relaxation oscillation frequency of the micropillar by superimposing optical pulse injection to a dc current. It is found that the optical pulse can be used to disturb the feedback-coupled laser within one roundtrip time in such a way that it reaches the same output power as if no feedback was present. Our results do not only expand the understanding of microlasers when subject to optical feedback from short external cavities, but pave the way towards tailoring the properties of this key nanophotonic system for studies in the quantum regime of self-feedback and its implementation to integrated photonic circuits.
The plasma membrane is one of the most thoroughly studied and at the same time most complex, diverse, and least understood cellular structures. Its function is determined by the molecular composition as well as the spatial arrangement of its components. Even after decades of extensive membrane research and the proposal of dozens of models and theories, the structural organization of plasma membranes remains largely unknown. Modern imaging tools such as super-resolution fluorescence microscopy are one of the most efficient techniques in life sciences and are widely used to study the spatial arrangement and quantitative behavior of biomolecules in fixed and living cells. In this work, direct stochastic optical reconstruction microscopy (dSTORM) was used to investigate the structural distribution of mem-brane components with virtually molecular resolution. Key issues are different preparation and staining strategies for membrane imaging as well as localization-based quantitative analyses of membrane molecules.
An essential precondition for the spatial and quantitative analysis of membrane components is the prevention of photoswitching artifacts in reconstructed localization microscopy images. Therefore, the impact of irradiation intensity, label density and photoswitching behavior on the distribution of plasma membrane and mitochondrial membrane proteins in dSTORM images was investigated. It is demonstrated that the combination of densely labeled plasma membranes and inappropriate photoswitching rates induces artificial membrane clusters. Moreover, inhomogeneous localization distributions induced by projections of three-dimensional membrane structures such as microvilli and vesicles are prone to generate artifacts in images of biological membranes. Alternative imaging techniques and ways to prevent artifacts in single-molecule localization microscopy are presented and extensively discussed.
Another central topic addresses the spatial organization of glycosylated components covering the cell membrane. It is shown that a bioorthogonal chemical reporter system consisting of modified monosaccharide precursors and organic fluorophores can be used for specific labeling of membrane-associated glycoproteins and –lipids. The distribution of glycans was visualized by dSTORM showing a homogeneous molecule distribution on different mammalian cell lines without the presence of clusters. An absolute number of around five million glycans per cell was estimated and the results show that the combination of metabolic labeling, click chemistry, and single-molecule localization microscopy can be efficiently used to study cell surface glycoconjugates.
In a third project, dSTORM was performed to investigate low-expressing receptors on cancer cells which can act as targets in personalized immunotherapy. Primary multiple myeloma cells derived from the bone marrow of several patients were analyzed for CD19 expression as potential target for chimeric antigen receptor (CAR)-modified T cells. Depending on the patient, 60–1,600 CD19 molecules per cell were quantified and functional in vitro tests demonstrate that the threshold for CD19 CAR T recognition is below 100 CD19 molecules per target cell. Results are compared with flow cytometry data, and the important roles of efficient labeling and appropriate control experiments are discussed.
Background:
Flap reconstruction of the distal lower extremity is challenging. Especially, the concept of perforator surgery has increased available surgical options. Although results are generally judged in terms of objective facts, patients-perceived quality of life has largely remained unexamined. The aim of the study was to compare quality of life after lower extremity reconstruction with pedicled and free flaps.
Methods:
Patients were evaluated retrospectively after reconstruction of defects of the distal lower extremity either with distally based adipofascial sural flap (pedicled reverse sural flap) or an anterior lateral thigh (ALT) flap. A specific questionnaire was developed to measure the patient’s quality of life, based on short form health survey-12, Dresden Body Image Score-35, Patient Health Questionnaire-4, and XSMFA questionnaires with additional specific questions. Furthermore, results, secondary surgeries, and complications were analyzed.
Results:
Thirty-seven patients with reconstruction of lower limb defects treated with a pedicled reverse sural flap and 34 patients treated with an ALT flap were included in the study. There was no statistical significant difference in the overall satisfaction with the procedure in the long-term follow-up between both groups, but patients with ALT showed a higher satisfaction with the treatment in the initial postoperative period. Both groups demonstrated approximately similar results in the long term for self-acceptance and vitality.
Conclusions:
Although anatomic situation may dictate flap choice coverage with free flaps, a less-complicated flap is by no means regarded as an inferior treatment option in patient’s estimation. Despite the intuitive speculation that patients with more advanced reconstruction methods should have better function and subsequently higher quality of life, this assumption was clearly not supported by data in this study.
Nowadays, the management of infectious diseases is especially threatened by the rapid emergence of drug resistance. It has been suggested that the medicine quality assurance combined with good medication adherence may help to reduce this impendence. Moreover, the search for new antimicrobial agents from medicinal plants is strongly encouraged for the exploration of alternatives to existing therapies. In this context, the present work focused on both the quality evaluation of commercialized antimalarial medicines from the Democratic Republic of the Congo and on the phytochemical investigations of a Congolese Ancistrocladus species.
Protein-like enwrapped perylene bisimide chromophore as bright microcrystalline emitter material
(2019)
Strongly emissive solid‐state materials are mandatory components for many emerging optoelectronic technologies, but fluorescence is often quenched in the solid state owing to strong intermolecular interactions. The design of new organic pigments, which retain their optical properties despite their high tendency to crystallize, could overcome such limitations. Herein, we show a new material with monomer‐like absorption and emission profiles as well as fluorescence quantum yields over 90 % in its crystalline solid state. The material was synthesized by attaching two bulky tris(4‐tert‐butylphenyl)phenoxy substituents at the perylene bisimide bay positions. These substituents direct a packing arrangement with full enwrapping of the chromophore and unidirectional chromophore alignment within the crystal lattice to afford optical properties that resemble those of their natural pigment counterparts, in which chromophores are rigidly embedded in protein environments.
Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
(2019)
Adaptation to alterations in nutrient availability ensures the survival of organisms. In vertebrates, adipocytes play a decisive role in this process due to their ability to store large amounts of excess nutrients and release them in times of food deprivation. In todays western world, a rather unlimited excess of nutrients leads to high-caloric food consumption in humans. Nutrient overload together with a decreased energy dissipation result in obesity as well as associated diseases such as insulin resistance, diabetes, and liver steatosis. Obesity causes a hormonal imbalance, which in combination with altered nutrient levels can aberrantly activate G-protein coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D (PKD) 1 is a DAG effector integrating multiple hormonal and nutritional inputs. Nevertheless, its physiological role in adipocytes has not been investigated so far. In this thesis, evidence is provided that the deletion of PKD1 in adipocytes suppresses lipogenesis as well as the accumulation of triglycerides. Furthermore, PKD1 depletion results in increased mitochondrial biogenesis as well as decoupling activity. Moreover, PKD1 deletion promotes the expression of the β3-adrenergic receptor (ADRB3) in a CCAAT/enhancer-binding protein (C/EBP)-α and δ-dependent manner. This results in elevated expression levels of beige markers in adipocytes in the presence of a β-agonist. Contrarily, adipocytes expressing a constitutive active form of PKD1 present a reversed phenotype. Additionally, PKD1 regulates adipocyte metabolism in an AMP-activated protein kinase (AMPK)-dependent manner by suppressing its activity through phosphorylation of AMPK α1/α2 subunits. Thus, PKD1 deletion results in an enhanced activity of the AMPK complex. Consistent with the in vitro findings, mice lacking PKD1 in adipocytes demonstrate a resistance to high-fat diet-induced obesity due to an elevated energy expenditure caused by trans-differentiation of white into beige adipocytes. Moreover, deletion of PKD1 in murine adipocytes improves systemic insulin sensitivity and ameliorates liver steatosis. Finally, PKD1 levels positively correlate with HOMA-IR as well as insulin levels in human subjects. Furthermore, inhibition of PKD1 in human adipocytes leads to metabolic alterations, which are comparable to the alterations seen in their murine counterparts. Taken together, these data demonstrate that PKD1 suppresses energy dissipation, drives lipogenesis, and adiposity. Therefore, increased energy dissipation induced by several complementary mechanisms upon PKD1 deletion might represent an attractive strategy to treat obesity and its related complications.
This thesis established the fabrication of organic solar cells of DA dye donors and fullerene acceptors under ambient conditions in our laboratory, however, with reduced power conversion efficiencies compared to inert conditions. It was shown that moisture had the strongest impact on the stability and reproducibility of the solar cells. Therefore, utilization of robust materials, inverted device architectures and fast fabrication/characterization are recommended if processing takes place in air. Furthermore, the dyad concept was successfully explored in merocyanine dye-fullerene dyads and power conversion efficiencies of up to 1.14 % and 1.59 % were measured under ambient and inert conditions, respectively. It was determined that the major drawback in comparison to comparable BHJ devices was the inability of the dyad molecules to undergo phase separation. Finally, two series of small molecules were designed in order to obtain electron transport materials, using the acceptor-core-acceptor motive. By variation of the acceptor units especially the LUMO levels could be lowered effectively. Investigation of the compounds in organic thin film transistors helped to identify promising molecules with electron transport properties. Electron transport mobilities of up to 7.3 × 10−2 cm2 V−1 s−1 (ADA2b) and 1.39 × 10−2 cm2 V−1 s−1 (AπA1b) were measured in air for the ADA and AπA dyes, respectively. Investigation of selected molecules in organic solar cells proved that these molecules work as active layer components, even though power conversion efficiencies cannot compete with fullerene based devices yet. Thus, this thesis shows new possibilities that might help to develop and design small molecules as substitutes for fullerene acceptors.
Background
Scattered extracellular deposits of amyloid within the brain parenchyma can be found in a heterogeneous group of diseases. Its condensed accumulation in the white matter without evidence for systemic amyloidosis is known as primary brain amyloidoma (PBA). Although originally considered as a tumor-like lesion by its space-occupying effect, this condition displays also common hallmarks of a neurodegenerative disorder.
Case presentation
A 50-year-old woman presented with a mild cognitive decline and seizures with a right temporal, irregular and contrast-enhancing mass on magnetic resonance imaging. Suspecting a high-grade glioma, the firm tumor was subtotally resected. Neuropathological examination showed no glioma, but distinct features of a neurodegenerative disorder. The lesion was composed of amyloid AL λ aggregating within the brain parenchyma as well as the adjacent vessels, partially obstructing the vascular lumina. Immunostaining confirmed a distinct perivascular inflammatory reaction. After removal of the PBA, mnestic impairments improved considerably, the clinical course and MRI-results are stable in the 8-year follow-up.
Conclusion
Based on our histopathological findings, we propose to regard the clinicopathological entity of PBA as an overlap between a neoplastic and neurodegenerative disorder. Since the lesions are locally restricted, they might be amenable to surgery with the prospect of a definite cure.
Background: Recent research has shown an increased risk of accidents and injuries in ADHD patients, which could potentially be reduced by stimulant treatment. Therefore, the first aim of our study was to evaluate the prevalence of adult ADHD in a trauma surgery population. The second aim was to investigate accident mechanisms and circumstances which could be specific to ADHD patients, in comparison to the general population. Methods: We screened 905 accident victims for ADHD using the ASRS 18-item self-report questionnaire. The basic demographic data and circumstances of the accidents were also assessed. Results: Prevalence of adult ADHD was found to be 6.18% in our trauma surgery patient sample. ADHD accident victims reported significantly higher rates of distraction, stress and overconfidence in comparison to non-ADHD accident victims. Overconfidence and being in thoughts as causal mechanisms for the accidents remained significantly higher in ADHD patients after correction for multiple comparison. ADHD patients additionally reported a history of multiple accidents. Conclusion: The majority of ADHD patients in our sample had not previously been diagnosed and were therefore not receiving treatment. The results subsequently suggest that general ADHD screening in trauma surgery patients may be useful in preventing further accidents in ADHD patients. Furthermore, psychoeducation regarding specific causal accident mechanisms could be implemented in ADHD therapy to decrease accident incidence rate
Sensitivity and selectivity remain the central technical requirement for analytical devices, detectors and sensors. Especially in the gas phase, concentrations of threat substances can be very low (e.g. explosives) or have severe effects on health even at low concentrations (e.g. benzene) while it contains many potential interferents. Preconcentration, facilitated by active or passive sampling of air by an adsorbent, followed by thermal desorption, results in these substances being released in a smaller volume, effectively increasing their concentration.
Traditionally, a wide range of adsorbents, such as active carbons or porous polymers, are used for preconcentration. However, many adsorbents either show chemical reactions due to active surfaces, serious water retention or high background emission due to thermal instability. Metal-organic frameworks (MOFs) are a hybrid substance class, composed inorganic and organic building blocks, being a special case of coordination polymers containing pores. They can be tailored for specific applications such as gas storage, separation, catalysis, sensors or drug delivery.
This thesis is focused on investigating MOFs for their use in thermal preconcentration for airborne detection systems. A pre-screening method for MOF-adsorbate interactions was developed and applied, namely inverse gas chromatography (iGC). Using this pulse chromatographic method, the interaction of MOFs and molecules from the class of explosives and volatile organic compounds was studied at different temperatures and compared to thermal desorption results.
In the first part, it is shown that archetype MOFs (HKUST-1, MIL-53 and Fe-BTC) outperformed the state-of-the-art polymeric adsorbent Tenax® TA in nitromethane preconcentration for a 1000 (later 1) ppm nitromethane source. For HKUST-1, a factor of more than 2000 per g of adsorbent was achieved, about 100 times higher than for Tenax. Thereby, a nitromethane concentration of 1 ppb could be increased to 2 ppm. High enrichment is addressed to the specific interaction of the nitro group as by iGC, which was determined by comparing nitromethane’s free enthalpy of adsorption with the respective saturated alkane. Also, HKUST-1 shows a similar mode of sorption (enthalpy-entropy compensation) for nitro and saturated alkanes.
In the second part, benzene of 1 ppm of concentration was enriched with a similar setup, using 2nd generation MOFs, primarily UiO-66 and UiO-67, under dry and humid (50 %rH) conditions using constant sampling times. Not any MOF within the study did surpass the polymeric Tenax in benzene preconcentration. This is most certainly due to low sampling times – while Tenax may be highly saturated after 600 s, MOFs are not. For regular UiO-66, four differently synthesized samples showed a strongly varying behavior for dry and humid enrichment which cannot be completely explained. iGC investigations with regular alkanes and BTEX compounds revealed that confinement factors and dispersive surface energy were different for all UiO-66 samples. Using physicochemical parameters from iGC, no unified hypothesis explaining all variances could be developed.
Altogether, it was shown that MOFs can replace or add to state-of-the-art adsorbents for the enrichment of specific analytes with preconcentration being a universal sensitivity-boosting concept for detectors and sensors. Especially with iGC as a powerful screening tool, most suitable MOFs for the respective target analyte can be evaluated. iGC can be used for determining “single point” retention volumes, which translate into partition coefficients for a specific MOF × analyte × temperature combination.
Introduction
Multidisciplinary, complex rehabilitation interventions are an important part of the treatment of chronic diseases. However, little is known about the effectiveness of routine rehabilitation interventions within the German healthcare system. Due to the nature of the social insurance system in Germany, randomised controlled trials examining the effects of rehabilitation interventions are challenging to implement and scarcely accessible. Consequently, alternative pre-post designs can be employed to assess pre-post effects of medical rehabilitation programmes. We present a protocol of systematic review and meta-analysis methods to assess the pre-post effects of rehabilitation interventions in Germany.
Methods and analysis
The respective study will be conducted within the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. A systematic literature review will be conducted to identify studies reporting the pre-post effects (start of intervention vs end of intervention or later) in German healthcare. Studies investigating the following disease groups will be included: orthopaedics, rheumatology, oncology, pulmonology, cardiology, endocrinology, gastroenterology and psychosomatics. The primary outcomes of interest are physical/mental quality of life, physical functioning and social participation for all disease groups as well as pain (orthopaedic and rheumatologic patients only), blood pressure (cardiac patients only), asthma control (patients with asthma only), dyspnoea (patients with chronic obstructive pulmonary disease only) and depression/anxiety (psychosomatic patients only). We will invite the principal investigators of the identified studies to provide additional individual patient data. We aim to perform the meta-analyses using individual patient data as well as aggregate data. We will examine the effects of both study-level and patient-level moderators by using a meta-regression method.
Ethics and dissemination
Only studies that have received institutional approval from an ethics committee and present anonymised individual patient data will be included in the meta-analysis. The results will be presented in a peer-reviewed publication and at research conferences. A declaration of no objection by the ethics committee of the University of Würzburg is available (number 20180411 01).
The investigation of trade-offs in political science receives only limited attention, although many scholars acknowledge the importance of trade-offs across a variety of different areas. A systematic and comprehensive examination of the topic is missing. This thematic issue of Politics and Governance sheds light on this research deficit by providing a holistic but also an integrative view on trade-offs in the political realm for the first time. Researchers of trade-offs from different political areas present and discuss their findings, and promote a fruitful exchange, which overcomes the current isolation of the approaches. They consider the theoretical and methodological questions as well as the identification of empirical tradeoffs. Furthermore, they provide insights into the possibility to balance trade-offs and strategies, which could help actors to find such compromises.
Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, the rapid recanalization of occluded cranial vessels is the primary therapeutic aim. However, experimental data (obtained using mostly the transient middle cerebral artery occlusion model) indicates that progressive stroke can still develop despite successful recanalization, a process termed “reperfusion injury.” Mounting experimental evidence suggests that platelets and T cells contribute to cerebral ischemia/reperfusion injury, and ischemic stroke is increasingly considered a thrombo-inflammatory disease. The interaction of von Willebrand factor and its receptor on the platelet surface, glycoprotein Ib, as well as many activatory platelet receptors and platelet degranulation contribute to secondary infarct growth in this setting. In contrast, interference with GPIIb/IIIa-dependent platelet aggregation and thrombus formation does not improve the outcome of acute brain ischemia but dramatically increases the susceptibility to intracranial hemorrhage. Here, we summarize the current understanding of the mechanisms and the potential translational impact of platelet contributions to cerebral ischemia/reperfusion injury.
Psoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes, but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are not well-defined. To identify PMN surface receptors that may explain PMN skin homing in psoriasis patients, we screened 332 surface antigens on primary human blood PMNs from healthy donors and psoriasis patients. We identified platelet surface antigens as a defining feature of psoriasis PMNs, due to a significantly increased aggregation of neutrophils and platelets in the blood of psoriasis patients. Similarly, in the imiquimod-induced experimental in vivo mouse model of psoriasis, disease induction promoted PMN-platelet aggregate formation. In psoriasis patients, disease incidence directly correlated with blood platelet counts and platelets were detected in direct contact with PMNs in psoriatic but not healthy skin. Importantly, depletion of circulating platelets in mice in vivo ameliorated disease severity significantly, indicating that both PMNs and platelets may be relevant for psoriasis pathology and disease severity.
In vitro co-cultures of different primary human cell types are pivotal for the testing and evaluation of biomaterials under conditions that are closer to the human in vivo situation. Especially co-cultures of macrophages and mesenchymal stem cells (MSCs) are of interest, as they are both present and involved in tissue regeneration and inflammatory reactions and play crucial roles in the immediate inflammatory reactions and the onset of regenerative processes, thus reflecting the decisive early phase of biomaterial contact with the host. A co-culture system of these cell types might thus allow for the assessment of the biocompatibility of biomaterials. The establishment of such a co-culture is challenging due to the different in vitro cell culture conditions. For human macrophages, medium is usually supplemented with human serum (hS), whereas hMSC culture is mostly performed using fetal calf serum (FCS), and these conditions are disadvantageous for the respective other cell type. We demonstrate that human platelet lysate (hPL) can replace hS in macrophage cultivation and appears to be the best option for co-cultivation of human macrophages with hMSCs. In contrast to FCS and hS, hPL maintained the phenotype of both cell types, comparable to that of their respective standard culture serum, as well as the percentage of each cell population. Moreover, the expression profile and phagocytosis activity of macrophages was similar to hS.
Abiotic stress by elevated tropospheric ozone and temperature can alter plants’ metabolism, growth, and nutritional value and modify the life cycle of their herbivores. We investigated how the duration of exposure of Sinapis arvensis plants to high ozone and temperature levels affect the life cycle of the large cabbage white, Pieris brassicae. Plants were exposed to ozone-clean (control) or ozone-enriched conditions (120 ppb) for either 1 or 5 days and were afterwards kept in a greenhouse with variable temperature conditions. When given the choice, P. brassicae butterflies laid 49% fewer eggs on ozone-exposed than on control plants when the exposure lasted for 5 days, but showed no preference when exposure lasted for 1 day. The caterpillars took longer to hatch on ozone-exposed plants and at lower ambient temperatures. The ozone treatment had a positive effect on the survival of the eggs. Ozone decreased the growth of caterpillars reared at higher temperatures on plants exposed for 5 days, but not on plants exposed for 1 day. Overall, longer exposure of the plants to ozone and higher temperatures affected the life cycle of the herbivore more strongly. With global warming, the indirect impacts of ozone on herbivores are likely to become more common.
According to the motivational priming hypothesis, unpleasant stimuli activate the motivational defense system, which in turn promotes congruent affective states such as negative emotions and pain. The question arises to what degree this bottom–up impact of emotions on pain is susceptible to a manipulation of top–down-driven expectations. To this end, we investigated whether verbal instructions implying pain potentiation vs. reduction (placebo or nocebo expectations)—later on confirmed by corresponding experiences (placebo or nocebo conditioning)—might alter behavioral and neurophysiological correlates of pain modulation by unpleasant pictures. We compared two groups, which underwent three experimental phases: first, participants were either instructed that watching unpleasant affective pictures would increase pain (nocebo group) or that watching unpleasant pictures would decrease pain (placebo group) relative to neutral pictures. During the following placebo/nocebo-conditioning phase, pictures were presented together with electrical pain stimuli of different intensities, reinforcing the instructions. In the subsequent test phase, all pictures were presented again combined with identical pain stimuli. Electroencephalogram was recorded in order to analyze neurophysiological responses of pain (somatosensory evoked potential) and picture processing [visually evoked late positive potential (LPP)], in addition to pain ratings. In the test phase, ratings of pain stimuli administered while watching unpleasant relative to neutral pictures were significantly higher in the nocebo group, thus confirming the motivational priming effect for pain perception. In the placebo group, this effect was reversed such that unpleasant compared with neutral pictures led to significantly lower pain ratings. Similarly, somatosensory evoked potentials were decreased during unpleasant compared with neutral pictures, in the placebo group only. LPPs of the placebo group failed to discriminate between unpleasant and neutral pictures, while the LPPs of the nocebo group showed a clear differentiation. We conclude that the placebo manipulation already affected the processing of the emotional stimuli and, in consequence, the processing of the pain stimuli. In summary, the study revealed that the modulation of pain by emotions, albeit a reliable and well-established finding, is further tuned by reinforced expectations—known to induce placebo/nocebo effects—which should be addressed in future research and considered in clinical applications.
The proliferative darkening syndrome (PDS) is a lethal disease of brown trout (Salmo trutta fario) which occurs in several alpine Bavarian limestone rivers. Because mortality can reach 100%, PDS is a serious threat for affected fish populations. Recently, Kuehn and colleagues reported that a high throughput RNA sequencing approach identified a piscine orthoreovirus (PRV) as a causative agent of PDS. We investigated samples from PDS-affected fish obtained from two exposure experiments performed at the river Iller in 2008 and 2009. Using a RT-qPCR and a well-established next-generation RNA sequencing pipeline for pathogen detection, PRV-specific RNA was not detectable in PDS fish from 2009. In contrast, PRV RNA was readily detectable in several organs from diseased fish in 2008. However, similar virus loads were detectable in the control fish which were not exposed to Iller water and did not show any signs of the disease. Therefore, we conclude that PRV is not the causative agent of PDS of brown trout in the rhithral region of alpine Bavarian limestone rivers. The abovementioned study by Kuehn used only samples from the exposure experiment from 2008 and detected a subclinical PRV bystander infection. Work is ongoing to identify the causative agent of PDS.
Background
Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disorder of the skeletal system of yet unknown etiology. Patients present with local bone pain and inflammation and - to our experience - often suffer from functional impairment with significant disabilities of daily life. The objective of this study was to assess physical activity, fitness and health-related quality of life (HRQOL) in adolescents with established diagnosis of CNO versus healthy controls (HC).
Methods
15 patients with CNO and 15 age and gender matched HC aged 13–18 years, completed questionnaires, performed an incremental exercise test with gas exchange measures up to voluntary fatigue and wore an accelerometer over 7 days at home to assess physical activity behavior.
Results
At the time of assessment, 5 CNO patients were in clinical, one in radiological and 5 in clinical and radiological remission. 7 did not receive any therapy at the time of assessment. The results of the exercise test and of the accelerometry did not show any significant difference between CNO and HC. However, reported sports participation was lower in patients with CNO and PedsQL3.0 and 4.0 showed significant lower values in most of the scores indicating reduced HRQOL.
Conclusion
Although most CNO patients showed a favorable course of disease without any relevant differences in objective measurements of physical activity and fitness versus HC at the time of assessment, questionnaires revealed perceived limitations. Further studies are needed to measure HRQOL and to validate questionnaires in patients with CNO against objective measures including more participants with a higher level of disease activity.
In this thesis, the photophysics and spin chemistry of donor-photosensitizer-acceptor triads were investigated. While all investigated triads comprised a TAA as an electron donor and a NDI as an electron acceptor, the central photosensitizers (PS) were different chromophores based on the dipyrrin-motif. The purity and identity of all target compounds could be confirmed by NMR spectroscopy, mass spectrometry and elemental analysis.
The first part of the work dealt with dipyrrinato-complexes of cyclometalated heavy transition metals. The successful synthesis of novel triads based on Ir(III), Pt(II) and Pd(II) was presented. The optical and electrochemical properties indicated charge separation (CS), which was confirmed by transient absorption (TA) spectroscopy. TA-spectroscopy also revealed that the process of CS is significantly slower and less efficient for the triads based on Pt(II) and Pd(II) than for the analogous Ir(III) triads. This is mostly due to a much more convoluted reaction pathway, comprising several intermediate states before the formation of the final charge separated state (CSS2). On the other hand, CSS2 exhibits long lifetimes which are dependent on the central metal ion. While the Ir(III) triads show lifetimes of about 0.5 µs in MeCN, the Pt(II) and Pd(II) analogues show lifetimes of 1.5 µs. The magnetic field effect on the charge recombination (CR) kinetics of CSS2 was investigated by magnetic field dependent ns-TA spectroscopy and could be rationalized based on a classical kinetic scheme comprising only one magnetic field dependent rate constant k±. The behavior of k± shows a clear separation of the coherent and incoherent spin interconversion mechanisms. While the coherent spin evolution is due to the isotropic hyperfine coupling with the magnetic nuclei of the radical centers, the incoherent spin relaxation is due to a rotational modulation of the anisotropic hyperfine coupling tensor and is strongly dependent on the viscosity of the solvent. This dependence could be used to measure the nanoviscosity of the oligomeric solvent pTHF, which was found to be distinctly different from its macroviscosity.
The second part of the work dealt with bisdipyrrinato complexes and their bridged porphodimethenato (PDM) analogues. Initially, the suitability of the different chromophores for the use as PS in donor-acceptor substituted triads was tested by a systematic investigation of their steady state and transient properties. While the PDM-complex of Zn(II) and Pd(II) exhibited promising characteristics such as a high exited state lifetime and relatively intense emission, the purely organic parent PDM and the non-bridged bisdipyrrinato-Pd(II) complex were less suitable. The difference between the two Pd(II) complexes could be explained by a structural rearrangement of the non-bridged complex which results in a non-emissive metal centered triplet state with disphenoidal geometry. This rearrangement is prevented by the dimethylmethylene-bridges in the bridged analogue resulting in higher phosphorescence quantum yields and excited state lifetimes.
With the exception of the Zn(II)PDM-complex, the synthesis of novel donor acceptor substituted triads could be realized for all desired central chromophores. They were investigated equivalently to the cyclometalated triads described in the first part. The steady state properties indicate a stronger electronic coupling between the subunits due to the lack of unsaturated bridges between the donor and the central chromophore. Photoinduced CS occurs in all investigated triads. Due to the low exited state lifetimes of the central chromophores, CSS is formed less efficiently for the triads based on the unbridged Pd(II)-complex as well as the purely organic PDM. In the triad based on the bridged Pd(II) complex, the CR of CSS2 is faster than its formation resulting in low intermediate concentrations. For its elongated analogue, this is not the case and CSS2 can be observed clearly. Although the spin-chemistry of the triads based on bisdipyrrinato-Pd(II) and porphodimethenato-Pd(II) is less well understood, first interpretations of the magnetic field dependent decay kinetics gave results approximately equivalent to those obtained for the cyclometalated triads. Furthermore, the MFE was shown to be useful for the investigation of the quantum yield of CS and the identity of the observed CSSs.
In both parts of this work, the influence of the central photosensitizer on the photophysics and the spin chemistry of the triads could be shown. While the process of CS is directly dependent on the PS, the PS usually is not directly involved in the final CSSs. None the less, it can still indirectly affect the CR and spin chemistry of the CSS since it influences the electronic coupling between donor and acceptor, as well as the geometry of the triads.
In this work, we elucidated recombination kinetics in organic and hybrid semiconductors by steady-state and time-resolved PL spectroscopy. Using these simple and very flexible experimental techniques, we probed the infrared emission from recombining free charge carriers in metal–halide perovskites, as well as the deep blue luminescence from intramolecular charge-transfer states in novel OLED emitters. We showed that similar state diagrams and kinetic models accurately describe the dynamics of excited species in these very different material systems.
In Chapters 4 and 5, we focused on lead iodide perovskites (MAPI and FAPI), whose comparatively developed deposition techniques suited the systematic material research. In MAPI, we harnessed the anomalous dependence of transient PL on the laser repetition rate in order to investigate the role of interfaces with the commonly used charge-selective layers: PC60BM, spiro-MeOTAD, and P3HT. The film was deposited on a large precut substrate and separated into several parts, which were then covered with the charge-selective layers. Thereby, the same bulk perovskite structure was maintained for all samples. Consequently, we were able to isolate interface-affected and bulk carrier recombination. The first one dominated the fast component of PL decay up to 300 ns, whereas the last was assigned to the remaining slow component. The laser repetition rate significantly prolonged PL decay in MAPI with additional interfaces while shortening the charge carrier lifetime in the pristine film. We qualitatively explained this effect by a kinetic model that included radiative electron–hole recombination and nonradiative trap-assisted recombination. All in all, we showed that the apparent PL lifetime in MAPI is to large extend defined by the laser repetition rate and by the adjacent interfaces.
Further, we studied photon recycling in MAPI and FAPI. We monitored how the microscopic PL transforms while propagating through the thin perovskite film. The emission was recorded within 5orders of magnitude in intensity up to 70μm away from the excitation spot. The Beer–Lambert law previously failed to describe the complex interplay of the intrinsic PL spectrum and the additional red-shifted peak. Therefore, we developed a general numerical model that accounts for self-absorption and diffusion of the secondary charge carriers. A simulation based on this model showed excellent agreement with the experimental spatially resolved PL maps. The proposed model can be applied to any perovskite film, because it uses easily measurable intrinsic PL spectrum and macroscopic absorption coefficient as seeding parameters.
In Chapter 6, we conducted an extensive photophysical study of a novel compact deep blue OLED emitter, SBABz4, containing spiro-biacridine and benzonitrile units. We also considered its single-donor monomer counterpart, DMABz4, in order to highlight the structure–property relationships. Both compounds exhibited thermally activated delayed fluorescence (TADF), which was independently proven by oxygen quenching and temperature-dependent transient PL measurements. The spiro-linkage in the double-donor core of SBABz4 rendered its luminescence pure blue compared to the blue-green emission from the single-donor DMABz4. Thus, the core-donor provided desirable color tuning in the deep blue region, as opposed to the common TADF molecular design with core-acceptor. Using PL lifetimes and efficiencies, we predicted EQEmax = 7.1% for SBABz4-based OLED, whereas a real test device showed EQEmax = 6.8%. Transient PL was recorded from the solutions and solid films in the unprecedentedly broad dynamic range covering up to 6orders of magnitude in time and 8orders of magnitude in intensity. The stretched exponent was shown to fit the transient PL in the films very well, whereas PL decay in dilute solution was found purely exponential. When the emitter was embedded in the host matrix that prevented aggregation, its TADF properties were superior in comparison with the pure SBABz4 film. Finally, using temperature-dependent transient PL data, we calculated the TADF activation energy of 70 meV.
To sum up, this Thesis contributes to the two fascinating topics of the last decade’s material research: perovskite absorbers for photovoltaics and TADF emitters for OLEDs. We were lucky to work with the emerging systems and tailor for them new models out of the well-known physical concepts. This was both exciting and challenging. In the end, science of novel materials is always a mess. We hope that we brought there a bit of clarity and light.
The lability of B=B, B-P and B-halide bonds is combined in the syntheses of the first diiododiborenes. In a series of reactivity tests, these diiododiborenes demonstrate cleavage of all six of their central bonds in different ways, leading to products of B=B hydrogenation and dihalogenation as well as halide exchange.
(1) In vitro, bone marrow-derived stromal cells (BMSCs) demonstrate inter-donor phenotypic variability, which presents challenges for the development of regenerative therapies. Here, we investigated whether the frequency of putative BMSC sub-populations within the freshly isolated mononuclear cell fraction of bone marrow is phenotypically predictive for the in vitro derived stromal cell culture. (2) Vertebral body, iliac crest, and femoral head bone marrow were acquired from 33 patients (10 female and 23 male, age range 14–91). BMSC sub-populations were identified within freshly isolated mononuclear cell fractions based on cell-surface marker profiles. Stromal cells were expanded in monolayer on tissue culture plastic. Phenotypic assessment of in vitro derived cell cultures was performed by examining growth kinetics, chondrogenic, osteogenic, and adipogenic differentiation. (3) Gender, donor age, and anatomical site were neither predictive for the total yield nor the population doubling time of in vitro derived BMSC cultures. The abundance of freshly isolated progenitor sub-populations (CD45−CD34−CD73+, CD45−CD34−CD146+, NG2+CD146+) was not phenotypically predictive of derived stromal cell cultures in terms of growth kinetics nor plasticity. BMSCs derived from iliac crest and vertebral body bone marrow were more responsive to chondrogenic induction, forming superior cartilaginous tissue in vitro, compared to those isolated from femoral head. (4) The identification of discrete progenitor populations in bone marrow by current cell-surface marker profiling is not predictive for subsequently derived in vitro BMSC cultures. Overall, the iliac crest and the vertebral body offer a more reliable tissue source of stromal progenitor cells for cartilage repair strategies compared to femoral head.
Background
Postoperative pulmonary complications (PPCs) increase morbidity and mortality of surgical patients, duration of hospital stay and costs. Postoperative atelectasis of dorsal lung regions as a common PPC has been described before, but its clinical relevance is insufficiently examined. Pulmonary electrical impedance tomography (EIT) enables the bedside visualization of regional ventilation in real-time within a transversal section of the lung. Dorsal atelectasis or effusions might cause a ventral redistribution of ventilation. We hypothesized the existence of ventral redistribution in spontaneously breathing patients during their recovery from abdominal and peripheral surgery and that vital capacity is reduced if regional ventilation shifts to ventral lung regions.
Methods
This prospective observational study included 69 adult patients undergoing elective surgery with an expected intermediate or high risk for PPCs. Patients undergoing abdominal and peripheral surgery were recruited to obtain groups of equal size. Patients received general anesthesia with and without additional regional anesthesia. On the preoperative, the first and the third postoperative day, EIT was performed at rest and during spirometry (forced breathing). The center of ventilation in dorso-ventral direction (COVy) was calculated.
Results
Both groups received intraoperative low tidal volume ventilation. Postoperative ventral redistribution of ventilation (forced breathing COVy; preoperative: 16.5 (16.0–17.3); first day: 17.8 (16.9–18.2), p < 0.004; third day: 17.4 (16.2–18.2), p = 0.020) and decreased forced vital capacity in percentage of predicted values (FVC%predicted) (median: 93, 58, 64%, respectively) persisted after abdominal surgery. In addition, dorsal to ventral shift was associated with a decrease of the FVC%predicted on the third postoperative day (r = − 0.66; p < 0.001). A redistribution of pulmonary ventilation was not observed after peripheral surgery. FVC%predicted was only decreased on the first postoperative day (median FVC%predicted on the preoperative, first and third day: 85, 81 and 88%, respectively). In ten patients occurred pulmonary complications after abdominal surgery also in two patients after peripheral surgery.
Conclusions
After abdominal surgery ventral redistribution of ventilation persisted up to the third postoperative day and was associated with decreased vital capacity. The peripheral surgery group showed only minor changes in vital capacity, suggesting a role of the location of surgery for postoperative redistribution of pulmonary ventilation.
Periodontal treatment prevents arthritis in mice and methotrexate ameliorates periodontal bone loss
(2019)
Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides. We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis. F1 (DBA/1 x B10.Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked. Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate. Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography. Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses. Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate. Likewise, all three therapies attenuated alveolar bone loss. Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment. This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis. Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.
Background: Controversy remains concerning the impact of Ureaplasma on preterm neonatal morbidity.
Methods: Prospective single-center study in very low birth weight infants <30 weeks' gestation. Cord blood and initial nasopharyngeal swabs were screened for Ureaplasma parvum and U. urealyticum using culture technique and polymerase chain reaction. Neonatal outcomes were followed until death or discharge. Multi-analyte immunoassay provided cord blood levels of inflammatory markers. Using multivariate regression analyses, perinatal Ureaplasma exposure was evaluated as risk factor for the development of bronchopulmonary dysplasia (BPD), other neonatal morbidities until discharge and systemic inflammation at admission.
Results: 40/103 (39%) infants were positive for Ureaplasma in one or both specimens, with U. parvum being the predominant species. While exposure to Ureaplasma alone was not associated with BPD, we found an increased risk of BPD in Ureaplasma-positive infants ventilated ≥5 days (OR 1.64; 95% CI 0.12–22.98; p = 0.009). Presence of Ureaplasma was associated with a 7-fold risk of late onset sepsis (LOS) (95% CI 1.80–27.39; p = 0.014). Moreover, Ureaplasma-positive infants had higher I/T ratios (b 0.39; 95% CI 0.08–0.71; p = 0.014), increased levels of interleukin (IL)-17 (b 0.16; 95% CI 0.02–0.30; p = 0.025) and matrix metalloproteinase 8 (b 0.77; 95% CI 0.10–1.44; p = 0.020), decreased levels of IL-10 (b −0.77; 95% CI −1.58 to −0.01; p = 0.043) and increased ratios of Tumor necrosis factor-α, IL-8, and IL-17 to anti-inflammatory IL-10 (p = 0.003, p = 0.012, p < 0.001).
Conclusions: Positive Ureaplasma screening was not associated with BPD. However, exposure contributed to BPD in infants ventilated ≥5 days and conferred an increased risk of LOS and imbalanced inflammatory cytokine responses.
This article focuses on selected Latin American female rap artists (Anita Tijoux, Rebeca Lane, and the duo Krudas Cubensi), and the way they perform feminism, autobiography and testimony through their lyrics and performances. The analysis concentrates on the synergies between the texts themselves, the official music videos shared on YouTube and the background music. It aims to demonstrate that only such a synergistic approach to rap allows a profound understanding of its particularities and its contributions to feminist discourses and spaces for feminist testimony in the current rise of both right-wing politics and feminist movements on the continent.
This thesis elucidates patterns and drivers of invertebrate herbivory, herbivore diversity, and community-level biomass along elevational and land use gradients at Mt. Kilimanjaro, Tanzania.
Chapter I provides background information on the response and predictor variables, study system, and the study design. First, I give an overview of the elevational patterns of species diversity/richness and herbivory published in the literature. The overview illuminates existing debates on elevational patterns of species diversity/richness and herbivory. In connection to these patterns, I also introduce several hypotheses and mechanisms put forward to explain macroecological patterns of species richness. Furthermore, I explain the main variables used to test hypotheses. Finally, I describe the study system and the study design used.
Chapter II explores the patterns of invertebrate herbivory and their underlying drivers along extensive elevational and land use gradients on the southern slopes of Mt. Kilimanjaro. I recorded standing leaf herbivory from leaf chewers, leaf miners and gall-inducing insects on 55 study sites located in natural and anthropogenic habitats distributed from 866 to 3060 meters above sea level (m asl) on Mt. Kilimanjaro. Standing leaf herbivory was related to climatic variables [mean annual temperature - (MAT) and mean annual precipitation - (MAP)], net primary productivity (NPP) and plant functional traits (leaf traits) [specific leaf area (SLA), carbon to nitrogen ratio (CN), and nitrogen to phosphorous ratio (NP)]. Results revealed an unimodal pattern of total leaf herbivory along the elevation gradient in natural habitats. Findings also revealed differences in the levels and patterns of herbivory among feeding guilds and between anthropogenic and natural habitats. Changes in NP and CN ratios which were closely linked to NPP were the strongest predictors of leaf herbivory. Our study uncovers the role of leaf nutrient stoichiometry and its linkages to climate in explaining the variation in leaf herbivory along climatic gradients.
Chapter III presents patterns and unravels direct and indirect effects of resource (food) abundance (NPP), resource (food) diversity [Functional Dispersion (FDis)], resource quality (SLA, NP, and CN rations), and climate variables (MAT and MAP) on species diversity of phytophagous beetles. Data were collected from 65 study sites located in natural and anthropogenic habitats distributed from 866 to 4550 m asl on the southern slopes of Mt. Kilimanjaro. Sweep net and beating methods were used to collect a total of 3,186 phytophagous beetles representing 21 families and 304 morphospecies. Two groups, weevils (Curculionidae) and leaf beetles (Chrysomelidae) were the largest and most diverse families represented with 898 and 1566 individuals, respectively. Results revealed complex (bimodal) and dissimilar patterns of Chao1-estimated species richness (hereafter referred to as species diversity) along elevation and land use gradients. Results from path analysis showed that temperature and climate-mediated changes in NPP had a significant positive direct and indirect effect on species diversity of phytophagous beetles, respectively. The results also revealed that the effect of NPP (via beetles abundance and diversity of food resources) on species diversity is stronger than that of temperature. Since we found that factors affecting species diversity were intimately linked to climate, I concluded that predicted climatic changes over the coming decades will likely alter the species diversity patterns which we observe today.
Chapter IV presents patterns and unravels the direct and indirect effects of climate, NPP and anthropogenic disturbances on species richness and community-level biomass of wild large mammals which represent endothermic organisms and the most important group of vertebrate herbivores. Data were collected from 66 study sites located in natural and anthropogenic habitats distributed from 870 to 4550 m asl on the southern slopes of Mt. Kilimanjaro. Mammals were collected using camera traps and used path analysis to disentangle the direct and indirect effects of climatic variables, NPP, land use, land area, levels of habitat protection and occurrence of domesticated mammals on the patterns of richness and community-level biomass of wild mammals, respectively. Results showed unimodal patterns for species richness and community-level biomass of wild mammals along elevation gradients and that the patterns differed depending on the type of feeding guild. Findings from path analysis showed that net primary productivity and levels of habitat protection had a strong direct effect on species richness and community-level biomass of wild mammals whereas temperature had an insignificant direct effect. Findings show the importance of climate-mediated food resources in determining patterns of species richness of large mammals. While temperature is among key predictors of species richness in several ectotherms, its direct influence in determining species richness of wild mammals was insignificant. Findings show the sensitivity of wild mammals to anthropogenic influences and underscore the importance of protected areas in conserving biodiversity.
In conclusion, despite a multitude of data sets on species diversity and ecosystem functions along broad climatic gradients, there is little mechanistic understanding of the underlying causes. Findings obtained in the three studies illustrate their contribution to the scientific debates on the mechanisms underlying patterns of herbivory and diversity along elevation gradients. Results present strong evidence that plant functional traits play a key role in determining invertebrate herbivory and species diversity along elevation gradients and that, their strong interdependence with climate and anthropogenic activities will shape these patterns in future. Additionally, findings from path analysis demonstrated that herbivore diversity, community-level biomass, and herbivory are strongly influenced by climate (either directly or indirectly). Therefore, the predicted climatic changes are expected to dictate ecological patterns, biotic interactions, and energy and nutrient fluxes in terrestrial ecosystems in the coming decades with stronger impacts probably occurring in natural ecosystems. Furthermore, findings demonstrated the significance of land use effects in shaping ecological patterns. As anthropogenic pressure is advancing towards more pristine higher elevations, I advocate conservation measures which are responsive to and incorporate human dimensions to curb the situation. Although our findings emanate from observational studies which have to take several confounding factors into account, we have managed to demonstrate global change responses in real ecosystems and fully established organisms with a wide range of interactions which are unlikely to be captured in artificial experiments. Nonetheless, I recommend additional experimental studies addressing the effect of top-down control by natural enemies on herbivore diversity and invertebrate herbivory in order to deepen our understanding of the mechanisms driving macroecological patterns along elevation gradients.
Objective
To establish individually expandable primary fibroblast and keratinocyte cultures from 3‐mm skin punch biopsies for patient‐derived in vitro skin models to investigate of small fiber pathology.
Methods
We obtained 6‐mm skin punch biopsies from the calf of two patients with small fiber neuropathy (SFN) and two healthy controls. One half (3 mm) was used for diagnostic intraepidermal nerve fiber density (IENFD). From the second half, we isolated and cultured fibroblasts and keratinocytes. Cells were used to generate patient‐derived full‐thickness three‐dimensional (3D) skin models containing a dermal and epidermal component. Cells and skin models were characterized morphologically, immunocyto‐ and ‐histochemically (vimentin, cytokeratin (CK)‐10, CK 14, ki67, collagen1, and procollagen), and by electrical impedance.
Results
Distal IENFD was reduced in the SFN patients (2 fibers/mm each), while IENFD was normal in the controls (8 fibers/mm, 7 fibers/mm). Two‐dimensional (2D) cultured skin cells showed normal morphology, adequate viability, and proliferation, and expressed cell‐specific markers without relevant difference between SFN patient and healthy control. Using 2D cultured fibroblasts and keratinocytes, we obtained subject‐derived 3D skin models. Morphology of the 3D model was analogous to the respective skin biopsy specimens. Both, the dermal and the epidermal layer carried cell‐specific markers and showed a homogenous expression of extracellular matrix proteins.
Interpretation
Our protocol allows the generation of disease‐specific 2D and 3D skin models, which can be used to investigate the cross‐talk between skin cells and sensory neurons in small fiber pathology.
The central nervous system (CNS) barriers are highly specialized cellular barriers that promote brain homeostasis while restricting pathogen and toxin entry. The primary cellular constituent regulating pathogen entry in most of these brain barriers is the brain endothelial cell (BEC) that exhibits properties that allow for tight regulation of CNS entry. Bacterial meningoencephalitis is a serious infection of the CNS and occurs when bacteria can cross specialized brain barriers and cause inflammation. Models have been developed to understand the bacterial – BEC interaction that lead to pathogen crossing into the CNS, however, these have been met with challenges due to these highly specialized BEC phenotypes. This perspective provides a brief overview and outlook of the in vivo and in vitro models currently being used to study bacterial brain penetration, and opinion on improved models for the future.
Parent-child relationship is developed and changed through reciprocal interactions between a child and his/her parent, and these interactions can strongly influence the child's development across domains (e.g., emotional, physical, and intellectual). However, little is known about the parental perception of the child's contribution to the dyadic parent-child relationship in terms of positive and negative behaviors. We therefore aimed to develop and validate an economical parent-report instrument to assess these important aspects. The validation study included 1642 mothers (M\(_{age}\) = 37.1) and 1068 fathers (M\(_{age}\) = 40.4) of 1712 children aged 2–10 years (M\(_{age}\) = 6.6) who completed the new instrument, the Child Relationship Behavior Inventory (CRBI). Statistical results indicated that the CRBI is a reliable and valid measure. Mothers reported more positive child behaviors towards them, whereas fathers perceived fewer problems with problematic relationship behavior than mothers. In their parents' perception, girls showed more positive and less problematic relationship behaviors than boys. The frequency of problematic child relationship behavior significantly decreased with increasing child age while positive relationship behavior did not show any correlation with the child's age. To assess both positive and negative child relationship behaviors could be helpful to better understand the relevance of these different aspects for the development of the parent-child relationship.
Background
Panniculitis-like T-cell lymphoma is an uncommon type of non-Hodgkin lymphoma, occurring usually in the form of nodules within the subcutaneous fat tissue of the extremities or trunk. In the literature, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is described as a distinct type of T-cell lymphoma with a variable clinical behavior, depending on molecular phenotype of T-cell receptor (TCR) and on the presence or absence of hemophagocytic syndrome.
Case presentation
We present a bioptic and autoptic case of a 65-years old Caucasian man with panniculitic T-cell lymphoma with morphological and immunohistochemical features of SPTCL, limited to the retroperitoneal and mesenteric mass, i.e. without any cutaneous involvement, and associated with severe hemophagocytic lymphohistiocytosis.
Conclusion
A panniculitic T-cell lymphoma with morphological and molecular features of SPTCL, which is limited to mesentery, i.e. does not involve subcutaneous fat, seems to be exceedingly rare.
Non-steroidal antiinflammatory drugs are most commonly used for inflammatory and postoperative pain. But they lack effectiveness and specificity, leading to severe side effects, like gastric ulcers, asthma and severe bleeding. Oxidized 1-palmitoyl-2-arachinidonoyl-sn-glycero-3-phosphocholine (OxPAPC) plays an important role in inflammatory pain. PAPC is a common phosphatidylcholine of membranes, which can be oxidized by reactive oxygen species. In preliminary experiments, our group found that local injection of OxPAPC in rat paws induces hyperalgesia.
In this study we examined the effect of OxPAPC on transient receptor potential A1 (TRPA1), an ion channel expressed in C-fiber neurons. Furthermore, we investigated if intracellular cysteine residues of TRPA1 were necessary for agonist-channel-interactions and if a subsequent TRPA1 activation could be prevented by OxPAPC scavengers.
To answer these questions, we performed calcium imaging using HEK-293 cells stably expressing hTRPA1, or transiently expressing the triple mutant channel hTRPA1-3C and naïve DRG neurons. Cells were incubated with the ratiometric, fluorescent dye Fura-2/AM and stimulated with OxPAPC. The change of light emission after excitation with 340 and 380 nm wavelengths allowed conclusions regarding changes of intracellular calcium concentrations after TRPA1 activation.
In our investigation we proved evidence that OxPAPC activates TRPA1, which caused a flow of calcium ions into the cytoplasm. The TRPA1-specific channel blocker HC-030031 eliminated this agonist-induced response. TRPA1-3C was not completely sensitive to OxPAPC. The peptide D-4F and the monoclonal antibody E06 neutralized OxPAPC-induced TRPA1 activation.
In this work, the importance of OxPAPC as a key mediator of inflammatory pain and as a promising target for drug design is highlighted. Our results indicate that TRPA1 activation by OxPAPC involves cysteine-dependent mechanisms, but there are other, cysteine-independent activation mechanisms as well. Potential pharmaceuticals for the treatment of inflammatory pain are D-4F and E06, whose efficiency has recently been confirmed in the animal model by our research group.
Background
Airway management is crucial and, probably, even the most important key competence in anaesthesiology, which directly influences patient safety and outcome. However, high-quality research is rarely published and studies usually have different primary or secondary endpoints which impedes clear unbiased comparisons between studies. The aim of the present study was to gather and analyse primary and secondary endpoints in video laryngoscopy studies being published over the last ten years and to create a core set of uniform or homogeneous outcomes (COS).
Methods
Retrospective analysis. Data were identified by using MEDLINE® database and the terms “video laryngoscopy” and “video laryngoscope” limited to the years 2007 to 2017. A total of 3351 studies were identified by the applied search strategy in PubMed. Papers were screened by two anaesthesiologists independently to identify study endpoints. The DELPHI method was used for consensus finding.
Results
In the 372 studies analysed and included, 49 different outcome categories/columns were reported. The items “time to intubation” (65.86%), “laryngeal view grade” (44.89%), “successful intubation rate” (36.56%), “number of intubation attempts” (23.39%), “complications” (21.24%), and “successful first-pass intubation rate” (19.09%) were reported most frequently. A total of 19 specific parameters is recommended.
Conclusions
In recent video laryngoscopy studies, many different and inhomogeneous parameters were used as outcome descriptors/endpoints. Based on these findings, we recommend that 19 specific parameters (e.g., “time to intubation” (inserting the laryngoscope to first ventilation), “laryngeal view grade” (C&L and POGO), “successful intubation rate”, etc.) should be used in coming research to facilitate future comparisons of video laryngoscopy studies.
Social robots are becoming increasingly prevalent in everyday life and sex robots are a sub-category of especially high public interest and controversy. Starting from the concept of the otaku, a term from Japanese youth culture that describes secluded persons with a high affinity for fictional manga characters, we examine individual differences behind sex robot appeal (anime and manga fandom, interest in Japanese culture, preference for indoor activities, shyness). In an online-experiment, 261 participants read one out of three randomly assigned descriptions of future technologies (sex robot, nursing robot, genetically modified organism) and reported on their overall evaluation, eeriness, and contact/purchase intentions. Higher anime and manga fandom was associated with higher appeal for all three future technologies. For our male subsample, sex robots and GMOs stood out as shyness yielded a particularly strong relationship to contact/purchase intentions for these new technologies.
Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
The Software Defined Networking (SDN) paradigm offers network operators numerous improvements in terms of flexibility, scalability, as well as cost efficiency and vendor independence. However, in order to maximize the benefit from these features, several new challenges in areas such as management and orchestration need to be addressed. This dissertation makes contributions towards three key topics from these areas.
Firstly, we design, implement, and evaluate two multi-objective heuristics for the SDN controller placement problem. Secondly, we develop and apply mechanisms for automated decision making based on the Pareto frontiers that are returned by the multi-objective optimizers. Finally, we investigate and quantify the performance benefits for the SDN control plane that can be achieved by integrating information from external entities such as Network Management Systems (NMSs) into the control loop. Our evaluation results demonstrate the impact of optimizing various parameters of softwarized networks at different levels and are used to derive guidelines for an efficient operation.
Opsin 1 and Opsin 2 of the corn smut fungus ustilago maydis are green light-driven proton pumps
(2019)
In fungi, green light is absorbed by rhodopsins, opsin proteins carrying a retinal molecule as chromophore. The basidiomycete Ustilago maydis, a fungal pathogen that infects corn plants, encodes three putative photoactive opsins, called ops1 (UMAG_02629), ops2 (UMAG_00371), and ops3 (UMAG_04125). UmOps1 and UmOps2 are expressed during the whole life cycle, in axenic cultures as well as in planta, whereas UmOps3 was recently shown to be absent in axenic cultures but highly expressed during plant infection. Here we show that expression of UmOps1 and UmOps2 is induced by blue light under control of white collar 1 (Wco1). UmOps1 is mainly localized in the plasma membrane, both when expressed in HEK cells and U. maydis sporidia. In contrast, UmOps2 was mostly found intracellularly in the membranes of vacuoles. Patch-clamp studies demonstrated that both rhodopsins are green light-driven outward rectifying proton pumps. UmOps1 revealed an extraordinary pH dependency with increased activity in more acidic environment. Also, UmOps1 showed a pronounced, concentration-dependent enhancement of pump current caused by weak organic acids (WOAs), especially by acetic acid and indole-3-acetic acid (IAA). In contrast, UmOps2 showed the typical behavior of light-driven, outwardly directed proton pumps, whereas UmOps3 did not exhibit any electrogenity. With this work, insights were gained into the localization and molecular function of two U. maydis rhodopsins, paving the way for further studies on the biological role of these rhodopsins in the life cycle of U. maydis.
The transcription factor 12 (tcf12) is a basic Helix-Loop-Helix protein (bHLH) of the E-protein family, proven to play an important role in developmental processes like neurogenesis, mesoderm formation, and cranial vault development. In humans, mutations in TCF12 lead to craniosynostosis, a congenital birth disorder characterized by the premature fusion of one or several of the cranial sutures. Current research has been primarily focused on functional studies of TCF12, hence the cellular expression profile of this gene during embryonic development and early stages of ossification remains poorly understood. Here we present the establishment and detailed analysis of two transgenic tcf12:EGFP fluorescent zebrafish (Danio rerio) reporter lines. Using these transgenic lines, we analyzed the general spatiotemporal expression pattern of tcf12 during different developmental stages and put emphasis on skeletal development and cranial suture patterning. We identified robust tcf12 promoter-driven EGFP expression in the central nervous system (CNS), the heart, the pronephros, and the somites of zebrafish embryos. Additionally, expression was observed inside the muscles and bones of the viscerocranium in juvenile and adult fish. During cranial vault development, the transgenic fish show a high amount of tcf12 expressing cells at the growth fronts of the ossifying frontal and parietal bones and inside the emerging cranial sutures. Subsequently, we tested the transcriptional activity of three evolutionary conserved non-coding elements (CNEs) located in the tcf12 locus by transient transgenic assays and compared their in vivo activity to the expression pattern determined in the transgenic tcf12:EGFP lines. We could validate two of them as tcf12 enhancer elements driving specific gene expression in the CNS during embryogenesis. Our newly established transgenic lines enhance the understanding of tcf12 gene regulation and open up the possibilities for further functional investigation of these novel tcf12 enhancer elements in zebrafish.
A sequential quadratic Hamiltonian (SQH) scheme for solving different classes of non-smooth and non-convex PDE optimal control problems is investigated considering seven different benchmark problems with increasing difficulty. These problems include linear and nonlinear PDEs with linear and bilinear control mechanisms, non-convex and discontinuous costs of the controls, L\(^1\) tracking terms, and the case of state constraints.
The SQH method is based on the characterisation of optimality of PDE optimal control problems by the Pontryagin's maximum principle (PMP). For each problem, a theoretical discussion of the PMP optimality condition is given and results of numerical experiments are presented that demonstrate the large range of applicability of the SQH scheme.
Objective: To test the hypothesis that olfactory (OF) and gustatory function (GF) is disturbed in patients with autoimmune encephalitides (AE).
Methods: The orthonasal OF was tested in 32 patients with AE and 32 age- and sex-matched healthy controls (HC) with the standardized Threshold Discrimination Identification (TDI) score. This validated olfactory testing method yields individual scores for olfactory threshold (T), odor discrimination (D), and identification (I), along with a composite TDI score. The GF was determined by the Taste Strip Test (TST).
Results: Overall, 24/32 (75%) of patients with AE, but none of 32 HC (p < 0.001) had olfactory dysfunction in TDI testing. The results of the threshold, discrimination and identification subtests were significantly reduced in patients with AE compared to HC (all p < 0.001). Assessed by TST, 5/19 (26.3%) of patients with AE, but none of 19 HC presented a significant limitation in GF (p < 0.001). The TDI score was correlated with the subjective estimation of the olfactory capacity on a visual analog scale (VAS; rs = 0.475, p = 0.008). Neither age, sex, modified Rankin Scale nor disease duration were associated with the composite TDI score.
Conclusions: This is the first study investigating OF and GF in AE patients. According to unblinded assessment, patients with AE have a reduced olfactory and gustatory capacity compared to HC, suggesting that olfactory and gustatory dysfunction are hitherto unrecognized symptoms in AE. Further studies with larger number of AE patients would be of interest to verify our results.
OCR4all—An open-source tool providing a (semi-)automatic OCR workflow for historical printings
(2019)
Optical Character Recognition (OCR) on historical printings is a challenging task mainly due to the complexity of the layout and the highly variant typography. Nevertheless, in the last few years, great progress has been made in the area of historical OCR, resulting in several powerful open-source tools for preprocessing, layout analysis and segmentation, character recognition, and post-processing. The drawback of these tools often is their limited applicability by non-technical users like humanist scholars and in particular the combined use of several tools in a workflow. In this paper, we present an open-source OCR software called OCR4all, which combines state-of-the-art OCR components and continuous model training into a comprehensive workflow. While a variety of materials can already be processed fully automatically, books with more complex layouts require manual intervention by the users. This is mostly due to the fact that the required ground truth for training stronger mixed models (for segmentation, as well as text recognition) is not available, yet, neither in the desired quantity nor quality. To deal with this issue in the short run, OCR4all offers a comfortable GUI that allows error corrections not only in the final output, but already in early stages to minimize error propagations. In the long run, this constant manual correction produces large quantities of valuable, high quality training material, which can be used to improve fully automatic approaches. Further on, extensive configuration capabilities are provided to set the degree of automation of the workflow and to make adaptations to the carefully selected default parameters for specific printings, if necessary. During experiments, the fully automated application on 19th Century novels showed that OCR4all can considerably outperform the commercial state-of-the-art tool ABBYY Finereader on moderate layouts if suitably pretrained mixed OCR models are available. Furthermore, on very complex early printed books, even users with minimal or no experience were able to capture the text with manageable effort and great quality, achieving excellent Character Error Rates (CERs) below 0.5%. The architecture of OCR4all allows the easy integration (or substitution) of newly developed tools for its main components by standardized interfaces like PageXML, thus aiming at continual higher automation for historical printings.
This Letter describes the observation of the light-by-light scattering process, gamma gamma -> gamma gamma, in Pb + Pb collisions at root S-NN = 5.02 TeV. The analysis is conducted using a data sample corresponding to an integrated luminosity of 1.73 nb(-1), collected in November 2018 by the ATLAS experiment at the LHC. Light-by-light scattering candidates are selected in events with two photons produced exclusively, each with transverse energy E-T(gamma) > 3 GeV and pseudorapidity vertical bar eta(gamma)vertical bar < 2.4, diphoton invariant mass above 6 GeV, and small diphoton transverse momentum and acoplanarity. After applying all selection criteria, 59 candidate events are observed for a background expectation of 12 +/- 3 events. The observed excess of events over the expected background has a significance of 8.2 standard deviations. The measured fiducial cross section is 78 +/- 13(stat) +/- 7(syst) +/- 3(lumi) nb.
Standardized reporting is more and more routinely implemented in clinical practice and such structured reports have a major impact on a large variety of medical fields, e.g. laboratory medicine, pathology, and, recently, radiology. Notably, the field of nuclear medicine is constantly evolving, as novel radiotracers for numerous clinical applications are developed. Thus, framework systems for standardized reporting in this field may a) increase clinical acceptance of new radiotracers, b) allow for inter- and intra-center comparisons for quality assurance, and c) may be used in (global) multi-center studies to ensure comparable results and enable efficient data abstraction. In the last two years, several standardized framework systems for positron emission tomography (PET) radiotracers with potential theranostic applications have been proposed. These include systems for prostate-specific membrane antigen (PSMA)-targeted PET agents for the diagnosis and treatment of prostate cancer (PCa) and somatostatin receptor (SSTR)-targeted PET agents for the diagnosis and treatment of neuroendocrine neoplasias. In the present review, those standardized framework systems for PSMA- and SSTR-targeted PET will be briefly introduced followed by an overview of their advantages and limitations. In addition, potential applications will be defined, approaches to validate such concepts will be proposed, and future perspectives will be discussed.
Defeat of the antibiotic resistance of pathogenic bacteria is one great challenge today and for the future. In the last century many classes of effective antibacterials have been developed, so that upcoming resistances could be met with novel drugs of various compound classes. Meanwhile, there is a certain lack of research of the pharmaceutical companies, and thus there are missing developments of novel antibiotics. Gram-positive bacteria are the most important cause of clinical infections. The number of novel antibacterials in clinical trials is strongly restricted. There is an urgent need to find novel antibacterials. We used synthetic chemistry to build completely novel hybrid molecules of substituted indoles and benzothiophene. In a simple one-pot reaction, two novel types of thienocarbazoles were yielded. Both indole substituted compound classes have been evaluated as completely novel antibacterials against the Staphylococcus and Enterococcus species. The evaluated partly promising activities depend on the indole substituent type. First lead compounds have been evaluated within in vivo studies. They confirmed the in vitro results for the new classes of small-molecule antibacterials.
The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.
Motivated by the great potential which is offered by the combination of additive manufacturing and tissue engineering, a novel polymeric bioink platform based on poly(2 oxazoline)s was developed which might help to further advance the young and upcoming field of biofabrication. In the present thesis, the synthesis as well as the characteristics of several diblock copolymers consisting of POx and POzi have been investigated with a special focus on their suitability as bioinks.
In general, the copolymerization of 2-oxazolines and 2-oxazines bearing different alkyl side chains was demonstrated to yield polymers in good agreement with the degree of polymerization aimed for and moderate to low dispersities.
For every diblock copolymer synthesized during the present study, a more or less pronounced dependency of the dynamic viscosity on temperature could be demonstrated. Diblock copolymers comprising a hydrophilic PMeOx block and a thermoresponsive PnPrOzi block showed temperature induced gelation above a degree of polymerization of 50 and a polymer concentration of 20 wt%. Such a behavior has never been described before for copolymers solely consisting of poly(cyclic imino ether)s.
Physically cross linked hydrogels based on POx b POzi copolymers exhibit reverse thermal gelation properties like described for solutions of PNiPAAm and Pluronic F127. However, by applying SANS, DLS, and SLS it could be demonstrated that the underlying gel formation mechanism is different for POx b POzi based hydrogels. It appears that polymersomes with low polydispersity are formed already at very low polymer concentrations of 6 mg/L. Increasing the polymer concentration resulted in the formation of a bicontinuous sponge like structure which might be formed due to the merger of several vesicles. For longer polymer chains a phase transition into a gyroid structure was postulated and corresponds well with the observed rheological data.
Stable hydrogels with an unusually high mechanical strength (G’ ~ 4 kPa) have been formed above TGel which could be adjusted over a range of 20 °C by changing the degree of polymerization if maintaining the symmetric polymer architecture. Variations of the chain ends revealed only a minor influence on TGel whereas the influence of the solvent should not be neglected as shown by a comparison of cell culture medium and MilliQ water.
Rotationally as well as oscillatory rheological measurements revealed a high suitability for printing as POx b POzi based hydrogels exhibit strong shear thinning behavior in combination with outstanding recovery properties after high shear stress.
Cell viability assays (WST-1) of PMeOx b PnPrOzi copolymers against NIH 3T3 fibroblasts and HaCat cells indicated that the polymers were well tolerated by the cells as no dose-dependent cytotoxicity could be observed after 24 h at non-gelling concentrations up to 100 g/L.
In summary, copolymers consisting of POx and POzi significantly increased the accessible range of properties of POx based materials. In particular thermogelation of aqueous solutions of diblock copolymers comprising PMeOx and PnPrOzi was never described before for any copolymer consisting solely of POx or POzi. In combination with other characteristics, e.g. very good cytocompatibility at high polymer concentrations and comparably high mechanical strength, the formed hydrogels could be successfully used for 3D bioprinting. Although the results appear promising and the developed hydrogel is a serious bioink candidate, competition is tough and it remains an open question which system or systems will be used in the future.
G protein-coupled receptor research looks out for new technologies to elucidate the complex
processes of receptor activation, function and downstream signaling with spatiotemporal
resolution, preferably in living cells and organisms. A thriving approach consists in making use
of the unsurpassed properties of light, including its high precision in space and time, noninvasiveness
and high degree of orthogonality regarding biological processes. This is realized
by the incorporation of molecular photoswitches, which are able to effectively respond to light,
such as azobenzene, into the structure of a ligand of a given receptor. The muscarinic
acetylcholine receptors belong to class A GPCRs and have received special attention in this
regard due to their role as a prototypic pharmacological system and their therapeutic potential.
They mediate the excitatory and inhibitory effects of the neurotransmitter acetylcholine and
thus regulate diverse important biological processes, especially many neurological functions in
our brain.
In this work, the application of photopharmacological tool compounds to muscarinic receptors
is presented, consisting of pharmacophores extended with azobenzene as light-responsive
motif. Making use of the dualsteric concept, such photochromic ligands can be designed to bind
concomitantly to the orthosteric and allosteric binding site of the receptor, which is
demonstrated for BQCAAI (M1) and PAI (M2) and may lead to subtype- and functionalselective
photoswitchable ligands, suitable for further ex vivo and in vivo studies.
Moreover, photoswitchable ligands based on the synthetic agonist iperoxo were investigated
extensively with regard to their photochemical behavior and pharmacological profile, outlining
the advantages and challenges of using red-shifted molecular photoswitches, such as tetraortho-
fluoro azobenzene. For the first time on a GPCR it was examined, which impact the
different substitution pattern has on both the binding and the activity on the M1 receptor. Results
show that substituted azobenzenes in photopharmacological compounds (F4-photoiperoxo and
F4-iper-azo-iper) not just represent analogs with other photophysical properties but can exhibit
a considerably different biological profile that has to be investigated carefully.
The achievements gained in this study can give important new insights into the binding mode
and time course of activation processes, enabling precise spatial and temporal resolution of the
complex signaling pathway of muscarinic receptors. Due to their role as exemplary model
system, these findings may be useful for the investigation into other therapeutically relevant
GPCRs.
The novel PET probe 2-deoxy-2-18F-fluoro-D-sorbitol (18F-FDS) has demonstrated favorable renal kinetics in animals. We aimed to elucidate its imaging properties in two human volunteers. 18F-FDS was produced by a simple one-step reduction from 18F-FDG. On dynamic renal PET, the cortex was delineated and activity gradually transited in the parenchyma, followed by radiotracer excretion. No adverse effects were reported. Given the higher spatiotemporal resolution of PET relative to conventional scintigraphy, 18F-FDS PET offers a more thorough evaluation of human renal kinetics. Due to its simple production from 18F-FDG, 18F-FDS is virtually available at any PET facility with radiochemistry infrastructure.
Calcium phosphate cements (CPC) represent valuable synthetic bone grafts, as they are self-setting, biocompatible, osteoconductive and in their composition similar to the inorganic phase of human bone. Due to their long shelf-life, neutral setting and since water is sufficient for setting, hydroxyapatite (HA) forming cements are processed in different paste formulations. Those comprise dual setting, Ca2+ binding and premixed cement systems. With dual setting formulations, both dissolution and precipitation of the cement raw powder occur simultaneously to the polymerization of water-soluble monomers to form a hydrogel. Chelating agents are able to form complexes with Ca2+ released from the raw powder. Premixed systems mostly contain the raw powder of the cement and a non-aqueous binder liquid which delays the setting reaction until application in the moist physiological environment. In the present work, two of those reaction mechanisms allowed the development of HA based cement applications.
Drillable cements are of high clinical interest, as the quality of screw and plate osteosynthesis techniques can be improved by cement augmentation. A drillable, dual setting composite from HA and a poly(2-hydroxyethyl methacrylate) hydrogel was analyzed with respect to the influence of monomer content and powder-to-liquid ratio on setting kinetics and mechanical outcome. While the conversion to HA and crystal growth were constantly confined with increased monomer amount, a minimum concentration of 50 % was required to see impressive ameliorations including a low bending modulus and high fracture energy at improved bending strength. Increasing the liquid amount enabled injection of the paste as well as drilling after 10 min of pre-setting.
While classic bone wax formulations have drawbacks such as infection, inflammation, hindered osteogenesis and a lack of biodegradability, the as-presented premixed formulation is believed to exhibit outmatching properties. It consisted of HA raw powders and a non-aqueous, but water-miscible carrier liquid from poly(ethylene glycol) (PEG). The bone wax was proved to be cohesive and malleable, it withstood blood pressure conditions and among deposition in an aqueous environment, PEG was exchanged such that porous, nanocrystalline HA was formed. Incorporation of a model antibiotic proved the suitability of the novel bone wax formulation for drug release purposes.
Prefabricated laminates from premixed carbonated apatite forming cement and poly(ε-caprolactone) fiber mats with defined pore architecture were presented as a potential approach for the treatment of 2-dimensional, curved cranial defects. They are flexible until application and were produced in a layer-by-layer approach from both components such that the polymer scaffold prevents the cement from flowing. It was demonstrated that solution electrospinning with a patterned collector for the fabrication of perforated fiber mats was suitable, as high fiber volume contents in combination with an appropriate interface enabled the successful fabrication of mechanically reinforced laminates. Mild immersion of the scaffolds under alkaline conditions additionally improved the interphase followed by an increase in bending-strength.
Since few years, magnesium phosphate cements (MPC) have attracted increasing attention for bone replacement. Compared to CPC, MPC exhibit a higher degradation potential and high early strength and they release biologically valuable Mg2+. However, common systems offer some challenges while using them in non-classic cement formulations such as the need for foreign ion supply, the potential acidity of the reaction or the fast setting kinetics. Here, it was possible to develop a chelate-setting MPC paste with a broad spectrum of potential applications.
The general mechanism of the novel setting principle was tested in a proof-of-principle manner. The cement paste consisted of farringtonite with differently concentrated phytic acid solution for chelate formation with Mg2+ from the raw powder. Adjusting the phytic acid content and adding a magnesium oxide as setting regulator to compensate its retarding effect resulted in drillable formulations. Additionally, there is a strong clinical demand for well working bone adhesives especially in a moist environment. Mostly the existing formulations are non-biodegradable. Ex vivo adhesion of the above presented MPC under wet conditions on bone demonstrated over a course of 7 d shear strengths of 0.8 MPa. Further, the hardened cement specimens showed a mass loss of 2 wt.% within 24 d in an aqueous environment and released about 0.17 mg/g of osteogenic Mg2+ per day. Together with the demonstrated cytocompatibility towards human fetal osteoblasts, this cement system showed promising characteristics in terms of degradable biocements with special application purposes.
An experimental setup for probing ultrafast dynamics at the diffraction limit was developed, characterized and demonstrated in the scope of the thesis, aiming for optical investigations while simultaneously approaching the physical limits on the length and timescale.
An overview of this experimental setup was given in Chapter 2, as well as the considerations that led to the selection of the individual components. Broadband laser pulses with a length of 9.3 fs, close to the transform limit of 7.6 fs, were focused in a NA = 1.4 immersion oil objective, to the diffraction limit of below 300 nm (FWHM).
The spatial focus shape was characterized with off-resonance gold nanorod scatterers scanned through the focal volume. For further insights into the functionality and limitations of the pulse shaper, its calibration procedure was reviewed. The deviations between designed and experimental pulse shapes were attributed to pulse-shaper artifacts, including voltage-dependent inter-layer as well as intra-layer LCD-pixel crosstalk, Fabry-Pérot-type reflections in the LCD layers, and space-time coupling. A pixel-dependent correction was experimentally carried out, which can be seen as an extension of the initial calibration to all possible voltage combinations of the two LCD layers.
The capabilities of the experimental setup were demonstrated in two types of experiments, targeting the nonlinearity of gold (Chapter 3) as well as two-dimensional spectroscopy at micro-structured surfaces (Chapter 4).
Investigating thin films, an upper bound for the absolute value for the imaginary part of the nonlinear refractive index of gold could be set to |n′′ 2 (Au)| < 0.6·10−16 m2/W, together with |n′ 2 (Au)| < 1.2·10−16 m2/W as an upper bound for the absolute value of the real part. Finite-difference time-domain simulations on y-shaped gold nanostructures indicated that a phase change of ∆Φ ≥ 0.07 rad between two plasmonic modes would induce a sufficient change in the spatial contrast of emission to the far-field to be visible in the experiment. As the latter could not be observed, this value of ∆Φ was determined as the upper bound for the experimentally induced phase change. An upper bound of 52 GW/cm2 was found for the damage threshold.
In Chapter 4, a novel method for nonlinear spectroscopy on surfaces was presented. Termed coherent two-dimensional fluorescence micro-spectroscopy, it is capable of exploring ultrafast dynamics in nanostructures and molecular systems at the diffraction limit. Two-dimensional spectra of spatially isolated hotspots in structured thin films of fluorinated zinc phthalocyanine (F16ZnPc) dye were taken with a 27-step phase-cycling scheme. Observed artifacts in the 2D maps were identified as a consequence from deviations between the desired and the experimental pulse shapes. The optimization procedures described in Chapter 2 successfully suppressed the deviations to a level where the separation from the nonlinear sample response was feasible.
The experimental setup and methods developed and presented in the scope of this thesis demonstrate its flexibility and capability to study microscopic systems on surfaces. The systems exemplarily shown are consisting of metal-organic dyes and metallic nanostructures, represent samples currently under research in the growing fields of organic semiconductors and plasmonics.
Plant–pathogen interactions have been widely studied, but mostly from the site of the plant secondary defense. Less is known about the effects of pathogen infection on plant primary metabolism. The possibility to transform a fluorescing protein into prokaryotes is a promising phenotyping tool to follow a bacterial infection in plants in a noninvasive manner. In the present study, virulent and avirulent Pseudomonas syringae strains were transformed with green fluorescent protein (GFP) to follow the spread of bacteria in vivo by imaging Pulse-Amplitude-Modulation (PAM) fluorescence and conventional binocular microscopy. The combination of various wavelengths and filters allowed simultaneous detection of GFP-transformed bacteria, PAM chlorophyll fluorescence, and phenolic fluorescence from pathogen-infected plant leaves. The results show that fluorescence imaging allows spatiotemporal monitoring of pathogen spread as well as phenolic and chlorophyll fluorescence in situ, thus providing a novel means to study complex plant–pathogen interactions and relate the responses of primary and secondary metabolism to pathogen spread and multiplication. The study establishes a deeper understanding of imaging data and their implementation into disease screening.
Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.
Obsessive-compulsive disorder (OCD) causes severe distress and is therefore counted by the World Health Organisation (WHO) as one of the 10 most impairing illnesses. There is evidence for a strong genetic underpinning especially in early onset OCD (eoOCD). Though several genes involved in neurotransmission have been reported as candidates, there is still a need to identify new pathways. In this study, we focussed on genetic variants of the Neuropeptide Y (NPY) system. NPY is one of the most abundant neuropeptides in the human brain with emerging evidence of capacity to modulate stress response, which is of high relevance in OCD. We focussed on tag-SNPs of NPY and its receptor gene NPY1R in a family-based approach. The sample comprised 86 patients (children and adolescents) with eoOCD with both their biological parents. However, this first study on genetic variants of the NPY-system could not confirm the association between the investigated SNPs and eoOCD. Based on the small sample size results have to be interpreted as preliminary and should be replicated in larger samples. However, also in an additional GWAS analysis in a large sample, we could not observe an associations between NPY and OCD. Overall, these preliminary results point to a minor role of NPY on the stress response of OCD.
Background
Shotgun metagenomes contain a sample of all the genomic material in an environment, allowing for the characterization of a microbial community. In order to understand these communities, bioinformatics methods are crucial. A common first step in processing metagenomes is to compute abundance estimates of different taxonomic or functional groups from the raw sequencing data.
Given the breadth of the field, computational solutions need to be flexible and extensible, enabling the combination of different tools into a larger pipeline.
Results
We present NGLess and NG-meta-profiler. NGLess is a domain specific language for describing next-generation sequence processing pipelines. It was developed with the goal of enabling user-friendly computational reproducibility. It provides built-in support for many common operations on sequencing data and is extensible with external tools with configuration files.
Using this framework, we developed NG-meta-profiler, a fast profiler for metagenomes which performs sequence preprocessing, mapping to bundled databases, filtering of the mapping results, and profiling (taxonomic and functional). It is significantly faster than either MOCAT2 or htseq-count and (as it builds on NGLess) its results are perfectly reproducible.
Conclusions
NG-meta-profiler is a high-performance solution for metagenomics processing built on NGLess. It can be used as-is to execute standard analyses or serve as the starting point for customization in a perfectly reproducible fashion.
NGLess and NG-meta-profiler are open source software (under the liberal MIT license) and can be downloaded from https://ngless.embl.de or installed through bioconda.
Immunotherapy with engineered T cells expressing a tumor-specific chimeric antigen receptor (CAR) is under intense preclinical and clinical investigation. This involves a rapidly increasing portfolio of novel target antigens and CAR designs that need to be tested in time- and work-intensive screening campaigns in primary T cells. Therefore, we anticipated that a standardized screening platform, similar as in pharmaceutical small molecule and antibody discovery, would facilitate the analysis of CARs by pre-selecting lead candidates from a large pool of constructs that differ in their extracellular and intracellular modules. Because CARs integrate structural elements of the T cell receptor (TCR) complex and engage TCR-associated signaling molecules upon stimulation, we reasoned that the transcription factors nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NFAT) could serve as surrogate markers for primary T cell function. The nuclear translocation of both transcription factors in primary T cells, which we observed following CAR stimulation, supported our rationale to use NF-κB and NFAT as indicators of CAR-mediated activation in a screening platform.
To enable standardized and convenient analyses, we have established a CAR-screening platform based on the human T cell lymphoma line Jurkat that has been modified to provide rapid detection of NF-κB and NFAT activation. For this purpose, Jurkat cells contained NF-κB and NFAT-inducible reporter genes that generate a duplex output of cyan fluorescent protein (CFP) and green fluorescent protein (GFP), respectively. Upon stimulation of NF-κB/NFAT reporter cells, the expression of both fluorophores could be readily quantified in high-throughput screening campaigns by flow cytometry.
We modified the reporter cells with CD19-specific and ROR1-specific CARs, and we co-cultured them with antigen-positive stimulator cells to analyze NF-κB and NFAT activation. CAR-induced reporter signals could already be detected after 6 hours. The optimal readout window with high-level reporter activation was set to 24 hours, allowing the CAR-screening platform to deliver results in a rapid turnaround time. A reporter cell-screening campaign of a spacer library with CARs comprising a short, intermediate or long IgG4-Fc domain allowed distinguishing functional from non-functional constructs. Similarly, reporter cell-based analyses identified a ROR1-CAR with 4-1BB domain from a library with different intracellular signal modules due to its ability to confer high NF-κB activation, consistent with data from in vitro and in vivo studies with primary T cells. The results of both CAR screening campaigns were highly reproducible, and the time required for completing each testing campaign was substantially shorter with reporter cells (6 days) compared to primary T cells (21 days). We further challenged the reporter cells in a large-scale screening campaign with a ROR1 CAR library comprising mutations in the VH CDR3 sequence of the R11 scFv. This region is crucial for binding the R11 epitope of ROR1, and we anticipated that mutations here would cause a loss of specificity and affinity for most of the CAR variants. This provided the opportunity to determine whether the CAR screening platform was able to retrieve functional constructs from a large pool of CAR variants. Indeed, using a customized pre enrichment and screening strategy, the reporter cells identified a functional CAR variant that was present with a frequency of only 6 in 1.05x10^6.
As our CAR-screening platform enabled the analysis of activating signal modules, it encouraged us to also evaluate inhibitory signal modules that change the CAR mode of action. Such an inhibitory CAR (iCAR) can be used in logic gates with an activating CAR to interfere with T cell stimulation. By selecting appropriate target antigens for iCAR and CAR, this novel application aims to improve the selectivity towards tumor cells, and it could readily be studied using our screening platform. Accordingly, we tested CD19-specific iCARs with inhibitory PD-1 signal module for their suppressive effect on reporter gene activation. In logic gates with CAR or TCR stimulation, a decrease of NF-κB and NFAT signals was only observed when activating and inhibitory receptors were forced into spatial proximity. These results were further verified by experiments with primary T cells.
In conclusion, our reporter cell system is attractive as a platform technology because it is independent of testing in primary T cells, exportable between laboratories, and scalable to enable small- to large-scale screening campaigns of CAR libraries. The pre-selection of appropriate lead candidates with optimal extracellular and intracellular modules can reduce the number of CAR constructs to be investigated in further in vitro and in vivo studies with primary T cells. We are therefore confident that our CAR-screening platform based on NF-κB/NFAT reporter cells will be useful to accelerate translational research by facilitating the evaluation of CARs with novel design parameters.
Neuroimaging research has highlighted the relevance of well-balanced functional brain interactions as an essential basis for efficient emotion regulation. In contrast, abnormal coupling of fear-processing regions such as the amygdala, the anterior cingulate cortex (ACC) and the insula could be an important feature of anxiety disorders. Although activity alterations of these regions have been frequently reported in specific phobia, little is known about their functional interactions during phobogenic stimulus processing.
To explore these interrelationships in two subtypes of specific phobia – i.e., the blood-injection-injury subtype and the animal subtype – functional connectivity (FC) was analyzed in three fMRI studies. Two studies examined fear processing in a dental phobia group (DP), a snake phobia group (SP) and a healthy control group (HC) during visual phobogenic stimuli presentation while a third study investigated differences between auditory and visual stimuli presentation in DP and HC.
Due to a priori hypotheses of impaired interactions between the amygdala, the ACC and the insula, a first analysis was conducted to explore the FC within these three regions of interest. Based on emerging evidence of functionally diverse subregions, the ACC was further divided into a subgenual, pregenual and dorsal ACC and the insula was divided into a ventral-anterior, dorsal-anterior and posterior region. Additionally, an exploratory seed-to-voxel analysis using the amygdala, ACC and insula as seeds was conducted to scan for connectivity patterns across the whole brain.
The analyses revealed a negative connectivity of the ACC and the amygdala during phobogenic stimulus processing in controls. This connectivity was predominantly driven by the affective ACC subdivision. By contrast, SP was characterized by an increased mean FC between the examined regions. Interestingly, this phenomenon was specific for auditory, but not visual symptom provocation in DP. During visual stimulus presentation, however, DP exhibited further FC alterations of the ACC and the insula with pre- and orbitofrontal regions.
These findings mark the importance of balanced interactions between fear-processing regions in specific phobia, particularly of the inhibitory connectivity between the ACC and the amygdala. Theoretically, this is assumed to reflect top-down inhibition by the ACC during emotion regulation. The findings support the suggestion that SP particularly is characterized by excitatory, or missing inhibitory, (para-) limbic connectivity, reflecting an overshooting fear response based on evolutionary conserved autonomic bottom-up pathways. Some of these characteristics applied to DP as well but only under the auditory stimulation, pointing to stimulus dependency. DP was further marked by altered pre- and orbitofrontal coupling with the ACC and the insula which might represent disturbances of superordinate cognitive control on basal emotion processes. These observations strengthen the assumption that DP is predominantly based on evaluation-based fear responses.
In conclusion, the connectivity patterns found may depict an intermediate phenotype that possibly confers risks for inappropriate phobic fear responses. The findings presented could also be of clinical interest. Particularly the ACC – amygdala circuit may be used as a predictive biomarker for treatment response or as a promising target for neuroscience-focused augmentation strategies as neurofeedback or repetitive transcranial magnetic stimulation.
Nectin‐2 is an adhesion molecule that has been reported to play a role in tumor growth, metastasis and tumor angiogenesis. Herein, we investigated Nectin‐2 in ovarian cancer patients and in cell culture. Tumor as well as peritoneal biopsies of 60 ovarian cancer patients and 22 controls were dual stained for Nectin‐2 and CD31 using immunohistochemistry. Gene expression of Nectin‐2 was quantified by real‐time PCR and differences analyzed in relation to various tumor characteristics. In the serum of patients, vascular endothelial growth factor (VEGF) was quantified by ELISA. Effect of VEGF on Nectin‐2 expression as well as permeability was investigated in HUVEC. In tumor biopsies, Nectin‐2 protein was mainly localized in tumor cells, whereas in peritoneal biopsies, clear colocalization was found in the vasculature. T3 patients had a significantly higher percentage of positive lymph nodes and this correlated with survival. Nectin‐2 was significantly upregulated in tumor biopsies in patients with lymph node metastasis and with residual tumor >1 cm after surgery. Nectin‐2 expression was significantly suppressed in the peritoneal endothelium of patients associated with significantly increased VEGF serum levels. In cell culture, VEGF stimulation led to a significant downregulation of Nectin‐2 which was reversed by VEGF‐inhibition. In addition, Nectin‐2 knockdown in endothelial cells was associated with significantly increased endothelial permeability. Nectin‐2 expression in ovarian cancer may support tumor cell adhesion, leading to growth and lymph node metastasis. In addition, VEGF‐induced Nectin‐2 suppression in peritoneal endothelium may support an increase in vascular permeability leading to ascites production.
Background
Incontinentia Pigmenti is a rare disease affecting multiple organs. Fifty of patients show affection of the eye with retinopathy and possible amaurosis being the worst outcome. Treatment has commonly been panretinal laser coagulation but intravitreal application of bevacizumab as VEGF-inhibitor has shown to effectively suppress retinal neovascularization.
Case presentation
A six-week-old female infant with Incontinentia Pigmenti developed a foudroyant necrotizing enterocolitis shortly after intravitreal injection of bevazicumab due to a retinopathy with impending tractional detachment of the left eye. Since the onset of abdominal symptoms occurred immediately after the intravitreal application, a link between the two events seemed likely. Sequential analyses of the VEGF serum concentrations showed a massive suppression of endogenous VEGF with only a very slow recovery over weeks. Such a severe systemic adverse event has not been reported after intravitreal treatment with bevacizumab in an infant.
Conclusion
This case report shows a relevant systemic uptake of bevacizumab after intravitreal application as suppressed VEGF levels show. There seems to be a connection between suppressed VEGF levels and the onset of necrotizing enterocolitis. Therefore, treatment with bevacizumab should be carefully considered and further research is needed to assess this drug’s safety profile.
In this work, two new quadrupolar A-π-D-π-A chromophores have been prepared featuring a strongly electron- donating diborene core and strongly electron-accepting dimesitylboryl F(BMes2) and bis(2,4,6-tris(trifluoromethyl)phenyl)boryl (BMes2) end groups. Analysis of the compounds by NMR spectroscopy, X-ray crystallography, cyclic voltammetry and UV-vis-NIR absorption and emission spectroscopy indicated that the compounds possess extended conjugated π-systems spanning their B4C8 cores. The combination of exceptionally potent π-donor (diborene) and π- acceptor (diarylboryl) groups, both based on trigonal boron, leads to very small HOMO-LUMO gaps, resulting in strong absorption in the near-IR region with maxima in THF at 840 and 1092 nm, respectively, and very high extinction coefficients of ca. 120,000 M-1cm-1. Both molecules also display weak near-IR fluorescence with small Stokes shifts.
The aim of this thesis was the application of the functional prepolymer NCO-sP(EO-stat-PO) for the development of new biomaterials. First, the influence of the star-shaped polymers on the mechanical properties of biocements and bone adhesives was investigated. 3-armed star-shaped macromers were used as an additive for a mineral bone cement, and the influence on the mechanical properties was studied. Additionally, a previously developed bone adhesive was examined regarding cytocompatibility. The second topic was the examination of novel functionalization steps which were performed on the surface of electrospun fibers modified with NCO-sP(EO-stat-PO). This established method of functionalizing electrospun meshes was advanced regarding the modification with proteins which was then demonstrated in a biological application. Two different kinds of antibodies were immobilized on the fiber surface in a consecutive manner and the influence of these proteins on the cell behavior was investigated. The final topic involved the quantification of surface-bound peptide sequences. By functionalization of the peptides with the UV-reactive molecule 2-mercaptopyridine it was possible to quantify this compound via UV measurements by cleavage of disulfide bridges and indirectly draw conclusions about the number of immobilized peptides.
In the field of mineral biocements and bone adhesives, NCO-sP(EO-stat-PO) was able to influence the setting behavior and mechanical performance of mineral bone cements based on calcium phosphate chemistry. The addition of NCO-sP(EO-stat-PO) resulted in a pseudo-ductile fracture behavior due to the formation of a hydrogel network in the cement, which was then mineralized by nanosized hydroxyapatite crystals following cement setting. Accordingly, a commercially available aluminum silicate cement from civil engineering could be modified.
In addition, it could be shown that the use of NCO-sP(EO-stat-PO) is beneficial for adjusting specific material properties of bone adhesives. Here, the crosslinking behavior of the prepolymer in an aqueous medium was exploited to form an interpenetrating network (IPN) together with a photochemically curing poly(ethylene glycol) dimethacrylate (PEGDMA) matrix. This could be used for the development of a bone adhesive with an improved adhesion to bone in a wet environment. The developed bone adhesive was further investigated in terms of possible influences of the initiator systems. In addition, the material system was tested for cytocompatibility by using different cell lines.
Moreover, the preparation of electrospun fiber meshes via solution electrospinning consisting of poly(lactide-co-glycolide) (PLGA) as a backbone polymer and NCO-sP(EO-stat-PO) as functional additive is an established method for the application of the meshes as a replacement of the native extracellular matrix (ECM). In general, these fibers reveal diameters in the nanometer range, are protein and cell repellent due to the hydrophilic properties of the prepolymer and show a specific biofunctionalization by immobilization of peptide sequences. Here, the isocyanate groups presented on the fiber surface after electrospinning were used to carry out various functionalization steps, while retaining the properties of protein and cell repellency. The modification of the electrospun fibers involved the immobilization of analogs or antagonists of tumor necrosis factor (TNF) and the indirect detection of these by interaction with a light-producing enzyme. Here, a multimodal modification of the fiber surface with RGD to mediate cell adhesion and two different antibodies could be achieved. After culturing the cell line HT1080, the pro- or anti-inflammatory response of cells could be detected by IL-8 specific ELISA measurements.
Furthermore, the quantification of molecules on the surface of electrospun fibers was investigated. It was tested whether the detection by means of super-resolution microscopy would be possible. Therefore, experiments were performed with short amino acid sequences such as RGD for quantification by fluorescence microscopy. Based on earlier results, in which a UV-spectrometrically active molecule was used to detect the quantification of RGD, it was shown that short peptides can also be quantified in a small scale on flat functional substrates (2D) such as NCO-sP(EO-stat-PO) hydrogel coatings, and modified electrospun fibers produced from PLGA and NCO-sP(EO-stat-PO) (3D). In addition, a collagen sequence was used to prove that a successful quantification can be carried out as well for longer peptide chains.
These studies have revealed that NCO-sP(EO-stat-PO) can serve as a functional additive for many applications and should be considered for further studies on the development of novel biomaterials. The rapid crosslinking reaction, the resulting hydrogel formation and the biocompatibility are to be mentioned as positive properties, which makes the prepolymer interesting for future applications.
Background:
Colonic cancer is the most common cancer of the gastrointestinal tract. The aim of this study was to determine mortality rates following colonic cancer resection and the effect of hospital caseload on in-hospital mortality in Germany.
Methods:
Patients admitted with a diagnosis of colonic cancer undergoing colonic resection from 2012 to 2015 were identifed from a nationwide registry using procedure codes. The outcome measure was in-hospital mortality. Hospitals were ranked according to their caseload for colonic cancer resection, and patients were categorized into five subgroups on the basis of hospital volume.
Results:
Some 129 196 colonic cancer resections were reviewed. The overall in-house mortality rate was 5⋅8 per cent, ranging from 6⋅9 per cent (1775 of 25 657 patients) in very low-volume hospitals to 4⋅8 per cent (1239 of 25 825) in very high-volume centres (P < 0⋅001). In multivariable logistic regression analysis the risk-adjusted odds ratio for in-house mortality was 0⋅75 (95 per cent c.i. 0⋅66 to 0⋅84) in very high-volume hospitals performing a mean of 85⋅0 interventions per year, compared with that in very low-volume hospitals performing a mean of only 12⋅7 interventions annually, after adjustment for sex, age, co-morbidity, emergency procedures, prolonged mechanical ventilation and transfusion.
Conclusion:
In Germany, patients undergoing colonic cancer resections in high-volume hospitals had with improved outcomes compared with patients treated in low-volume hospitals
Background: Cancer patients are increasingly treated with alpha-particle-emitting radiopharmaceuticals. At the subcellular level, alpha particles induce densely spaced ionizations and molecular damage. Induction of DNA lesions, especially clustered DNA double-strand breaks (DSBs), threatens a cell's survival. Currently, it is under debate to what extent the spatial topology of the damaged chromatin regions and the repair protein arrangements are contributing. Methods: Super-resolution light microscopy (SMLM) in combination with cluster analysis of single molecule signal-point density regions of DSB repair markers was applied to investigate the nano-structure of DNA damage foci tracks of Ra-223 in-solution irradiated leukocytes. Results: Alpha-damaged chromatin tracks were efficiently outlined by γ-H2AX that formed large (super) foci composed of numerous 60–80 nm-sized nano-foci. Alpha damage tracks contained 60–70% of all γ-H2AX point signals in a nucleus, while less than 30% of 53BP1, MRE11 or p-ATM signals were located inside γ-H2AX damage tracks. MRE11 and p-ATM protein fluorescent tags formed focal nano-clusters of about 20 nm peak size. There were, on average, 12 (±9) MRE11 nanoclusters in a typical γ-H2AX-marked alpha track, suggesting a minimal number of MRE11-processed DSBs per track. Our SMLM data suggest regularly arranged nano-structures during DNA repair in the damaged chromatin domain.
N‐heterocyclic olefins (NHOs), relatives of N‐heterocyclic carbenes (NHCs), exhibit high nucleophilicity and soft Lewis basic character. To investigate their π‐electron donating ability, NHOs were attached to triarylborane π‐acceptors (A) giving donor (D)–π–A compounds 1–3. In addition, an enamine π‐donor analogue (4) was synthesized for comparison. UV–visible absorption studies show a larger red shift for the NHO‐containing boranes than for the enamine analogue, a relative of cyclic (alkyl)(amino) carbenes (CAACs). Solvent‐dependent emission studies indicate that 1–4 have moderate intramolecular charge‐transfer (ICT) behavior. Electrochemical investigations reveal that the NHO‐containing boranes have extremely low reversible oxidation potentials (e.g., for 3, \(E^{ox}_{1/2}\) =−0.40 V vs. ferrocene/ferrocenium, Fc/Fc\(^+\), in THF). Time‐dependent (TD) DFT calculations show that the HOMOs of 1–3 are much more destabilized than that of the enamine‐containing 4, which confirms the stronger donating ability of NHOs.
MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.
Synchronization of coupled oscillators at the transition between classical physics and quantum physics has become an emerging research topic at the crossroads of nonlinear dynamics and nanophotonics. We study this unexplored field by using quantum dot microlasers as optical oscillators. Operating in the regime of cavity quantum electrodynamics (cQED) with an intracavity photon number on the order of 10 and output powers in the 100 nW range, these devices have high β-factors associated with enhanced spontaneous emission noise. We identify synchronization of mutually coupled microlasers via frequency locking associated with a sub-gigahertz locking range. A theoretical analysis of the coupling behavior reveals striking differences from optical synchronization in the classical domain with negligible spontaneous emission noise. Beyond that, additional self-feedback leads to zero-lag synchronization of coupled microlasers at ultra-low light levels. Our work has high potential to pave the way for future experiments in the quantum regime of synchronization.
Protein kinase A (PKA) is the main effector of cyclic-adenosine monophosphate (cAMP) and plays an important role in steroidogenesis and proliferation of adrenal cells. In a previous study we found two mutations (L206R, 199_200insW) in the main catalytic subunit of protein kinase A (PKA C) to be responsible for cortisol-producing adrenocortical adenomas (CPAs). These mutations interfere with the formation of a stable holoenzyme, thus causing constitutive PKA activation. More recently, we identified additional mutations affecting PKA C in CPAs associated with overt Cushing syndrome: S213R+insIILR, 200_201insV, W197R, d244 248+E249Q, E32V.
This study reports a functional characterization of those PKA Cmutations linked to CPAs of Cushing’s patients. All analyzed mutations except for E32V showed a reduced interaction with at least one tested regulatory (R) subunit. Interestingly the results of the activity differed among the mutants and between the assays employed. For three mutants (L206R, 199_200insW, S213R+insIILR), the results showed enhanced translocation to the nucleus. This was also observed in CRISPR/Cas9 generated PRKACA L206R mutated HEK293T cells. The enhanced nuclear translocation of this mutants could be due to the lack of R subunit binding, but also other mechanisms could be at play. Additionally, I used an algorithm, which predicted an effect of the mutation on substrate specificity for four mutants (L206R, 199_200insW, 200_201insV, d244 248+E249Q). This was proven using phosphoproteomics for three mutants (L206R, 200_201insV, d244 248+E249Q). In PRKACA L206R mutated CPAs this change in substrate specificity also caused hyperphosphorylation of H1.4 on serine 36, which has been reported to be implicated in mitosis. Due to these observations, I hypothesized, that there are several mechanisms of action of PRKACA mutations leading to increased cortisol secretion and cell proliferation in adrenal cells: interference with the formation of a stable holoenzyme, altered subcellular localization and a change in substrate specificity. My data indicate that some PKA C mutants might act via just one, others by a combination of these mechanisms. Altogether, these findings indicate that several mechanisms contribute to the development of CPAs caused by PRKACA mutations. Moreover, these findings provide a highly illustrative example of how alterations in a protein kinase can cause a human disease.
(1) Background: After the discovery and application of Chlamydomonas reinhardtii channelrhodopsins, the optogenetic toolbox has been greatly expanded with engineered and newly discovered natural channelrhodopsins. However, channelrhodopsins of higher Ca\(^{2+}\) conductance or more specific ion permeability are in demand. (2) Methods: In this study, we mutated the conserved aspartate of the transmembrane helix 4 (TM4) within Chronos and PsChR and compared them with published ChR2 aspartate mutants. (3) Results: We found that the ChR2 D156H mutant (XXM) showed enhanced Na\(^+\) and Ca\(^{2+}\) conductance, which was not noticed before, while the D156C mutation (XXL) influenced the Na\(^+\) and Ca\(^{2+}\) conductance only slightly. The aspartate to histidine and cysteine mutations of Chronos and PsChR also influenced their photocurrent, ion permeability, kinetics, and light sensitivity. Most interestingly, PsChR D139H showed a much-improved photocurrent, compared to wild type, and even higher Na+ selectivity to H\(^+\) than XXM. PsChR D139H also showed a strongly enhanced Ca\(^{2+}\) conductance, more than two-fold that of the CatCh. (4) Conclusions: We found that mutating the aspartate of the TM4 influences the ion selectivity of channelrhodopsins. With the large photocurrent and enhanced Na\(^+\) selectivity and Ca\(^{2+}\) conductance, XXM and PsChR D139H are promising powerful optogenetic tools, especially for Ca\(^{2+}\) manipulation.
We consider the process of muon-electron elastic scattering, which has been proposed as an ideal framework to measure the running of the electromagnetic coupling constant at space-like momenta and determine the leading-order hadronic contribution to the muon g-2 (MUonE experiment). We compute the next-to-leading (NLO) contributions due to QED and purely weak corrections and implement them into a fully differential Monte Carlo event generator, which is available for first experimental studies. We show representative phenomenological results of interest for the MUonE experiment and examine in detail the impact of the various sources of radiative corrections under different selection criteria, in order to study the dependence of the NLO contributions on the applied cuts. The study represents the first step towards the realisation of a high-precision Monte Carlo code necessary for data analysis.
The aim of this thesis was to develop new automatic enhanced sampling methods by extending the idea of Parrinello’s metadynamics to multistate problems and by introducing new quantum-mechanical electronic collective variables. These methods open up a rich perspective for applications to the photophysical processes in complex molecular systems, which play a major role in many natural processes such as vision and photosynthesis, but also in the development of new materials for organic electronics, whose function depends on specific electronic properties such as biradicalicity.
The link between multi‐host use and host switching in host–parasite interactions is a continuing area of debate. Lycaenid butterflies in the genus Maculinea, for example, exploit societies of different Myrmica ant species across their ranges, but there is only rare evidence that they simultaneously utilise multiple hosts at a local site, even where alternative hosts are present.
We present a simple population‐genetic model accounting for the proportion of two alternative hosts and the fitness of parasite genotypes on each host. In agreement with standard models, we conclude that simultaneous host use is possible whenever fitness of heterozygotes on alternative hosts is not too low.
We specifically focus on host‐shifting dynamics when the frequency of hosts changes. We find that (i) host shifting may proceed so rapidly that multiple host use is unlikely to be observed, (ii) back and forth transition in host use can exhibit a hysteresis loop, (iii) the parasites' host use may not be proportional to local host frequencies and be restricted to the rarer host under some conditions, and (iv) that a substantial decline in parasite abundance may typically precede a shift in host use.
We conclude that focusing not just on possible equilibrium conditions but also considering the dynamics of host shifting in non‐equilibrium situations may provide added insights into host–parasite systems.
Advances in remote inventory and analysis of forest resources during the last decade have reached a level to be now considered as a crucial complement, if not a surrogate, to the long-existing field-based methods. This is mostly reflected in not only the use of multiple-band new active and passive remote sensing data for forest inventory, but also in the methodic and algorithmic developments and/or adoptions that aim at maximizing the predictive or calibration performances, thereby minimizing both random and systematic errors, in particular for multi-scale spatial domains. With this in mind, this editorial note wraps up the recently-published Remote Sensing special issue “Remote Sensing-Based Forest Inventories from Landscape to Global Scale”, which hosted a set of state-of-the-art experiments on remotely sensed inventory of forest resources conducted by a number of prominent researchers worldwide.
Background
Atrial fibrillation (AF) without other stroke risk factors is assumed to have a low annual stroke risk comparable to patients without AF. Therefore, current clinical guidelines do not recommend oral anticoagulation for stroke prevention of AF in patients without stroke risk factors. We analyzed brain magnetic resonance imaging (MRI) imaging to estimate the rate of clinically inapparent (“silent”) ischemic brain lesions in these patients.
Methods
We pooled individual patient-level data from three prospective studies comprising stroke-free patients with symptomatic AF. All study patients underwent brain MRI within 24–48 h before planned left atrial catheter ablation. MRIs were analyzed by a neuroradiologist blinded to clinical data.
Results
In total, 175 patients (median age 60 (IQR 54–67) years, 32% female, median CHA\(_2\)DS\(_2\)-VASc = 1 (IQR 0–2), 33% persistent AF) were included. In AF patients without or with at least one stroke risk factor, at least one silent ischemic brain lesion was observed in 4 (8%) out of 48 and 10 (8%) out of 127 patients, respectively (p > 0.99). Presence of silent ischemic brain lesions was related to age (p = 0.03) but not to AF pattern (p = 0.77). At least one cerebral microbleed was detected in 5 (13%) out of 30 AF patients without stroke risk factors and 25 (25%) out of 108 AF patients with stroke risk factors (p = 0.2). Presence of cerebral microbleeds was related to male sex (p = 0.04) or peripheral artery occlusive disease (p = 0.03).
Conclusion
In patients with symptomatic AF scheduled for ablation, brain MRI detected silent ischemic brain lesions in approximately one in 12 patients, and microbleeds in one in 5 patients. The prevalence of silent ischemic brain lesions did not differ in AF patients with or without further stroke risk factors.
The mechanisms behind carbon dioxide (CO2) dependency in non-autotrophic bacterial isolates are unclear. Here we show that the Staphylococcus aureus mpsAB operon, known to play a role in membrane potential generation, is crucial for growth at atmospheric CO2 levels. The genes mpsAB can complement an Escherichia coli carbonic anhydrase (CA) mutant, and CA from E. coli can complement the S. aureus delta-mpsABC mutant. In comparison with the wild type, S. aureus mps mutants produce less hemolytic toxin and are less virulent in animal models of infection. Homologs of mpsA and mpsB are widespread among bacteria and are often found adjacent to each other on the genome. We propose that MpsAB represents a dissolved inorganic carbon transporter, or bicarbonate concentrating system, possibly acting as a sodium bicarbonate cotransporter.
Promising initial insights show that offices designed to permit physical activity (PA) may reduce workplace sitting time. Biophilic approaches are intended to introduce natural surroundings into the workplace, and preliminary data show positive effects on stress reduction and elevated productivity within the workplace. The primary aim of this pilot study was to analyze changes in workplace sitting time and self-reported habit strength concerning uninterrupted sitting and PA during work, when relocating from a traditional office setting to “active” biophilic-designed surroundings. The secondary aim was to assess possible changes in work-associated factors such as satisfaction with the office environment, work engagement, and work performance, among office staff. In a pre-post designed field study, we collected data through an online survey on health behavior at work. Twelve participants completed the survey before (one-month pre-relocation, T1) and twice after the office relocation (three months (T2) and seven months post-relocation (T3)). Standing time per day during office hours increased from T1 to T3 by about 40 min per day (p < 0.01). Other outcomes remained unaltered. The results suggest that changing office surroundings to an active-permissive biophilic design increased standing time during working hours. Future larger-scale controlled studies are warranted to investigate the influence of office design on sitting time and work-associated factors during working hours in depth.
The role of multicellularity as the predominant microbial lifestyle has been affirmed by studies on the genetic regulation of biofilms and the conditions driving their formation. Biofilms are of prime importance for the pathology of chronic infections of the opportunistic human pathogen Staphylococcus aureus.
The recent development of a macrocolony biofilm model in S. aureus opened new opportunities to study evolution and physiological specialization in biofilm communities in this organism. In the macrocolony biofilm model, bacteria form complex aggregates with a sophisticated spatial organization on the micro- and macroscale. The central positive and negative regulators of this organization in S. aureus are the alternative sigma factor σB and the quorum sensing system Agr, respectively. Nevertheless, nothing is known on additional factors controlling the macrocolony morphogenesis.
In this work, the genome of S. aureus was screened for novel factors that are required for the development of the macrocolony architecture. A central role for basic metabolic pathways was demonstrated in this context as the macrocolony architecture was strongly altered by the disruption of nucleotide and carbohydrate synthesis. Environmental signals further modulate macrocolony morphogenesis as illustrated by the role of an oxygen-sensitive gene regulator, which is required for the formation of complex surface structures. A further application of the macrocolony biofilm model was demonstrated in the study of interstrain interactions. The integrity of macrocolony communities was macroscopically visibly disturbed by competitive interactions between clinical isolates of S. aureus.
The results of this work contribute to the characterization of the macrocolony biofilm model and improve our understanding of developmental processes relevant in staphylococcal infections. The identification of anti-biofilm effects exercised through competitive interactions could lead to the design of novel antimicrobial strategies targeting multicellular bacterial communities.
Morphological and Functional Ultrashort Echo Time (UTE) Magnetic Resonance Imaging of the Human Lung
(2019)
In this thesis, a 3D Ultrashort echo time (3D-UTE) sequence was introduced in the Self-gated Non-Contrast-Enhanced Functional Lung Imaging (SENCEFUL) framework. The sequence was developed and implemented on a 3 Tesla MR scanner. The 3D-UTE technique consisted of a nonselective RF pulse followed by a koosh ball quasi-random sampling order of the k-space. Measurements in free-breathing and without contrast agent were performed in healthy subjects and a patient with lung cancer.
A gating technique, using a combination of different coils with high signal correlation, was evaluated in-vivo and compared with a manual approach of coil selection. The gating signal offered an estimation of the breathing motion during measurement and was used as a reference to segment the acquired data into different breathing phases.
Gradient delays and trajectory errors were corrected during post-processing using the Gradient Impulse Response Function. Iterative SENSE was then applied to determine the fully sampled data.
In order to eliminate signal changes caused by motion, a 3D image registration was employed, and the results were compared to a 2D image registration method.
Ventilation was assessed in 3D and regionally quantified by monitoring the signal changes in the lung parenchyma. Finally, image quality and quantitative ventilation values were compared to the standard 2D-SENCEFUL technique.
3D-UTE, combined with an automatic gating technique and SENCEFUL MRI, offered ventilation maps with high spatial resolution and SNR. Compared to the 2D method, UTE-SENCEFUL greatly improved the clinical quality of the structural images and the visualization of the lung parenchyma.
Through‐plane motion, partial volume effects and ventilation artifacts were also reduced with a three-dimensional method for image registration.
UTE-SENCEFUL was also able to quantify regional ventilation and presented similar results to previous studies.
Background
Ureaplasma species (spp.) are commonly regarded as low-virulent commensals but may cause invasive diseases in immunocompromised adults and in neonates, including neonatal meningitis. The interactions of Ureaplasma spp. with host defense mechanisms are poorly understood. This study addressed Ureaplasma-driven cell death, concentrating on apoptosis as well as inflammatory cell death.
Methods
Human brain microvascular endothelial cells (HBMEC) were exposed to Ureaplasma (U.) urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). Resulting numbers of dead cells as well as mRNA levels and enzyme activity of key agents in programmed cell death were assessed by flow cytometry, RNA sequencing, and qRT-PCR, respectively. xCELLigence data were used for real-time monitoring of changes in cell adhesion properties.
Results
Both Ureaplasma isolates induced cell death (p < 0.05, vs. broth). Furthermore, Ureaplasma spp. enhanced mRNA levels for genes in apoptosis, including caspase 3 (Up3 p < 0.05, vs. broth), caspase 7 (p < 0.01), and caspase 9 (Up3 p < 0.01). Caspase 3 activity was increased upon Uu8 exposure (p < 0.01). Vice versa, Ureaplasma isolates downregulated mRNA levels for proteins involved in inflammatory cell death, namely caspase 1 (Uu8 p < 0.01, Up3 p < 0.001), caspase 4 (Uu8 p < 0.05, Up3 p < 0.01), NOD-like receptor pyrin domain-containing 3 (Uu8 p < 0.05), and receptor-interacting protein kinase 3 (p < 0.05).
Conclusions
By inducing apoptosis in HBMEC as main constituents of the blood-brain barrier, Ureaplasma spp. may provoke barrier breakdown. Simultaneous suppression of inflammatory cell death may additionally attenuate host defense strategies. Ultimate consequence could be invasive and long-term CNS infections by Ureaplasma spp.
Statistical Procedures for modelling a random phenomenon heavily depend on the choice of a certain family of probability distributions. Frequently, this choice is governed by a good mathematical feasibility, but disregards that some distribution properties may contradict reality. At most, the choosen distribution may be considered as an approximation. The present thesis starts with a construction of distributions, which uses solely available information and yields distributions having greatest uncertainty in the sense of the maximum entropy principle. One of such distributions is the monotonic distribution, which is solely determined by its support and the mean. Although classical frequentist statistics provides estimation procedures which may incorporate prior information, such procedures are rarely considered. A general frequentist scheme for the construction of shortest confidence intervals for distribution parameters under prior information is presented. In particular, the scheme is used for establishing confidence intervals for the mean of the monotonic distribution and compared to classical procedures. Additionally, an approximative procedure for the upper bound of the support of the monotonic distribution is proposed. A core purpose of auditing sampling is the determination of confidence intervals for the mean of zero-inflated populations. The monotonic distribution is used for modelling such a population and is utilised for the procedure of a confidence interval under prior information for the mean. The results are compared to two-sided intervals of Stringer-type.
The study of ultrafast dynamics is a new tool to understand and control the properties of correlated oxides. By enhancing some properties and realizing new dynamically excited phrases, this tool has opened new routes for technological applications. LaCoO3 is one paradigmatic example where the strong electron, spin, and lattice coupling induced by electronic correlations results in a low-temperature spin transition and a high-temperature semiconductor-to-metal transition that is still not completely understood. Here, we monitor ultrafast metallization in LaCoO3 using time-resolved soft x-ray reflectivity experiments. While the process is entangled at the Co L3 edge, the time information of the different channels is decrypted at different resonant energies of the O K edge. Metallization is shown to occur via transient electronic, spin, and lattice separation. Our results agree with the thermodynamical model and demonstrate the potential of femtosecond soft x-ray experiments at the O K edge to understand correlated oxides.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.
Woodhouse-Sakati syndrome (WSS) is a rare multisystemic, autosomal recessive disease. The underlying cause of WSS are mutations of C2orf37 gene, which result in a truncated protein. Little is known about the function of C2orf37 (DDB1-CUL4A-associated factor 17, DCAF17) apart from it being part of the DDB1-CUL4-ROC1 E3 ubiquitin ligase complex, specifically binding directly to DDB1 and serving as a substrate recruiter for E3. There are two major isoforms of DCAF17: beta (65 kDa, 520 amino acids) and alpha (27 kDa, 240 amino acids), which is a C-terminal part of beta. The intracellular localization of the WSS protein is thought to be primarily the nucleolus. A murine ortholog protein was found to be expressed in all tissues with a relatively higher expression in the brain, liver, and skin.The aim of this work was to investigate DCAF17 in HeLa cells in more detail, in particular the redistribution of both WSS isoforms on the subcellular and -nuclear level as well as their chemical features. For these experiments, I developed, through recombinant expression and affinity purification, a specific polyclonal antibody against a WSS-epitope 493-520. Furthermore, three other specific polyclonal antibodies were obtained through affinity purification with help of commercially produced high-affinity epitope peptides.By means of these antibodies, I determined- through immunofluorescence and subcellular protein fractionation- that, apart from the redistribution of the WSS protein within the non-soluble = chromatin-bound nuclear fraction, a significant amount of both WSS isoforms is present in the soluble nuclear fraction. Indeed, treatment of purified nuclear envelopes with an increasing concentration of NaCl as well as urea confirmed a non-covalent binding of the WSS protein to the nuclear envelope with the detachment ofbeta-WSS at a lower NaCl concentration than alpha-WSS. In regard to the chromatin-bound WSS protein, I performed hydrolysis of nuclear and nucleolar extract with DNase and RNase. The results indicate that the WSS protein is bound to DNA but not RNA, with alpha-WSS being possibly located more abundantly in the nucleolus, whereas beta-WSS within other subnuclear departments. Furthermore, in all the above-mentioned experiments, a presence of an 80-kDa protein, which specifically reacted with the polyclonal high-affinity antibodies and showed similar redistribution and chemical features as alpha- and beta-WSS, was observed. In order to investigate whether this protein is a posttranslationally modified WSS isoform, I performed deglycosylation and dephosphorylation of nuclear extract, which showed no disappearance or change in abundance of the 80-kDa band on Western blot. While other ways of poststranslational modification cannot be excluded as the cause of occurrence of the 80-kDa protein, an existence of a third, yet undescribed, major isoform is also conceivable. Summarizing, this work contributed to a deeper characterization of the WSS protein, which can help future investigators in developing new experimental ideas to better understand the pathology of WSS.
Molecular Effects of Polyphenols in Experimental Type 2 Diabetes Mellitus and Metabolic Syndrome
(2019)
The growing prevalence of type 2 diabetes mellitus (T2DM) demands novel therapeutic and adjuvant strategies. Polyphenols (PPs) are plant secondary metabolites. Epidemiological studies demonstrate an inverse relationship between their increased intake and the risk of development of T2DM and cardiovascular complications. However, the PPs’ mechanism of action remains largely unknown. The present work aimed to expand knowledge regarding the effects of PPs on diabetes relevant molecular targets.
Pycnogenol® (PYC) is a standardized pine bark extract which consists of oligomeric and monomeric PPs. Its anti-diabetic effects have been demonstrated in clinical trials. As a part of a human study involving 20 healthy volunteers, the extract’s effects on dipeptidyl peptidase IV (DPP IV) were investigated. This protease terminates the insulin secretagogue action of incretins. Its inhibition is a promising strategy in T2DM treatment. This study uncovered that PYC-intake of 100 mg daily over 14 days statistically significantly reduced DPP IV serum concentrations by 8.2 % (n= 38, p= 0.032). Contrary to expectations, this decrease was not paralleled by a reduction in the serum DPP IV enzymatic activity. To the best of our knowledge, the present study was the first investigating the effects of PPs on DPP IV serum concentrations and activities in humans. The finding that PYC is capable of reducing DPP IV serum concentrations might be important with regard to diabetes, where DPP IV levels are increased.
Screenings for PPs’ in vitro effects on DPP IV activity were performed employing a purified enzyme. The effects of tested PPs (among which PYC ingredients) at a physiologically relevant concentration of 5 µM were weak (< 10 %) and too small compared to the reference compound sitagliptin, and thus not likely to be clinically relevant. This result is in discordance with some published data, but consistent with the outcome from the present human study. In addition, fluorescence interactions with the experimental setup were registered: under certain conditions urolithin B exhibited an autofluorescence which might mask eventual inhibitory activity. Quercetin quenched the fluorescence slightly which might contribute to false positive results. No statistically significant effects of selected constituents and metabolites of PYC on the total DPP IV protein expression were observed in 3T3-L1 adipocytes. Thus, the lower DPP IV in vivo concentrations after intake of PYC cannot be explained with down-regulation of the DPP IV expression in adipocytes.
Akt kinase is responsible for the transmission of insulin signals and its dysregulation is related to insulin resistance and plays an important role in development of cardiovascular complications in T2DM. Thus, the modulation of the phosphorylation status of endothelial Akt-kinase, respectively its activity, might be a promising strategy in the management of these pathologies. This work aimed to uncover the effects of PPs from different structural subclasses on Akt-phosphorylation (pAkt) in endothelial cells (Ea.hy926). Short-term effects (5 – 30 min) were investigated at a concentration of 10 µM. In a pilot study two model PPs induced a moderate, but reproducible inhibition of pAkt Ser473 of 52.37 ± 21.01 % (quercetin; p= 0.006, n= 3) and 37.79 ± 7.14 % (resveratrol; p= 0.021, n= 4) compared to the negative control. A primary screening with Western blot analysis investigated the effects of eight compounds from different subclasses on pAkt Ser473 and Thr308 to reveal whether the observed inhibition PPs a group effect or specific to certain compounds. In addition to resveratrol and quercetin, statistically significant inhibitions of pAkt Ser473 were induced by luteolin (29.96 ± 11.06 %, p< 0.01, n= 6) and apigenin (22.57 ± 10.30 %, p< 0.01, n= 6). In contrast, genistein, 3,4,5-trimethoxystilbene, taxifolin and (+)-catechin caused no inhibition. A strong positive and statistically significant correlation between the mean inhibitory effects of the tested PPs on both Akt-residues Ser473 and Thr308 (r= 0.9478, p= 0.0003) was determined. A comprehensive secondary screening via ELISA involving 44 compounds from nine structural groups quantified the effects of PPs on pAkt Ser473 to uncover potential structure-activity features. The most potent inhibitors were luteolin (44.31 ± 17.95 %), quercetin (35.71 ± 8.33 %), urolithin A (35.28 ± 11.80 %), apigenin (31.79 ± 6.16 %), fisetin (28.09 ± 9.09 %), and resveratrol (26.04 ± 5.58 %). These effects were statistically significant (p< 0.01, n= 3 to 6). Further lead structure optimization might be based on the fact that the effects of luteolin and resveratrol also differed statistically significantly from each other (p= 0.008).
To the best of our knowledge, the present study is the first to compare quantitatively the short term effects of PPs from different subclasses on pAkt in endothelial cells. Basic structure-activity relationships revealed that for flavones and flavonols the presence of a C2=C3 double bond (ring C) was essential for inhibitory activity and hydroxylation on the m- and p- positions in the ring B contributed to it. For stilbenoids, three free OH-groups appeared to be optimal. The comparison of the inhibitory potentials of ellagic acid and its microbial metabolites showed that urolithin A was statistically significantly more effective than its progenitor compound. Despite their structural similarities, the only active compound among all urolithins tested was urolithin A, hydroxylated at the C3 and C8 positions. This suggested a specific effect for urolithin A. Based on the common structural determinants and molecular geometry of the most active PPs a pharmacophore model regarding Akt-inhibition was proposed.
In summary, the effects of a wide variety of PPs from diverse structural subclasses on the in vitro phosphorylation of endothelial Akt were quantitatively analyzed for the first time, the effects of previously undescribed compounds were determined and structure activity relationships were elucidated. The inhibitory potential of individual PPs might be beneficial in cases of sustained over-activation of Akt-kinase and its substrates such as S6 kinase as reported for certain T2DM-related pathological states, such as insulin resistance, endothelial dysfunction, excessive angiogenesis, vascular calcification, and insulin triggered DNA-damage. The results of the present work suggest potential molecular mechanisms of action of PP involving Akt-inhibition and DPP IV-down-regulation and thus contribute to the understanding of anti-diabetic effects of these compounds on the molecular level.
Staphylococcus aureus asymptomatically colonizes the skin and anterior nares of 20-30% of the healthy human population. As an opportunistic human pathogen it elicits a variety of infections ranging from skin and soft tissue infections to highly severe manifestations such as pneumonia, endocarditis and osteomyelitis. Due to the emergence of multi resistant strains, treatment of staphylococcal infections becomes more and more challenging and the WHO therefore classified S. aureus as a “superbug”. The variety of diseases triggered by S. aureus is the result of a versatile expression of a large set of virulence factors. The most prominent virulence factor is the cytotoxic and haemolytic pore-forming α-toxin whose expression is mediated by a complex regulatory network involving two-component systems such as the agr quorum-sensing system, accessory transcriptional regulators and alternative sigma-factors. However, the intricate regulatory network is not yet understood in its entirety. Recently, a transposon mutation screen identified the AraC-family transcriptional regulator ‘Repressor of surface proteins’ (Rsp) to regulate haemolysis, cytotoxicity and the expression of various virulence associated factors. Deletion of rsp was accompanied by a complete loss of transcription of a 1232 nt long non-coding RNA, SSR42.
This doctoral thesis focuses on the molecular and functional characterization of SSR42. By analysing the transcriptome and proteome of mutants in either SSR42 or both SSR42 and rsp, as well as by complementation of SSR42 in trans, the ncRNA was identified as the main effector of Rsp-mediated virulence. Mutants in SSR42 exhibited strong effects on transcriptional and translational level when compared to wild-type bacteria. These changes resulted in phenotypic alterations such as strongly reduced haemolytic activity and cytotoxicity towards epithelial cells as well as reduced virulence in a murine infection model. Deletion of SSR42 further promoted the formation of small colony variants (SCV) during long term infection of endothelial cells and demonstrated the importance of this molecule for intracellular bacteria. The impact of this ncRNA on staphylococcal haemolysis was revealed to be executed by modulation of sae mRNA stability and by applying mutational studies functional domains within SSR42 were identified.
Moreover, various stressors modulated the transcription of SSR42 and antibiotic challenge resulted in SSR42-dependently increased haemolysis and cytotoxicity. Transcription of SSR42 itself was found under control of various important global regulators including AgrA, SaeS, CodY and σB, thereby illustrating a central position in S. aureus virulence gene regulation.
The present study thus demonstrates SSR42 as a global virulence regulatory RNA which is important for haemolysis, disease progression and adaption of S. aureus to intracellular conditions via formation of SCVs.
Modulation of insulin-induced genotoxicity in vitro and genomic damage in gestational diabetes
(2019)
Diabetes mellitus is a global health problem, where the risk of diabetes increases rapidly
due to the lifestyle changes. Patients with type II diabetes have many complications
with increased risk of morbidity and mortality. High levels of insulin may lead to DNA
oxidation and damage. Several studies proposed that hyperinsulinemia may be an
important risk factor for various types of cancer. To investigate insulin signaling
pathway inducing oxidative stress and genomic damage, pharmaceutical and natural
compounds which can interfere with the insulin pathway including PI3K inhibitors,
resveratrol, lovastatin, and RAD-001 were selected due to their beneficial effects
against metabolic disorder. Thus, the anti-genotoxic potential of these compounds
regarding insulin-mediated oxidative stress were investigated in normal rat kidney cells
in vitro. Our compounds showed protective effect against genotoxic damage and
significantly decreased reactive oxygen specious after treatment of cells with insulin
with different mechanisms of protection between the compounds. Thus, these
compounds may be attractive candidates for future support of diabetes mellitus therapy.
Next, we explored the link between gestational diabetes mellitus and genomic damage
in cells derived from human blood. Moreover, we investigated the influence of
estradiol, progesterone, adrenaline and triiodothyronine on insulin-induced genomic
damage in vitro. First, we studied the effect of these hormones in human promyelocytic
leukemia cells and next ex vivo with non-stimulated and stimulated peripheral blood
mononuclear cells. In parallel, we also measured the basal genomic damage using three
conditions (whole blood, non-stimulated and stimulated peripheral blood mononuclear
cells) in a small patient study including non-pregnant controls with/without hormonal
contraceptives, with a subgroup of obese women, pregnant women, and gestational
diabetes affected women. A second-time point after delivery was also applied for
analysis of the blood samples. Our results showed that GDM subjects and obese
individuals exhibited higher basal DNA damage compared to lower weight nonpregnant
or healthy pregnant women in stimulated peripheral blood mononuclear cells
in both comet and micronucleus assays. On the other hand, the DNA damage in GDM
women had decreased at two months after birth. Moreover, the applied hormones also
showed an influence in vitro in the enhancement of the genomic damage in cells of the control and pregnant groups but this damage did not exceed the damage which existed
in obese and gestational diabetes mellitus patients with high level of genomic damage.
In conclusion, insulin can induce genomic damage in cultured cells, which can be
modulated by pharmaceutical and naturals substances. This may be for future use in the
protection of diabetic patients, who suffer from hyperinsulinemia during certain disease
stages. A particular form of diabetes, GDM, was shown to lead to elevated DNA
damage in affected women, which is reduced again after delivery. Cells of affected
women do not show an enhanced, but rather a reduced sensitivity for further DNA
damage induction by hormonal treatment in vitro. A potential reason may be an
existence of a maximally inducible damage by hormonal influences.
CRISPR-Cas systems inherently multiplex through CRISPR arrays—whether to defend against different invaders or mediate multi-target editing, regulation, imaging, or sensing. However, arrays remain difficult to generate due to their reoccurring repeat sequences. Here, we report a modular, one-pot scheme called CRATES to construct CRISPR arrays and array libraries. CRATES allows assembly of repeat-spacer subunits using defined assembly junctions within the trimmed portion of spacers. Using CRATES, we construct arrays for the single-effector nucleases Cas9, Cas12a, and Cas13a that mediated multiplexed DNA/RNA cleavage and gene regulation in cell-free systems, bacteria, and yeast. CRATES further allows the one-pot construction of array libraries and composite arrays utilized by multiple Cas nucleases. Finally, array characterization reveals processing of extraneous CRISPR RNAs from Cas12a terminal repeats and sequence- and context-dependent loss of RNA-directed nuclease activity via global RNA structure formation. CRATES thus can facilitate diverse multiplexing applications and help identify factors impacting crRNA biogenesis.
The correct behavior of spacecraft components is the foundation of unhindered mission operation. However, no technical system is free of wear and degradation. A malfunction of one single component might significantly alter the behavior of the whole spacecraft and may even lead to a complete mission failure. Therefore, abnormal component behavior must be detected early in order to be able to perform counter measures. A dedicated fault detection system can be employed, as opposed to classical health monitoring, performed by human operators, to decrease the response time to a malfunction. In this paper, we present a generic model-based diagnosis system, which detects faults by analyzing the spacecraft’s housekeeping data. The observed behavior of the spacecraft components, given by the housekeeping data is compared to their expected behavior, obtained through simulation. Each discrepancy between the observed and the expected behavior of a component generates a so-called symptom. Given the symptoms, the diagnoses are derived by computing sets of components whose malfunction might cause the observed discrepancies. We demonstrate the applicability of the diagnosis system by using modified housekeeping data of the qualification model of an actual spacecraft and outline the advantages and drawbacks of our approach.