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- Comet Assay (12)
- Computer Center University of Wuerzburg (12)
- Dialyse (12)
- Diboren (12)
- Dopamin (12)
- Durchflusscytometrie (12)
- EGFR (12)
- ERP (12)
- Enzym (12)
- FRET (12)
- Fibrose (12)
- Fluorescence (12)
- Gen (12)
- Grundschule (12)
- Hirntumor (12)
- Immunotherapy (12)
- Kinderheilkunde (12)
- Klima (12)
- Klimawandel (12)
- Kohlenstoff-Nanoröhre (12)
- Komplikationen (12)
- Kulturwissenschaften (12)
- Kutikula (12)
- Lymphom (12)
- Magnetische Kernresonanz (12)
- Medienkompetenz (12)
- Metastase (12)
- Modell (12)
- Monitoring (12)
- NFAT (12)
- Nanostrukturiertes Material (12)
- Netzhaut (12)
- Nigeria (12)
- Non-Hodgkin-Lymphom (12)
- Onkogen (12)
- PCR (12)
- PRRT (12)
- Pharmakologie (12)
- Pilzkörper (12)
- Polytrauma (12)
- Quality of Experience (12)
- Quantenchemie (12)
- Rekonstruktion (12)
- Religion (12)
- Replikation (12)
- Rotatorenmanschette (12)
- Ruthenium (12)
- SMN (12)
- SNP (12)
- Schule (12)
- Siliciumorganische Verbindungen (12)
- Spracherwerb (12)
- Supraleitung (12)
- T cell (12)
- Toll-like-Rezeptoren (12)
- Transplantat-Wirt-Reaktion (12)
- Tumor-Nekrose-Faktor <alpha> (12)
- Ubiquitin (12)
- Ultrakurzer Lichtimpuls (12)
- Validierung (12)
- Westafrika (12)
- Zelladhäsion (12)
- adhesion (12)
- antibody (12)
- blood–brain barrier (12)
- carbenes (12)
- catalysis (12)
- clinical trial (12)
- colorectal carcinoma (12)
- complications (12)
- database (12)
- dementia (12)
- drug delivery (12)
- dynamics (12)
- emotions (12)
- endothelium (12)
- genomics (12)
- heart rate (12)
- immunology (12)
- interaction (12)
- lung (12)
- malignant hyperthermia (12)
- measles (12)
- mechanism (12)
- microarray (12)
- microbiome (12)
- molecular beam epitaxy (12)
- molecular biology (12)
- monoclonal antibodies (12)
- neural networks (12)
- neuropathy (12)
- nuclear envelope (12)
- oncology (12)
- optimization (12)
- periodontitis (12)
- phenotype (12)
- plasticity (12)
- pollen (12)
- polymers (12)
- recombination (12)
- review (12)
- screening (12)
- synaptic plasticity (12)
- systematic review (12)
- tinnitus (12)
- topological insulator (12)
- total knee arthroplasty (12)
- trabeculectomy (12)
- tumor microenvironment (12)
- ultrasound (12)
- water oxidation (12)
- ++ (11)
- 3D (11)
- Alzheimer's disease (11)
- Alzheimer’s disease (11)
- Anorexia nervosa (11)
- Antigen CD8 (11)
- Atherosclerosis (11)
- B-Zelle (11)
- Bakterielle Infektion (11)
- Bauchspeicheldrüsenkrebs (11)
- Bioisosterie (11)
- Biosynthese (11)
- Bioverfügbarkeit (11)
- Blazar (11)
- Bruchpilot (11)
- CRISPR/Cas9 (11)
- Chromatin (11)
- Computertomografie (11)
- Dynamik (11)
- Elektronentransfer (11)
- Epidemiologie (11)
- Epidermaler Wachstumsfaktor-Rezeptor (11)
- Flavonoide (11)
- Fließverhalten (11)
- Fotovoltaik (11)
- Genom (11)
- Geschlecht (11)
- Handlungsorientierung (11)
- Hypoxie (11)
- Immuncytochemie (11)
- Immunology (11)
- Japankärpfling (11)
- Knochen (11)
- Knochenersatz (11)
- Kolorektales Karzinom (11)
- Kommunikation (11)
- LASP1 (11)
- LPS (11)
- Laser (11)
- Längsschnittuntersuchung (11)
- MS (11)
- Mais (11)
- Mathematik (11)
- Megakaryozyt (11)
- Mensch-Maschine-Kommunikation (11)
- Mesenchymale Stammzellen (11)
- Mesenchymzelle (11)
- Model (11)
- Multiple Myeloma (11)
- Mutagenität (11)
- NIRS (11)
- Nanodiamant (11)
- Neuropathie (11)
- Niereninsuffizienz (11)
- Operation (11)
- Osteoinduktion (11)
- Parasit (11)
- Parathormon (11)
- Perylenbisimid (11)
- Phylogenie (11)
- Proteaseinhibitor (11)
- Proteasen (11)
- Psychotherapie (11)
- Pulmonale Hypertonie (11)
- Quality of life (11)
- Quanten-Hall-Effekt (11)
- Reperfusion (11)
- Risikofaktoren (11)
- Salmonella (11)
- Schizophrenia (11)
- Schlafapnoe (11)
- Schließzelle (11)
- Schultergelenk (11)
- Schädel-Hirn-Trauma (11)
- Sentinel-1 (11)
- Silicate (11)
- Skala (11)
- Small RNA (11)
- Sprache (11)
- Squark (11)
- Stammzellen (11)
- Sterblichkeit (11)
- Symbiose (11)
- TWEAK (11)
- Training (11)
- Tuberkelbakterium (11)
- USA (11)
- Vasodilatator-stimuliertes Phosphoprotein (11)
- Wahrnehmung (11)
- X-ray crystallography (11)
- Zebrabärbling (11)
- Zelltod (11)
- allergy (11)
- biocompatibility (11)
- biofilm (11)
- cancer therapy (11)
- cancer treatment (11)
- cell adhesion (11)
- chemokines (11)
- cochlear implant (11)
- communication (11)
- coping (11)
- dosimetry (11)
- emotion regulation (11)
- fatigue (11)
- fear (11)
- fluorescence microscopy (11)
- glioblastoma multiforme (11)
- hydrogels (11)
- kinetics (11)
- membrane proteins (11)
- microglia (11)
- molecular dynamics (11)
- nervous system (11)
- neuroendocrine tumor (11)
- next generation sequencing (11)
- oncolytic virus (11)
- psychiatric disorders (11)
- randomized controlled trial (11)
- reactive oxygen species (11)
- relapse (11)
- signaling (11)
- tight junctions (11)
- transport (11)
- university (11)
- Alkohol (10)
- Alps (10)
- Antigen CD28 (10)
- BERA (10)
- BMP-2 (10)
- Bacteria (10)
- Beschichtung (10)
- Bildverarbeitung (10)
- Bioinformatics (10)
- Biokompatibilität (10)
- Borole (10)
- Cadherine (10)
- Calciumphosphate (10)
- Carbene (10)
- Children (10)
- Chiralität <Chemie> (10)
- Chronische Niereninsuffizienz (10)
- Churritisch (10)
- Cochlear-Implantat (10)
- Computational chemistry (10)
- Coronaviren (10)
- Covid-19 (10)
- Cyclo-GMP (10)
- Depressivität (10)
- Diamant (10)
- Digital Humanities (10)
- Dimerisierung (10)
- Dotierung (10)
- Echokardiographie (10)
- Eierstockkrebs (10)
- Elektrochemie (10)
- Elektronenkorrelation (10)
- Englisch (10)
- Enzyminhibitor (10)
- Erbkrankheit (10)
- Ereigniskorreliertes Potenzial (10)
- Erwachsener (10)
- Franken (10)
- Frau (10)
- Funktionalisierung <Chemie> (10)
- Funktionelle Kernspintomografie (10)
- Förderung (10)
- Geldpolitik (10)
- Glatter Krallenfrosch (10)
- Grenzfläche (10)
- HSM-Satztest (10)
- Herzmuskelzelle (10)
- Honigbiene (10)
- Hypophosphatasie (10)
- IL-4 (10)
- Immunfluoreszenz (10)
- Impfstoff (10)
- Induzierte pluripotente Stammzelle (10)
- Interleukin 4 (10)
- Interview (10)
- JNK (10)
- Klassifikation (10)
- Kleinsatellit (10)
- Kniegelenk (10)
- Kohlenstoff (10)
- Komplikation (10)
- Kooperation (10)
- Kultur (10)
- LC-MS (10)
- Ladungstransfer (10)
- Ligand (10)
- Lokalisation (10)
- Magnesiumphosphate (10)
- Magnetismus (10)
- Mathematikunterricht (10)
- Mathematisches Modell (10)
- Medulloblastom (10)
- Metakognition (10)
- Metallocene (10)
- Methylphenidat (10)
- Mikrokerne (10)
- Musik (10)
- NAFLD (10)
- Nahrungserwerb (10)
- Nebennierenrindenkarzinom (10)
- Neolithikum (10)
- Neuropathischer Schmerz (10)
- Niger (10)
- Osteosynthese (10)
- PD-1 (10)
- PD-L1 (10)
- Pain (10)
- Panikstörung (10)
- Parodontitis (10)
- Pathogenität (10)
- Platelets (10)
- Plattenepithelkarzinom (10)
- Prevalence (10)
- Prostaglandine (10)
- Präfrontaler Cortex (10)
- Pädagogik (10)
- Qualitätskontrolle (10)
- RNA interference (10)
- RNA-seq (10)
- RNS-Spleißen (10)
- Radiotherapy (10)
- Remote Sensing (10)
- Rhodium (10)
- Rituximab (10)
- SAR (10)
- Schilddrüse (10)
- Schmalwand <Arabidopsis> (10)
- Silaanaloga (10)
- Silber (10)
- Silicon (10)
- South Africa (10)
- Sprachverstehen (10)
- Staphylococcus (10)
- Starke Kopplung (10)
- Stickstoffmonoxid-Synthase (10)
- Stressreaktion (10)
- Stroke (10)
- Struktur (10)
- T-Lymphozyten (10)
- T-Lymphozyten-Rezeptor (10)
- Tagesrhythmus (10)
- Theologie (10)
- Totalsynthese (10)
- Toxizität (10)
- Transthorakale Echokardiographie (10)
- Treg (10)
- Trypanosomen (10)
- Verwaltungsrecht (10)
- Vitamin D (10)
- Vor- und Frühgeschichte (10)
- Vorschulkind (10)
- Wachstum (10)
- agriculture (10)
- aldosterone (10)
- amino acids (10)
- antimicrobial resistance (10)
- bariatric surgery (10)
- bioinformatics (10)
- biosynthesis (10)
- body size (10)
- boranes (10)
- cell wall (10)
- chronic heart failure (10)
- circadian rhythms (10)
- cognitive impairment (10)
- collagen (10)
- comparison (10)
- complex (10)
- coronary artery disease (10)
- cortisol (10)
- decision-making (10)
- density functional calculations (10)
- dispersal (10)
- eNOS (10)
- education (10)
- efficacy (10)
- forest (10)
- gene therapy (10)
- genome-wide association (10)
- glioma (10)
- global change (10)
- glycine receptor (10)
- human behaviour (10)
- immunomodulation (10)
- induced pluripotent stem cells (10)
- injury (10)
- insect (10)
- knockout (10)
- leaf-cutting ants (10)
- leukemia (10)
- lymph nodes (10)
- mapping (10)
- membrane potential (10)
- metapopulation (10)
- motivation (10)
- near-infrared spectroscopy (10)
- neuroscience (10)
- oncolytic virotherapy (10)
- oxidativer Stress (10)
- quality assurance (10)
- quantification (10)
- regulatorische T-Zellen (10)
- remodeling (10)
- senescence (10)
- silicon (10)
- social interaction (10)
- stem cell transplantation (10)
- subthalamic nucleus (10)
- synapse (10)
- tDCS (10)
- transcriptomics (10)
- transient absorption (10)
- tumors (10)
- vaccination (10)
- vertigo (10)
- walking (10)
- Östrogene (10)
- 3 (9)
- Adenosin (9)
- Adenosine receptors (9)
- Affekt (9)
- Afrika (9)
- Analyse (9)
- Angeregter Zustand (9)
- Antigen CD40 (9)
- Anxiety (9)
- Aorta (9)
- Aortenstenose (9)
- Autoaggressionskrankheit (9)
- Autophagie (9)
- Beyond Standard Model (9)
- Biotransformation (9)
- Biradikal (9)
- Bordetella pertussis (9)
- Borylierung (9)
- Boğazkale (9)
- Butyrat (9)
- CT (9)
- Carcinogenese (9)
- Catalysis (9)
- Cloud Computing (9)
- Deep learning (9)
- Dendritic cells (9)
- Diagnose (9)
- Diborane (9)
- Diskursanalyse (9)
- Dünndarm (9)
- Einzelphotonenemission (9)
- Elektroencephalographie (9)
- Elektronenmikroskopie (9)
- Elektronenstruktur (9)
- Elementarteilchenphysik (9)
- Epithel (9)
- Ernährung (9)
- Europe (9)
- Experimentelle Psychologie (9)
- Extremwertstatistik (9)
- Familie (9)
- Fanconi Anämie (9)
- Fettgewebe (9)
- Fibroblastenwachstumsfaktor (9)
- Fibromyalgie (9)
- Finite-Elemente-Methode (9)
- Frühgeborene (9)
- GIS (9)
- Geistigbehindertenpädagogik (9)
- Gentherapie (9)
- Geoinformationssystem (9)
- Geruchswahrnehmung (9)
- Glioblastoma (9)
- Google Earth Engine (9)
- Grammatik (9)
- Haut (9)
- Herzmuskelkrankheit (9)
- Hethiter (9)
- Hyaluronsäure (9)
- Immunisierung (9)
- Impulsivität (9)
- Innovation (9)
- Instrumentelle Analytik (9)
- Integrine (9)
- Iran (9)
- Isolierung <Chemie> (9)
- Jugendliche (9)
- Juvenile chronische Arthritis (9)
- Kapillarelektrophorese (9)
- Knorpel (9)
- Konflikt (9)
- Koordinationslehre (9)
- Korpus <Linguistik> (9)
- LC-MS/MS (9)
- Landsat (9)
- Leber (9)
- Lehre (9)
- Linguistik (9)
- Löslichkeit (9)
- MAPK (9)
- Macrophage (9)
- Magnetische Resonanz (9)
- Mehrfachbindung (9)
- Mehrsprachigkeit (9)
- Messenger-RNS (9)
- Mice (9)
- Molekulare Erkennung (9)
- Monozyt (9)
- Morphologie (9)
- Mukoviszidose (9)
- Myokardprotektion (9)
- NO (9)
- NSCLC (9)
- Nebennierenrindenkrebs (9)
- Neuroinflammation (9)
- Nierentransplantation (9)
- Oberfläche (9)
- Oberflächenphysik (9)
- Optoelektronik (9)
- Pankreaskarzinom (9)
- Pathogenese (9)
- Persönlichkeit (9)
- Pharmakotherapie (9)
- Photolumineszenzspektroskopie (9)
- Physiologie (9)
- Plasmamembran (9)
- Polycyclische Aromaten (9)
- Protein (9)
- Pseudomonas syringae (9)
- Psychoonkologie (9)
- Quantenmechanik (9)
- Rechenzentrum (9)
- Rechtsvergleich (9)
- Regeneration (9)
- Regionalentwicklung (9)
- Revision (9)
- Sarkoidose (9)
- Satellit (9)
- Schwindel (9)
- Schüttgut (9)
- Spin-Bahn-Wechselwirkung (9)
- Squaraine (9)
- Stathmin (9)
- Stereoselektive Synthese (9)
- Supply Chain Management (9)
- Syntax (9)
- Systembiologie (9)
- Südafrika (9)
- TDM (9)
- Textverstehen (9)
- Therapy (9)
- Tourismus (9)
- Trabekulektomie (9)
- Transplantat (9)
- Transport (9)
- Trypanosoma (9)
- Tumorantigen (9)
- Vakuole (9)
- Vergleich (9)
- Visuelle Aufmerksamkeit (9)
- Wurzel (9)
- Zellkern (9)
- Zentralnervensystem (9)
- Zinkselenid (9)
- actin cytoskeleton (9)
- adolescence (9)
- aggregation (9)
- amyotrophic lateral sclerosis (9)
- antennal lobe (9)
- anxiety disorders (9)
- aromaticity (9)
- astrocytes (9)
- biomechanics (9)
- bladder cancer (9)
- blood brain barrier (9)
- bone cement (9)
- bone marrow (9)
- cardiac surgery (9)
- cardiovascular disease (9)
- cell culture (9)
- cell migration (9)
- central nervous system (9)
- ceramide (9)
- cerebrospinal fluid (9)
- chromatin (9)
- computed tomography (9)
- coronary heart disease (9)
- cuticular hydrocarbons (9)
- cystic fibrosis (9)
- cytotoxic T cells (9)
- decision making (9)
- dendritische Zellen (9)
- dialysis (9)
- earth observation (9)
- electroencephalography (9)
- electron microscopy (9)
- electrophysiology (9)
- energy (9)
- experimental autoimmune encephalomyelitis (9)
- family (9)
- foamy virus (9)
- genes (9)
- gephyrin (9)
- glucose (9)
- high energy physics (9)
- hip (9)
- hyaluronic acid (9)
- hydrogel (9)
- impact (9)
- incidence (9)
- inhibitor (9)
- interferon (9)
- latency (9)
- macrophage (9)
- major depression (9)
- mechanotransduction (9)
- mesenchymale Stammzellen (9)
- methylation (9)
- mitosis (9)
- monitoring (9)
- monoklonale Antikörper (9)
- myocardium (9)
- navigation (9)
- neurogenesis (9)
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- pathogens (9)
- pathway (9)
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- permeability (9)
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- platelet activation (9)
- platelet aggregation (9)
- prognostic factors (9)
- quantum dots (9)
- radiation (9)
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- reveals (9)
- selection (9)
- serum (9)
- sleep (9)
- species richness (9)
- spinal muscular atrophy (9)
- stomata (9)
- systematic uncertainty (9)
- temperature (9)
- tolerance (9)
- transcription factor (9)
- transmission (9)
- type 2 diabetes (9)
- vaccine (9)
- water (9)
- wound healing (9)
- Übersetzung (9)
- ATLAS (8)
- AdS-CFT-Korrespondenz (8)
- Adhärenz (8)
- Aggregat <Chemie> (8)
- Akt (8)
- Aktiver galaktischer Kern (8)
- Algorithmus (8)
- Alltagskultur (8)
- Ancistrocladaceae (8)
- Anthocyane (8)
- Antibiotika (8)
- Antigen (8)
- Aortenklappenersatz (8)
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- Arthroskopie (8)
- Arzneimittelforschung (8)
- Astrophysik (8)
- Asymmetrie (8)
- Asymmetrische Synthese (8)
- Auge (8)
- Autonomer Roboter (8)
- Bauchspeicheldrüse (8)
- Blimp-1 (8)
- Blutdruck (8)
- Blutstammzelle (8)
- Botanik (8)
- Brain (8)
- Burkina Faso (8)
- CD28 (8)
- CD40 (8)
- CD95 (8)
- COMT (8)
- Caenorhabditis elegans (8)
- Camponotus floridanus (8)
- Chlamydia (8)
- Compressed Sensing (8)
- Cross-Section (8)
- Cysteinproteasen (8)
- Cytomegalie-Virus (8)
- DLBCL (8)
- Darm (8)
- Data Mining (8)
- Datenbank (8)
- Degradation (8)
- Demenz (8)
- Deutschunterricht (8)
- Diborene (8)
- Didaktik (8)
- ELISA (8)
- ELISPOT (8)
- ERK (8)
- Elektronenspin (8)
- Elektronenspinresonanz (8)
- Emotionsregulation (8)
- Endothelzellen (8)
- Engagement (8)
- Erbrechen (8)
- Europa (8)
- Exziton-Polariton (8)
- FISH (8)
- Fachdidaktik (8)
- Femtosekundenbereich (8)
- Fibroblasten (8)
- Fitness (8)
- Fluoreszenzspektroskopie (8)
- Forschung (8)
- Fußball (8)
- GABA (8)
- Gammastrahlung (8)
- Gedächtnisleistung (8)
- Geistige Behinderung (8)
- Genotoxicity (8)
- Geschlechtsunterschied (8)
- Gewebe (8)
- Gliom (8)
- Graphen (8)
- HPLC-MS (8)
- Habichtskraut (8)
- Haemophilus influenzae (8)
- Harnwegsinfektion (8)
- Hernie (8)
- Hochbegabung (8)
- Hubbard-Modell (8)
- Humangenetik (8)
- Hymenoptera (8)
- Hypertrophie (8)
- Hüftgelenk (8)
- IL-10 (8)
- Immunantwort (8)
- In vivo (8)
- India (8)
- Indien (8)
- Inklusion (8)
- Keilschrifttext (8)
- Kephalometrie (8)
- Kieferorthopädie (8)
- Kinetik (8)
- Knochenersatzmaterial (8)
- Knockout (8)
- Komposit <Zahnmedizin> (8)
- Kondo-Effekt (8)
- Korrelation (8)
- Kreuzband (8)
- Kristallstruktur (8)
- Landwirtschaft (8)
- Langerhans-Inseln (8)
- Lanthanoide (8)
- Leishmania (8)
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- Lower Franconia (8)
- Lumineszenz (8)
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- Machine Learning (8)
- Magenbypass (8)
- Makuladegeneration (8)
- Mass (8)
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- Meningitis (8)
- Meningokokken (8)
- Metaanalyse (8)
- Methode (8)
- Mikroglia (8)
- Mikrokerntest (8)
- Mikrostruktur (8)
- Mitochondrien (8)
- Mobiler Roboter (8)
- Molekül (8)
- Monozyten (8)
- Multiple myeloma (8)
- Myokarditis (8)
- N-heterocyclic carbenes (8)
- Nachsorge (8)
- Nanodraht (8)
- Naturstoff (8)
- Nervendegeneration (8)
- Neugeborenes (8)
- Neutrino (8)
- Notfallmedizin (8)
- Obesity (8)
- Onkolyse (8)
- Optogenetik (8)
- Organisches Molekül (8)
- Oxylipine (8)
- PONV (8)
- Parton distributions (8)
- Pemphigus (8)
- Peptide (8)
- Periphere arterielle Verschlusskrankheit (8)
- Permeabilität (8)
- Pharmakodynamik (8)
- Photodissoziation (8)
- Photovoltaik (8)
- Platin (8)
- Pollen (8)
- Protein p53 (8)
- Protein-Tyrosin-Kinasen (8)
- Proteinbindung (8)
- Protonen-NMR-Spektroskopie (8)
- Präkonditionierung (8)
- Psychische Störung (8)
- Pump-Probe-Technik (8)
- Quantendynamik (8)
- Quelle (8)
- Quran (8)
- RNA sequencing (8)
- Radikal <Chemie> (8)
- Raf <Biochemie> (8)
- Raf-Kinasen (8)
- Raman spectroscopy (8)
- Rastertunnelmikroskop (8)
- Rechenzentrum Universität Würzburg (8)
- Rechnungslegung (8)
- Regenerative Medizin (8)
- Rekombination (8)
- Retroviren (8)
- Ringöffnungspolymerisation (8)
- Roman (8)
- Röntgen-Photoelektronenspektroskopie (8)
- Salmonella typhimurium (8)
- Schmerzforschung (8)
- Schwämme (8)
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- Siliciumcarbid (8)
- Sozialpsychologie (8)
- Spin (8)
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- Statistik (8)
- Stent (8)
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- Survival (8)
- Synthesis (8)
- T cell activation (8)
- T lymphocytes (8)
- T-Zelle (8)
- Tabak (8)
- Tagung (8)
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- Tight junction (8)
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- UAV (8)
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- Zeitreihenanalyse (8)
- absorption (8)
- acute kidney injury (8)
- adaptation (8)
- adherence (8)
- adipose tissue (8)
- adults (8)
- ageing (8)
- aggression (8)
- allogeneic stem cell transplantation (8)
- analysis of variance (8)
- animal models (8)
- antigen (8)
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- behaviour (8)
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- borylene (8)
- caffeine (8)
- calcium phosphate (8)
- cell biology (8)
- central complex (8)
- charge transfer (8)
- chronic pain (8)
- classical conditioning (8)
- cleft lip and palate (8)
- coagulation (8)
- coherence (8)
- copper (8)
- crystallization (8)
- decay (8)
- distribution (8)
- division of labor (8)
- domain (8)
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- electronic structure (8)
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- implant (8)
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- integrins (8)
- iron (8)
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- kinematic alignment (8)
- knee (8)
- learning and memory (8)
- lithium (8)
- mHealth (8)
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- microbiology (8)
- microenvironment (8)
- microstructure (8)
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- vestibular schwannoma (8)
- 3D tissue model (7)
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- Einwandige Kohlenstoff-Nanoröhre (7)
- Eisen (7)
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- translocation (7)
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- - (6)
- 18F-FDG (6)
- 19. Jahrhundert (6)
- 2 (6)
- ABA (6)
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- AMPK (6)
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- Lewis-Säure (4)
- LiDAR (4)
- Localization (4)
- Lopinavir (4)
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- Low-density-Lipoproteine (4)
- Lung cancer (4)
- Lungenembolie (4)
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- Lysosom (4)
- MALDI-MS (4)
- MALT (4)
- MCP-1 (4)
- MIBG (4)
- MIZ1 (4)
- MMB (4)
- MMP (4)
- MOLLI (4)
- MPEC (4)
- MPFL (4)
- MR (4)
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- MSCs (4)
- MTUS1 (4)
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Identifizierung und Strukturaufklärung von Anthocyanen und ihrer Metabolite erfolgten mit Hilfe der mittels Hochleistungsflüssigchromatographie-Diodenarray-Detektion-Elektro-spray-Tan¬dem¬massen¬spektrometrie (HPLC-DAD-ESI-MS/MS). Quantitative Analysen wurden via HPLC-DAD durchgeführt. Die hierzu erforderlichen Referenzverbindungen wurden mittels präparativer HPLC aus Heidelbeeren isoliert (Reinheit zwischen 85,8% und 99,4%). Der Gehalt an Anthocyanen in den untersuchten Heidelbeerfrüchten lag bei 6 g/kg. Bezüglich der mengen¬mäßigen Verteilung dominierten Delphinidin- und Cyanidin¬glykoside vor den Glykosiden von Malvidin, Petunidin und Peonidin. Als konjugierte Zucker¬reste kamen vor allem Glukose und Galaktose vor, der Gehalt an Arabinosiden war weit geringer. Bei oraler Aufnahme erfolgt ein erster Kontakt der Anthocyane mit Speichel. Daher wurde dessen Wirkung auf die Heidelbeeranthocyane in ex vivo-Studien über einen (unphysio-logisch langen) Zeitraum von bis zu 30 Minuten untersucht. Dabei konnte wurde ins-besondere der Einfluß des pH-Wertes auf die Stabilität der Anthocyane aufgezeigt werden. Zur Simulation des Verhaltens von Anthocyanen im Magen wurden die einzelnen Heidelbeeranthocyane mit künstlichem Magensaft (pH 1,81) über vier Stunden inkubiert. Hier erwiesen sich alle untersuchten Verbindungen als stabil. Die anschließend von uns mit simuliertem Duodenalsekret (pH 7,2) über einen Zeitraum von 24 Stunden durchgeführten Studien zeigten, dass die Anthocyane unterschiedlich starken Modifizierungen unterlagen. Unter den schwach alkalischen Bedingungen wurden vor allem die Glykoside des Delphinidins schnell abgebaut, aber auch die übrigen Anthocyane erwiesen sich unter diesen Bedingungen als nicht stabil; nach 24 h war kein Anthocyan mehr nachweisbar. Um die Metabolisierungsvorgänge der Anthocyane im Dünn- und Dickdarm zu untersuchen, wurden ex vivo-Inkubationen jeweils mit frischem Ileo- bzw. Kolo¬stoma-beutel¬inhalt durchgeführt. Während die Abbaugeschwindigkeit in der ilealen Flüssigkeit vor allem von der pH-Stabilität des Aglykons abhänig war, konnten im Dickdarm einzig die Arabinoside nach einer Stunde noch alle in geringen Konzentrationen identifiziert werden. Die meisten Glukoside und Galaktoside waren zu diesem Zeitpunkt schon vollständig abgebaut. Da im Darm von einer hydrolytischen Spaltung der Anthocyane in Anthocyanidin und Zucker ausgegangen wird, wurde die Metabolisierung von Anthocyanidinen unter physio-logischen pH-Bedingungen untersucht. Neben der jeweiligen Spaltung in das Benzoe¬säure-derivat des B-Ringes sowie Phloroglucinessigsäure traten verschiedene Poly¬merisierungs¬-produkte auf, deren Strukturen nicht aufgeklärt werden konnten. In einer weiteren Versuchsreihe wurde die renale Ausscheidung von Anthocyanen bei Ileostomieprobanden nach oraler Applikation von 300 g Heidelbeeren über einen Zeitraum von acht Stunden untersucht. Es zeigte sich, dass ein Stoma des terminalen Ileums keinen Einfluss auf die Absorption und Metabolisierung der Anthocyane hatte. Die Bilanzierung der Anthocyane im Urin erfolgte als Äquvalente von Malvidin-3-O-glukosid, da nicht alle Anthocyanmetabolite zur Verfügung standen. Der Zeitpunkt der maximalen renalen Anthocyanausscheidung sowie die Menge der ausgeschiedenen Anthocyane waren starken interindividuellen Schwankungen unterworfen. Das Aus¬sscheidungs¬maximum (tmax) lag zwischen 0,5 und zwei Stunden. Bei der ausge¬schiedenen Menge wurden Werte zwischen 0,007% und 0.019% der auf¬ge¬nommenen Anthocyane ermittelt. Aufgrund der literaturbekannten Unterschiede zwischen den in Serum und Urin gefunden Anthocyanmengen ist davon auszugehen, dass es nach Anthocyanverzehr zu Inter-aktionen mit Proteinen in Blut oder Geweben kommt. Mittels Blutfraktionierung wurde das humane Serumalbumin (HSA) als wichtigster Bindungspartner der Anthocyane im Blut identifiziert. Anhand spektroskopischer Methoden war es möglich, die Bindungs¬parameter zu berechnen. Als Bindungsort wurde der hydrophile Eingang der lipophilen Warfarin-Bindungstasche in der Subdomäne IIA des HSA-Moleküls mittels "molecular modelling" identifiziert. Nasschemische Untersuchungen ergaben, dass die Bindung der Anthocyane an HSA diese vor ihrem pH-abhängigen Abbau schützt. Eine signifikante Herab¬setzung der chemischen Abbaugeschwindig¬keit konnte auch für bovines Serumalbumin beobachtet werden. Diese Erkenntnis ließ sich auf andere, mit dem HSA-Molekül nicht strukurverwandte lebensmittelrelevante Albumine übertragen. So zeigten Anthocyane große Stabilität in Milch und Eiklar, wobei die Stabilisierung auf eine Wechselwirkung mit den Proteinen Laktalbumin und Ovalbumin zurückgeführt werden konnte. Die in dieser Arbeit erlangten Erkenntnisse hinsichtlich Absorption, Metabolisierung und systemischer Verfügbarkeit im menschlichen Organismus leisten einen Beitrag zum besseren Verständnis der Wirkungen von Anthocyanen. Die neuen Erkenntnisse der Protein¬bindung sind vor allem für die Bewertung der Verfügbarkeit der Anthocyane in humanem Gewebe relevant.
Ziel dieser Arbeit war es, die Auswirkungen der Änderungen der Therapiestandards in der Behandlung des Kolonkarzinoms und die Auswirkungen der Einführung der Vorsorgekoloskopie auf die Überlebensraten der Patienten mit Kolonkarzinom zu untersuchen.
Die umfassende Analyse der therapieabhängigen Überlebensraten von 1016 Patienten mit Kolonkarzinom aus 20 Jahren zeigt eine Verbesserung der Überlebenswahrscheinlichkeit durch den Einsatz adjuvanter Therapie und multimodaler Therapieregime. Durch Neuerungen in der Therapie konnten die 5-Jahres-Überlebensraten seit Anfang der 90er Jahre nahezu verdoppelt werden. Als wichtigste Prädiktoren für das Langzeitüberleben stellten sich das Alter der Patienten bei Erstdiagnose, das UICC Stadium und die Art der adjuvanten Therapie heraus. Der Überlebenszeit verlängernde Effekt war für den Einsatz der heutigen Standardtherapie mit 5-Flourouracil (5-FU) schon signifikant und zeigt sich für die Kombination mit neueren Medikamenten, insbesondere Oxaliplatin, noch deutlicher. Neue Operationstechniken, Fortschritte in der Metastasenchirurgie, ein optimiertes supportives Management und weitere Erkenntnisse onkologischer Prinzipien beeinflussten die erzielten Erfolge synergistisch.
Das Gesamtüberleben der Patienten, die per Vorsorgekoloskopie detektiert werden ist besser als das der Patienten, die aufgrund klinischer Symptome diagnostiziert werden. Neben dem signifikanten Überlebensvorteil der Früherkennungs-Patienten, der sich durch die niedrigeren UICC Stadien in dieser Gruppe ergibt, finden sich auch Trends bezüglich eines besseren Outcomes dieser Patienten innerhalb der selben UICC Stadien. Die Patienten, deren Tumor im Rahmen des Screenings detektiert wurde, waren signifikant jünger, wiesen signifikant weniger Begleiterkrakungen auf und zeigten signifikant niedrigere Tumorstadien. Eine adjuvante Therapie wurde in der Screening-Gruppe signifikant häufiger durchgeführt. Mehr als einer von fünf tumorbedingten Todesfällen der Patienten, die augrund von Symptomen diagnostiziert wurden, hätte in dieser Studienpopulation verhindert werden können, wenn eine routinemäßige Vorsorgekoloskopie durchgeführt worden wäre.
Das Fazit lautet: die Vorsorgekoloskopie ist effektiv. Die Tumorgenese kann durch Entfernung von Voräuferläsionen durchbrochen werden, Tumoren können in frühen asymptomatischen Stadien detektiert werden. Screeningprogramme sollten erweitert werden, um die Inzidenz und die Mortalität von Darmkrebs weiter zu senken.
TERRAINS OF CONSCIOUSNESS emerges from an Indian-German-Swiss research collaboration. The book makes a case for a phenomenology of globalization that pays attention to locally situated socioeconomic terrains, everyday practices, and cultures of knowledge. This is exemplified in relation to three topics:
- the tension between ‘terrain’ and ‘territory’ in Defoe’s ‘Robinson Crusoe’ as a pioneering work of the globalist mentality (chapter 1)
- the relationship between established conceptions of feminism and the concrete struggles of women in India since the 19th century (chapter 2)
- the exploration of urban space and urban life in writings on India’s capital – from Ahmed Ali to Arundhati Roy (chapter 3).
Large-Scale Assessment of a Fully Automatic Co-Adaptive Motor Imagery-Based Brain Computer Interface
(2016)
In the last years Brain Computer Interface (BCI) technology has benefited from the development of sophisticated machine leaning methods that let the user operate the BCI after a few trials of calibration. One remarkable example is the recent development of co-adaptive techniques that proved to extend the use of BCIs also to people not able to achieve successful control with the standard BCI procedure. Especially for BCIs based on the modulation of the Sensorimotor Rhythm (SMR) these improvements are essential, since a not negligible percentage of users is unable to operate SMR-BCIs efficiently. In this study we evaluated for the first time a fully automatic co-adaptive BCI system on a large scale. A pool of 168 participants naive to BCIs operated the co-adaptive SMR-BCI in one single session. Different psychological interventions were performed prior the BCI session in order to investigate how motor coordination training and relaxation could influence BCI performance. A neurophysiological indicator based on the Power Spectral Density (PSD) was extracted by the recording of few minutes of resting state brain activity and tested as predictor of BCI performances. Results show that high accuracies in operating the BCI could be reached by the majority of the participants before the end of the session. BCI performances could be significantly predicted by the neurophysiological indicator, consolidating the validity of the model previously developed. Anyway, we still found about 22% of users with performance significantly lower than the threshold of efficient BCI control at the end of the session. Being the inter-subject variability still the major problem of BCI technology, we pointed out crucial issues for those who did not achieve sufficient control. Finally, we propose valid developments to move a step forward to the applicability of the promising co-adaptive methods.
Auf dem Weg vom Primärtumor zur systemischen Metastasierung, der Haupttodesursache von Krebserkrankungen, ist die Einzelzellmigration von Tumorzellen durch dreidimensionales Bindegewebe ein entscheidender Schritt. Die vorliegende Arbeit zeigt Untersuchungen zur Tumorzellmigration und –plastizität in einem 3D-Migrationsmodell. Kleine G-Proteine kontrollieren Zytoskelettfunktionen, insbesondere Aktinpolymerisation und die Bildung von Zellprotrusionen durch Rac sowie Actomyosinkontraktion durch Rho. Durch pharmakologische Inhibitoren von Rac und dem Rho-Effektor ROCK soll deren Bedeutung für Einzelzellmigration in einem dreidimensionalen Modell und vor allem der Effekt auf Morphologie, Plastizität und Migration von Tumorzellen geklärt werden. Nach Inhibition von ROCK zeigen hochinvasive HT1080 Fibrosarkomzellen einen multipolar-dendritischen und sessilen Phänotyp. Nach Hemmung von Rac wird hingegen ein rundlicher, aber ebenfalls apolarer und sessiler Phänotyp induziert. Bei simultaner Inhibition von Rac und ROCK entstehen rundliche, apolare, sessile Zellen mit abortiven Pseudopodien. Wird das Gleichgewicht von Rac und ROCK durch konstitutive Aktivierung von ROCK gestört, so entsteht eine zweigeteilte Population, bestehend aus rundlichen Zellen, die Blebs bilden, und langgezogenen Zellen. Nach Sortierung nach ihrem ß1-Integrinexpressionsniveau zeigten Zellen mit niedriger Integrin-Expression einen rundlichen Migrationstyp mit blasenartigen dynamischen Protrusionen, während Zellen mit hoher Integrin-Expression langgezogen-mesenchymal migrierten. Somit steuern ROCK und Rac gemeinsam und zeitgleich die mesenchymale Einzelzellmigration. Während Rac Protrusion vermittelt, ist ROCK für Kontraktilität und Retraktion verantwortlich. Erst durch Koordination von Rac und Rho/ROCK entsteht somit Polarität und 3D mesenchymale Migration.
Infants and young children (IYC) remain the most vulnerable population group to environmental hazards worldwide, especially in economically developing regions such as sub-Saharan Africa (SSA). As a result, several governmental and non-governmental institutions including health, environmental and food safety networks and researchers have been proactive toward protecting this group. Mycotoxins, toxic secondary fungal metabolites, contribute largely to the health risks of this young population. In SSA, the scenario is worsened by socioeconomic status, poor agricultural and storage practices, and low level of awareness, as well as the non-establishment and lack of enforcement of regulatory limits in the region. Studies have revealed mycotoxin occurrence in breast milk and other weaning foods. Of concern is the early exposure of infants to mycotoxins through transplacental transfer and breast milk as a consequence of maternal exposure, which may result in adverse health effects. The current paper presents an overview of mycotoxin occurrence in foods intended for IYC in SSA. It discusses the imperative evidence of mycotoxin exposure of this population group in SSA, taking into account consumption data and the occurrence of mycotoxins in food, as well as biomonitoring approaches. Additionally, it discusses the health implications associated with IYC exposure to mycotoxins in SSA.
Fungi possess diverse photosensory proteins that allow them to perceive different light wavelengths and to adapt to changing light conditions in their environment. The biological and physiological roles of the green light-sensing rhodopsins in fungi are not yet resolved. The rice plant pathogen Fusarium fujikuroi exhibits two different rhodopsins, CarO and OpsA. CarO was previously characterized as a light-driven proton pump. We further analyzed the pumping behavior of CarO by patch-clamp experiments. Our data show that CarO pumping activity is strongly augmented in the presence of the plant hormone indole-3-acetic acid and in sodium acetate, in a dose-dependent manner under slightly acidic conditions. By contrast, under these and other tested conditions, the Neurospora rhodopsin (NR)-like rhodopsin OpsA did not exhibit any pump activity. Basic local alignment search tool (BLAST) searches in the genomes of ascomycetes revealed the occurrence of rhodopsin-encoding genes mainly in phyto-associated or phytopathogenic fungi, suggesting a possible correlation of the presence of rhodopsins with fungal ecology. In accordance, rice plants infected with a CarO-deficient F. fujikuroi strain showed more severe bakanae symptoms than the reference strain, indicating a potential role of the CarO rhodopsin in the regulation of plant infection by this fungus.
Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.
Melanoma formation in the teleost Xiphophorus is caused by a dominant genetic locus, Tu. This locus includes the Xmrk oncogene, which encodes a receptor tyrosine kinase. Tumor induction is. suppressed in wild-type fish by a tumor suppressor locus, R. Molecular genetic analyses revealed that the Tu locus emerged by nonhomologaus recombination of the Xmrk proto-oncogene with a previously uncharacterized sequence, D. This event generated an additional copy of Xmrk with a new promoter. Suppression of the new Xmrk promoter by R in parental fish and its deregulation in hybrids explain the genetics of melanoma formation in Xiphophorus.
The melanoma inducing locus of Xiphophorus encodes a tumorigenic version of a novel putative receptor tyrosine kinase (Xmrk). To elucidate the mechanism of oncogenic activation of Xmrk, we compared the structure and expression of two oncogenic loci with the corresponding proto-oncogene. Only minor structural alterations were found to be specific for the oncogenic Xmrk genes. Marked overexpression of the oncogene transcripts in melanoma, which are approximately 1 kb shorter than the proto-oncogene transcript, correlates with the malignancy of the tumors. The tumor transcripts are derived from an alternative transcription start site that is used only in the oncogenic loci. Thus, oncogenic activation of the melanoma inducing Xmrk gene appears primarily to be due to novel transcriptional control and overexpression.
Background
Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.
Materials and Methods
Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.
Results
PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.
Conclusion
High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
Hintergrund: Die therapeutischen Optionen für das gering differenzierte (PDTC) und anaplastische (ATC) Schilddrüsenkarzinom sind limitiert, weshalb diese Erkrankungen überwiegend mit einer schlechten Prognose einhergehen. Lenvatinib (LEN) ist ein Multityrosinkinase-Inhibitor, der unter anderem die Fibroblasten-Wachstumsfaktor-Rezeptoren (FGFR) 1-4 inhibiert und zur Therapie des fortgeschrittenen radiojodrefraktären Schilddrüsenkarzinoms zugelassen ist. Es zeigt sich nur ein geringes Ansprechen auf die Monotherapie bei ATCs, wobei neuere Studien eine therapeutische Überlegenheit der Kombination aus LEN und dem PD-1-Inhibitor Pembrolizumab (PEM) beschreiben.
Material und Methoden: Die Expression von PD-L1 wurde in ATC (n=93)- und PDTC (n=47)-Primärtumorgewebe von 1997-2019 aus fünf deutschen (Universitäts-)Kliniken mittels Immunhistochemie analysiert und mit dem Tumor Proportion Score (TPS) quantifiziert. Der Nachweis von FGFR1-4-mRNA wurde bei 31 ATC- und 14 PDTC-Gewebeproben mittels RNAscope In-situ-Hybridisierung quantifiziert. Als Kontrollgruppe wurde normales Schilddrüsengewebe (NT) und Gewebe von papillären Schilddrüsenkarzinomen (PTC) verwendet. Der primäre Endpunkt war das krankheitsspezifische Überleben (DSS).
Ergebnisse: Eine PD-L1-Expression mit einem TPS ≥50% konnte in 42% der ATC- und in 26% der PDTC-Proben nachgewiesen werden. Die mediane PD-L1-Expression war in ATC-(TPS 30%) signifikant höher im Vergleich zu PDTC-Proben (5%; p<0,01) und NT (0%; p<0,001). 53% der PDTC-Proben zeigten eine PD-L1-Expression ≤5%. Die Expression von FGFR-mRNA war in allen Proben sehr gering, wobei die kombinierte FGFR1-4-Expression in PDTC- und ATC-Gewebe im Vergleich zu normalem Schilddrüsengewebe signifikant höher war (jeweils p<0,001). Es ergab sich keine Assoziation zwischen der PD-L1- und FGFR1-4-Expression mit dem krankheitsspezifischen Überleben.
Schlussfolgerung: Eine hohe PD-L1-Expression in einem großen Anteil der ATCs und einem Viertel der PDTCs, könnte auf eine Rationale zur Therapieentscheidung für Immuncheckpoint-Inhibioren hinweisen. Die FGFR-Expression war in allen Schilddrüsenkarzinomen sehr gering. Der klinisch beobachtete Synergismus von PEM und LEN könnte durch immunmodulatorische Effekte hervorgerufen werden.
1.2-Dioxetanes, very reactive and high energy molecules. are involved as labile intermediates in dioxygenase- activated aerobic metabolism and in physiological processes. Various toxico1ogica1 tests reveal that dioxetanes are indeed genotoxic. In supercoiled DNA of bacteriophage PM2 they induce endonucleasesensitive sites, most of them are FPG protein-sensitive base modifications (8-hydroxyguanine, fonnamidopyrimidines). Pyrimidinedimersand sites ofbase loss (AP sites) which were probed by UV endonuclease and exonuclease 111 are minor lesions in this system. While the alky1-substituted dioxetanes do not show any significant mutagenic activity in different Salmonella typhimurium strains, heteroarene dioxetanes such as benzofuran and furocoumarin dioxetanes are strongly mutagenic in S. typhimurium strain TA I 00. DNA adducts formed with an intermediary alkyJating agent appear to be responsible for the mutagenic activity of benzofuran dioxetane. We assume that the benzofuran epoxides, generated in situ from benzofuran dioxetanes by deoxygenation are the ultimate mutagens of the latter. since benzofuran epoxides are highly mutagenic in the S. typhimurium strain TAIOO and they form DNA adducts. as detected by the 212Ppostlabelling technique. Our results imply that the type of D NA darnage promoted by dioxetanes is dependent on the structural feature of dioxetanes. Furthermore, the direct photochemical DNA darnage by energy transfer. i.e., pyrimidine dimers, plays a minor role in the genotoxicity of dioxetanes. Instead, photooxidation dominates in isolated DNA. while radical darnage and alkylation prevail in the cellular system.
Die Entwicklung von therapeutischen Strategien, die den infarktbedingten Untergang des Myokardgewebes minimieren und die Gewebsheilung nach abgelaufenem Myokardinfarkt unterstützen, gehört zu dem Hauptziel in der modernen Kardiologie. Bis jedoch eine spezifische Intervention als Therapieform anerkannt wird, ist ein detailliertes Entschlüsseln der zellulären und molekularen Mechanismen während und nach der Myokardschädigung notwendig. Die vorliegende Arbeit beschäftigt sich intensiv mit den Vorgängen der Stickstoffmonoxid- (NO) Produktion und der Inflammation nach Okklusion von Kranzarterien. Im ersten Teil der Dissertation steht die endotheliale NO-Synthase-Expression (eNOS) im Mittelpunkt der Untersuchung. eNOS ist als wichtiger Katalysator an der Biosynthese von Stickstoffmonoxid, das als protektiver Faktor für die Gefäßhomöostase seit Jahren bekannt ist, beteiligt. Ferner besteht experimentell sehr gute Evidenz dafür, dass der endothelialen NO-Synthase am Ausmaß des kardialen Ischämie-/ Reperfusionsschadens eine entscheidende Rolle zukommt. Folglich wurde mittels der Substanz AVE 9488 versucht, die eNOS-Expression in Mäusen zu steigern und den Effekt auf das Infarktgeschehen näher zu betrachten. Die Behandlung mit AVE 9488 erzielte einen signifikant reduzierten Ischämie-/Reperfusionsschaden. Bei anschließenden Ischämie-/Reperfusionsveruchen mit eNOS defizienten Mäusen war der protektive Effekt wieder aufgehoben. Der Erfolg dieser Substanz wird in der signifikanten Reduktion des oxidativen Stresses vermutet. Ein zusätzlicher wichtiger Parameter, der während der Ischämie/Reperfusion aktiviert wird, ist der Schlüssel-Transkriptionsfaktor Nuclear Factor kappa B (NF-kB). Durch seine Bindung an bestimmte Enhancer und Promotoren reguliert der Faktor die Entzündungsprozesse, indem er die Genexpression proinflammatorischer Marker verstärkt. Folglich wurden eine Reduktion der Inflammation sowie ein protektiver Effekt nach erfolgter ischämischer Schädigung durch Hemmung von NF-kB angenommen. Zur Prüfung dieser Hypothese wurden NF-kB-Untereinheit p50 defiziente Mäuse (p50 KO) einer Okklusion einer Herzkranzarterie unterzogen. Durch die Hemmung der NF-kB-Aktivierung kam es zu einer signifikanten Reduzierung des Infarktareals im Vergleich zu den entsprechenden Wildtyp-Mäusen. Der große Benefit konnte auf die geringere Einwanderung der neutrophilen Granulozyten in das infarzierte Gebiet zurückgeführt werden. Knochenmarktransplantationsversuche mit p50 KO- und Wildtyp-Knochenmark untermauerten die Beobachtung, dass die beeinträchtigte Aktivierung von NF-kB in p50 defizienten Leukozyten protektive Effekte in der Ischämie/Reperfusion vermittelt. Die Aktivierung der proinflammatorischen Proteine während des linksventrikulären Remodelings nach Myokardinfarkt gehört zum Fokus des dritten Teils dieser Arbeit. Dieser Teil beschäftigt sich mit der Frage, inwieweit eine hochdosierte Aspirin-Therapie die linksventrikulären Umbauprozesse günstig beeinflussen kann. Dafür wurden Mäuse für 4 Wochen mit Placebo oder Aspirin (120 mg/kg pro Tag) mittels osmotischer Mini-Pumpen, die 2 Stunden nach Ligatur der Kranzarterie implantiert wurden, behandelt. In beiden Gruppen kam es zur erwarteten linksventrikulären Dilatation nach Myokardinfarkt, jedoch ohne signifikanten Unterschied zwischen Placebo- und Aspirin-behandelten Tieren. Es kam allerdings zu einer erwarteten Reduktion proinflammatorischer Proteine durch die Aspirin-Therapie. So war die Expression von Tumor-Nekrose-Faktor-alpha; (TNF-alpha) und Interleukin-1ß (IL-ß) in der Aspirin-Gruppe signifikant reduziert. Zusammenfassend lässt sich sagen, dass durch die gezielte Beeinflussung bestimmter Faktoren in der Ischämie/Reperfusion wie z. B. die Verstärkung der eNOS-Expression oder die Hemmung der NF-kB-Aktivierung die Ischämieschädigung signifikant reduziert werden kann.
The idea that our observable Universe may have originated from a quantum tunneling event out of an eternally inflating false vacuum state is a cornerstone of the multiverse paradigm. Modern theories that are considered as an approach towards the ultraviolet-complete fundamental theory of particles and gravity, such as the various types of string theory, even suggest that a vast landscape of different vacuum configurations exists, and that gravitational tunneling is an important mechanism with which the Universe can explore this landscape. The tunneling scenario also presents a unique framework to address the initial conditions of our observable Universe. In particular, it allows to introduce deviations from the cosmological concordance model in a controlled and well-motivated way. These deviations are a central topic of this work. An important feature in most of the theories mentioned above is the presumed existence of additional space dimensions in excess of the three which we observe in our every-day experience. It was realized that these extra dimensions could avoid our detection if they are compactified to microscopic length scales far beyond the reach of current experiments. There also seem to be natural mechanisms available for dynamical compactification in those theories. These typically lead to a vast landscape of different vacuum configurations which also may differ in the number of macroscopic dimensions, only the total number of dimensions being determined by the theory. Transitions between these vacuum configurations may hence open up new directions which were previously compact, spontaneously compactify some previously macroscopic directions, or otherwise re-arrange the configuration of compact and macroscopic dimensions in a more general way. From within the bubble Universe, such a process may be perceived as an anisotropic background spacetime - intuitively, the dimensions which open up may give rise to preferred directions. If our 3+1 dimensional observable Universe was born in a process as described above, one may expect to find traces of a preferred direction in cosmological observations. For instance, two directions could be curved like on a sphere, while the third space direction is flat. Using a scenario of gravitational tunneling to fix the initial conditions, I show how the primordial signatures in such an anisotropic Universe can be obtained in principle and work out a particular example in more detail. A small deviation from isotropy also has phenomenological consequences for the later evolution of the Universe. I discuss the most important effects and show that backreaction can be dynamically important. In particular, under certain conditions, a buildup of anisotropic stress in different components of the cosmic fluid can lead to a dynamical isotropization of the total stress-energy tensor. The mechanism is again demonstrated with the help of a physical example.
In most foreign language learning contexts, there are only rare chance for contact with native speakers of the target language. In such a situation, reading plays an important role in language acquisition as well as in gaining cultural information about the target language and its speakers.
Previous research indicated that reading in foreign language is a complex process, which is influenced by various linguistic, cognitive and affective factors. The aim of the present study was to test two structural models of the relationship between reading comprehension in native language (L1), English language (L2) reading motivation, metacognitive awareness of L2 reading strategies, and reading comprehension of English as a foreign language among the two samples. Furthermore, the current study aimed to examine the differences between Egyptian and German students in their perceived usage of reading strategies during reading English texts, as well as to explore the pattern of their motivation toward reading English texts. For this purpose, 401 students were recruited from Germany (n=200) and Egypt (n=201) to participate in the current study. In order to have information about metacognitive awareness of reading strategies, a self-report questionnaire (SORS) developed by Moktari and Sheory (2002) was used. While the L2 reading motivation variable, was measured by a reading motivation survey (L2RMQ) which was based on reviewed reading motivation research. In addition, two reading tests were administrated one to measure reading comprehension for native language (German/Arabic) and the other to measure English reading comprehension.
To analyze the collected data, descriptive statistics and independent t-tests were performed. In addition, further analysis using structural equation modeling was applied to test the strength of relationships between the variables under study.
The results from the current research revealed that L1 reading comprehension, whether in a German or Arabic language, had the strongest relationship with L2 reading comprehension. However, the relationship between L2 intrinsic reading motivation was not proven to be significant in either the German or Egyptian models. On the other hand, the relationship between L2 extrinsic reading motivation, metacognitive awareness of reading strategies, and L2 reading comprehension was only proven significant in the German sample. The discussion of these results along with their pedagogical implications for education and practice will be illustrated in the following study.
Nach Einschätzung der Weltgesundheitsorganisation WHO wird Krebs im Jahr 2013 die weltweit häufigste Todesursache bei Menschen und Haustieren sein. Diese Situation erfordert die Entwicklung neuer therapeutischer Ansätze. Hauptziel einer Tumortherapie ist es, sowohl den Primärtumor als auch die Metastasen möglichst vollständig zu entfernen. Dabei wird nach Methoden gesucht, die im Gegensatz zu den meisten gegenwärtigen therapeutischen Einsätzen, wie der chirurgischen Entfernung bösartiger Neubildungen, Chemotherapie und Strahlentherapie, selektiv die bösartigen Zellen erkennen und zerstören können. Eine faszinierende Möglichkeit in dieser Hinsicht ist die Verwendung von onkolytischen Viren, die die Fähigkeit besitzen, sich selektiv sowohl in Primärtumoren als auch in Metastasen anzusiedeln und die Krebszellen dort zu zerstören. Das Konzept, dass Viren nützlich für die Bekämpfung von Krebs sein könnten, ist nicht neu. Allerdings konnte erst in den letzten Jahren durch zahlreiche Studien bestätigt werden, dass verschiedene Viren in der Lage sind, eine signifikante Antitumorwirkung in vivo auszuüben. Zu den erfolgversprechenden onkolytischen Viren zählen insbesondere Adenovirus, Herpes simplex Virus, Reovirus und Vaccinia-Virus, die sich bereits in Phase III der klinischen Studien befinden oder kurz davor sind. Die therapeutische Nutzung von tumorspezifischen onkolytischen Viren beim Menschen hat bereits begonnen. Im Rahmen der vorliegenden Doktorarbeit wurden verschiedene Aspekte der Wirkungsweise von Vaccinia-Virus-Stämmen bei der Therapie verschiedener Tumore aus Mensch und Hund im Xenotransplantat-Mausmodell bearbeitet: die Onkolyse der Krebszellen und Inhibition des Tumorwachstums sowie die Effekte der Virusinfektion auf das Tumormikromilieu und die Mitwirkung des angeborenen Immunsystems bei der Virotherapie. Das Tumormikromilieu (Stroma) setzt sich aus einer Vielzahl verschiedener Zellen und Komponenten der extrazellulären Matrix zusammen. Die Krebszellen bilden unter anderem mit Endothelzellen des Blut- und Lymphsystems und verschiedenen Immunzellen eine komplexe Organ-ähnliche Struktur. Weitere wichtige Bestandteile des Stromas sind Wachstumsfaktoren, Chemokine und Zytokine und die Tumorvaskulatur. Diese ist durch zahlreiche strukturelle und funktionelle Abnormalitäten charakterisiert, wodurch die Effektivität von Strahlen- und Chemotherapie herabgesetzt wird. Weiterhin ist das Tumormikromilieu durch seine Ähnlichkeit mit einer chronischen Entzündungsreaktion gekennzeichnet und wirkt immunsupprimierend auf rekrutierte Leukozyten, die wiederum die Inflammation verstärken und die Angiogenese und das Tumorwachstum weiter fördern. Aufgrund dieser vielen Komponenten ist die Zusammensetzung jedes Tumors einzigartig, weswegen Standardtherapien häufig nicht zu einer Heilung führen. Die Wirkung der Viren bei der Virotherapie beruht vermutlich auf 4 Mechanismen, die einzeln oder in Kombination auftreten können: die direkte Onkolyse der Krebszellen, die Zerstörung des Tumorblutgefäßsystems, die Aktivierung des Immunsystems des Wirts und die Suppression der microRNA-Expression des Wirtes. Zusätzlich kann die Expression therapeutischer Gene die onkolytische Wirkung verstärken. Zum Nachweis der Onkolyse der Krebszellen und Inhibition des Tumorwachstums wurde zuerst das Virus GLV-1h68 in einem autologen humanen Melanomzellpaar, 888-MEL und 1936-MEL, eingesetzt. Das GLV-1h68-Virus wurde auf Basis des Wildtyp Vaccinia-Virus LIVP durch die Insertion von 3 Expressionskassetten in den drei Genloci F14.5L, J2R und A56 genetisch konstruiert. 888-MEL, eine zu einem frühen Zeitpunkt der Krebserkrankung aus einer Metastase isolierte Zelllinie, zeigt nach Infektion mit GLV-1h68 im Mausmodell Tumornekrose („Responder“), während 1936-MEL aus einer späten Metastasierungsphase kaum mit Onkolyse auf eine Virusinfektion reagiert („Poor-Responder“). Die onkolytische Wirkung konnte mittels Durchflusszytometrie in Tumoren beider Zelllinien zu einem frühen Zeitpunkt nach Virusinfektion nachgewiesen werden. In 888-MEL-Tumoren wurde hierbei eine große Zahl infizierter und toter Zellen nach Virusinfektion gefunden. Gleichzeitig wurde eine hohe Zahl an Immunzellen detektiert, die nach Virusinfektion reduziert war. In den schwächer reagierenden 1936-MEL-Tumoren konnte eine Onkolyse bei Infektion mit höherer Virusmenge und zu einem früheren Zeitpunkt demonstriert werden, wodurch mehr Zellen infiziert wurden. Zusätzlich wurde eine Steigerung der nur in geringer Zahl vorhandenen Immunzellen nachgewiesen. Trotz des unterschiedlichen Tumormikromilieus konnte somit ein onkolytischer Effekt in beiden Tumormodellen erzielt werden. ...
Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a novel approach for canine cancer therapy. Here we describe, for the first time, the characterization and the use of VACV strain GLV-5b451 expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as therapeutic agent against different canine cancers. Cell culture data demonstrated that GLV-5b451 efficiently infected and destroyed all four tested canine cancer cell lines including: mammary carcinoma (MTH52c), mammary adenoma (ZMTH3), prostate carcinoma (CT1258), and soft tissue sarcoma (STSA-1). The GLV-5b451 virus-mediated production of GLAF-2 antibody was observed in all four cancer cell lines. In addition, this antibody specifically recognized canine VEGF. Finally, in canine soft tissue sarcoma (CSTS) xenografted mice, a single systemic administration of GLV-5b451 was found to be safe and led to anti-tumor effects resulting in the significant reduction and substantial long-term inhibition of tumor growth. A CD31-based immuno-staining showed significantly decreased neo-angiogenesis in GLV-5b451-treated tumors compared to the controls. In summary, these findings indicate that GLV-5b451 has potential for use as a therapeutic agent in the treatment of CSTS.
Virotherapy on the basis of oncolytic vaccinia virus (VACV) infection is a promising approach for cancer therapy. In this study we describe the establishment of a new preclinical model of feline mammary carcinoma (FMC) using a recently established cancer cell line, DT09/06. In addition, we evaluated a recombinant vaccinia virus strain, GLV-5b451, expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as an oncolytic agent against FMC. Cell culture data demonstrate that GLV-5b451 virus efficiently infected, replicated in and destroyed DT09/06 cancer cells. In the selected xenografts of FMC, a single systemic administration of GLV-5b451 led to significant inhibition of tumor growth in comparison to untreated tumor-bearing mice. Furthermore, tumor-specific virus infection led to overproduction of functional scAb GLAF-2, which caused drastic reduction of intratumoral VEGF levels and inhibition of angiogenesis.
In summary, here we have shown, for the first time, that the vaccinia virus strains and especially GLV-5b451 have great potential for effective treatment of FMC in animal model.
Einfluß der Dialysetherapie auf den Genomschaden von Nierenpatienten in einer prospektiven Studie
(2007)
Patienten mit terminaler Niereninsuffizienz haben im Vergleich zur Normalbevölkerung eine deutlich erhöhte Inzidenz maligner Erkrankungen. Frühere Untersuchungen zeigten, dass periphere Blutlymphozyten dieser Patienten einen höheren genetischen Schaden aufweisen, wodurch das Risiko einer malignen Entartung steigt. In dieser Arbeit wurde der genetische Schaden mithilfe zweier Testverfahren, Comet Assay und Mikrokerntest, untersucht. Es handelte sich um eine prospektive Studie mit zwei Patientenkollektiven. Die erste Gruppe bestand aus Patienten, die aufgrund einer terminalen Niereninsuffizienz innerhalb der nächsten Monate eine Dialysetherapie mittels konventioneller Hämodialyse beginnen mußten. Die zweite Gruppe bildeten Dialysepatienten, die im Verlauf von konventioneller Dialyse auf Hämodiafiltration umgestellt wurden. Bei allen Patienten wurde der genetische Schaden der peripheren Blutlymphozyten in den Monaten vor und nach Therapiebeginn bzw. Therapieumstellung regelmäßig untersucht. Unsere Ergebnisse zeigen, dass 4 der 10 Prädialysepatienten nach Beginn der Dialyse einen niedrigeren genetischen Schaden hatten, 2 Patienten hatten unterschiedliche Werte in Comet Assay und Mikrokerntest und bei 2 Patienten ergab sich im Verlauf eine höhere DNA-Schädigung. Die verbliebenen 2 Patienten mußten aufgrund einer konstant bleibenden Niereninsuffizienz nicht mit der Dialysetherapie beginnen. Bei Zusammenfassung aller Einzelwerte zeigte sich, dass das Kollektiv der Prädialysepatienten insgesamt vom Beginn der Behandlung profitiert hat. In der Gruppe der Dialysepatienten hatte 2 von 7 Patienten nach Umstellung auf Hämodiafiltration eine geringere DNA-Schädigung, 2 Patienten zeigten unterschiedliche Ergebnisse im Comet Assay und Mikrokerntest und 2 weitere Patienten wiesen eine höheren genetischen Schaden in den Lymphozyten auf. Ein Patient konnte bei fehlenden Vorwerten nicht berücksichtigt werden. Im Gruppenvergleich zeigte sich für alle Dialysepatienten ein gleichbleibender DNA-Schaden, gemessen mithilfe des Comet Assays bei leicht erhöhten Mikrokernraten. Jedoch hatte sich die Zellproliferation ebenfalls etwas verbessert. Zusammenfassend ergibt sich somit in beiden Gruppen kein eindeutiges Ergebnis, woraus neue Therapieempfehlungen für Patienten mit terminaler Niereninsuffizienz abzuleiten wären. Um weiter Einflußvariablen auf die Höhe des genetischen Schadens festzustellen, sind weiter Untersuchungen mit größeren Patientenkollektiven erforderlich.
We quantify the contemporaneous relationships among stock markets in the euro area, the United States, and a group of emerging economies over the period from 2008 to 2017. Exploiting the heteroskedasticity in the stock market data, we identify shocks that originated in the respective domestic markets and shocks that are common to all markets. Our results underline the leading role of the United States in international equity markets, but also point to the importance of indirect spillovers for all economies. Variance decompositions show that while domestic shocks explain the bigger part of the variation in each stock market, a substantial part of the variation in the euro area and the emerging economies can be attributed to foreign shocks. A comparison with a sample covering the pre‐crisis period from 1999 to 2007 suggests a strengthening of the linkages among global stock markets in recent years. In particular, the spillovers from advanced to emerging economies have become more pronounced.
The putative attachment protein G of pneumonia virus of mice (PVM), a member of the Pneumoviruses, is an important virulence factor with so far ambiguous function in a virus-cell as well as in virus-host context. The sequence of the corresponding G gene is characterized by significant heterogeneity between and even within strains, affecting the gene and possibly the protein structure. This accounts in particular for the PVM strain J3666 for which two differing G gene organizations have been described: a polymorphism in nucleotide 65 of the G gene results in the presence of an upstream open reading frame (uORF) that precedes the main ORF in frame (GJ366665A) or extension of the major G ORF for 18 codons (GJ366665U). Therefore, this study was designed to analyse the impact of the sequence variations in the respective G genes of PVM strains J3666 and the reference strain 15 on protein expression, replication and virulence.
First, the controversy regarding the consensus sequence of PVM J3666 was resolved. The analysis of 45 distinct cloned fragments showed that the strain separated into two distinct virus populations defined by the sequence and structure of the G gene. This division was further supported by nucleotide polymorphisms in the neighbouring M and SH genes. Sequential passage of this mixed strain in the cell line standardly used for propagation of virus stocks resulted in selection for the GJ366665A-containing population in one of two experiments pointing towards a moderate replicative advantage. The replacement of the G gene of the recombinant PVM 15 with GJ366665A or GJ366665U, respectively, using a reverse genetic approach indicated that the presence of uORF within the GJ366665A significantly reduced the expression of the main G ORF on translational level while the potential extension of the ORF in GJ366665U increased G protein expression. In comparison, the effect of the G gene-structure on virus replication was inconsistent and dependent on cell line and type. While the presence of uORF correlated with a replication advantage in the standardly used BHK-21 cells and primary murine embryonic fibroblasts, replication in the murine macrophage cell line RAW 264.7 did not. In comparison, the GJ366665U variant was not associated with any effect on replication in cultured cells at all. Nonetheless, in-vivo analysis of the recombinant viruses associated the GJ366665U gene variant, and hence an increased G expression, with higher virulence whereas the GJ366665A gene, and therefore an impaired G expression, conferred an attenuated phenotype to the virus.
To extend the study to other G gene organizations, a recombinant PVM expressing a G protein without the cytoplasmic domain and for comparison a G-deletion mutant, both known to be attenuated in vivo, were studied. Not noticed before, this structure of the G gene was associated with a 75% reduction in G protein expression and a significant attenuation of replication in macrophage-like cells. This attenuation was even more prominent for the virus lacking G. Taking into consideration the higher reduction in G protein levels compared to the GJ366665A variant indicates that a threshold amount of G is required for efficient replication in these cells.
In conclusion, the results gathered indicated that the expression levels of the G protein were modulated by the sequence of the 5’ untranslated region of the gene. At the same time the G protein levels modulated the virulence of PVM.
Cardio-respiratory changes and mortality in the conscious rat induced by (+)- and (±)- anatoxin-a
(1992)
0. M. ADEYEMO and A.-L. SIREN. Cardio-respiratory changes and mortality in the conscious rat induced by ( + )- and ( ± )-anatoxin-a. Toxicon 30, 899-905, 1992.-Anatoxin-a (AnTx-a) isapotent nicotinic cholinergic receptor agonist. The relative potencies of the ( + )-AnTx-a and the racemic mixture ( ± )-AnTxa were investigated in the conscious rat by comparing their effects on mean arterial blood pressure (BP), heart rate (HR), blood oxygen and carbon dioxide pressures (p02 and pC02, respective1y), acid-base balance (pH) and mortality. The present experiments show that while both forms of AnTx-a produce dose-dependent increases in BP and decreases in HR, ( + )-AnTx-a is about IO-fo1d morepotent than the optically inactive isomer. ( + )-AnTx-a was also 6-fo1d more potent than ( ± )-AnTx-a in produclog severe hypoxemia, and more than 4-fold as potent as the (±}-AnTx-a in producing significant hypercapnia accompanied with severe acidosis. The approximate median Iethai dose (Ln so) of ( + )-AnTx-a was about 5-fold less than that of ( ± )-AnTx-a. We conclude that ( + )-AnTx-a is more potent than the ( ± )-AnTx-a racemic mixture in causing detrimental cardio-respiratory changes and therefore increased mortality in the rat.
A Goldfish Model for Evaluation of the Neurotaxicity of \(\omega\)-Conotoxin GVI A and Screening of Monoclonal Antibodies. ADEYEMO, 0. M .. SHAPIRA, S., TOMBACCINI, D., POLLARD, H. 8 .• FEUERSTEIN, G .. AND SIREN, A-L. ( 1991 ). Toxicol. App/. Pharmaco/. 108, 489-496. The neurotoxicity of \(\omega\)-conotoxin (\(\omega\)-CgTx), a potent neuronal voltage-sensitive calcium channel blocker, was measured using a new bioassay. \(\omega\)-CgTx was administered intraperitoneally (ip) to goldfish weighing approximately 1.6 g, and dose-related changes were observed over a 2-hr period. \(\omega\)CgTx induced time- and dose-dependent abnormal swimming behavior (ASB) and mortality. The antitoxin activity of the antiborlies was investigated in vivo by either ( l) preincubation of the antibody with w-CgTx at 4°C overnight, or (2) pretreatment with antibody, 30 min before \(\omega\)CgTx injection in a 10:1 antibody/\(\omega\)-CgTx molar ratio. The LD50 dose of \(\omega\)-CgTx in goldfish was 5 nmol/kg ip, and preincubation of monoclonal antibody (50 nmol/kg ip) with \(\omega\)-CgTx (5 nmol/kg ip) significantly (p < 0.05) reduced mortality. ASB, and toxicity time. The antitoxin activity of the monoclonal antiborlies evidenced in the goldfish bioassay was further tested in the conscious rat. In the rat, the increases in mean arterial pressure and heart rate induced by \(\omega\)-CgTx (0.03 nmol/rat icv) were significantly (p < 0.02 and p < 0.0 l, respectively) attenuated by preincubation of the toxin with the antibody (0.3 nmol/rat). We conclude that the goldfish bioassay provides a simple. accurate, and inexpensive in vivo model for the study of the toxicity of \(\omega\)CgTx
The hallmark oncoprotein Myc is a major driver of tumorigenesis in various human cancer entities. However, Myc’s structural features make it challenging to develop small molecules against it. A promising strategy to indirectly inhibit the function of Myc is by targeting its interactors. Many Myc-interacting proteins have reported scaffolding functions which are difficult to target using conventional occupancy- driven inhibitors. Thus, in this thesis, the proteolysis targeting chimera (PROTAC) approach was used to target two oncoproteins interacting with Myc which promote the oncogenicity of Myc, Aurora-A and WDR5. PROTACs are bifunctional small molecules that bind to the target protein with one ligand and recruit a cellular E3- ligase with the other ligand to induce target degradation via the ubiquitin- proteasome system. So far, the most widely used E3-ligases for PROTAC development are Cereblon (CRBN) and von Hippel–Lindau tumor suppressor (VHL). Furthermore, there are cases of incompatibility between some E3-ligases and proteins to bring about degradation. Hence there is a need to explore new E3- ligases and a demand for a tool to predict degradative E3-ligases for the target protein in the PROTAC field.
In the first part, a highly specific mitotic kinase Aurora-A degrader, JB170, was developed. This compound utilized Aurora-A inhibitor alisertib as the target ligand and thalidomide as the E3-ligase CRBN harness. The specificity of JB170 and the ternary complex formation was supported by the interactions between Aurora-A and CRBN. The PROTAC-mediated degradation of Aurora-A induced a distinct S- phase defect rather than mitotic arrest, shown by its catalytic inhibition. The finding demonstrates that Aurora-A has a non-catalytic role in the S-phase. Furthermore, the degradation of Aurora-A led to apoptosis in various cancer cell lines.
In the second part, two different series of WDR5 PROTACs based on two protein- protein inhibitors of WDR5 were evaluated. The most efficient degraders from both series recruited VHL as a E3-ligase and showed partial degradation of WDR5. In addition, the degradation efficiency of the PROTACs was significantly affected by the linker nature and length, highlighting the importance of linker length and composition in PROTAC design. The degraders showed modest proliferation defects at best in cancer cell lines. However, overexpression of VHL increased the degradation efficiency and the antiproliferative effect of the PROTACs.
In the last part, a rapamycin-based assay was developed to predict the degradative E3-ligase for a target. The assay was validated using the WDR5/VHL and Aurora- A/CRBN pairs. The result that WDR5 is degraded by VHL but not CRBN and Aurora-A is degraded by CRBN, matches observations made with PROTACs. This technique will be used in the future to find effective tissue-specific and essential E3-ligases for targeted degradation of oncoproteins using PROTACs.
Collectively, the work presented here provides a strategy to improve PROTAC development and a starting point for developing Aurora-A and WDR5 PROTACs for cancer therapy.
Two-dimensional triangular lattices of group IV adatoms on semiconductor substrates provide a rich playground for the investigation of Mott-Hubbard physics. The possibility to combine various types of adatoms and substrates makes members of this material class versatile model systems to study the influence of correlation strength, band filling and spin-orbit coupling on the electronic structure - both experimentally and with dedicated many-body calculation techniques. The latter predict exotic ground states such as chiral superconductivity or spin liquid behavior for these frustrated lattices, however, experimental confirmation is still lacking. In this work, three different systems, namely the \(\alpha\)-phases of Sn/SiC(0001), Pb/Si(111), and potassium-doped Sn/Si(111) are investigated with scanning tunneling microscopy and photoemission spectroscopy in this regard. The results are potentially relevant for spintronic applications or quantum computing.
For the novel group IV triangular lattice Sn/SiC(0001), a combined experimental and theoretical study reveals that the system features surprisingly strong electronic correlations because they are boosted by the substrate through its partly ionic character and weak screening capabilities. Interestingly, the spectral function, measured for the first time via angle-resolved photoemission, does not show any additional superstructure beyond the intrinsic \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) reconstruction, thereby raising curiosity regarding the ground-state spin pattern.
For Pb/Si(111), preceding studies have noted a phase transition of the surface reconstruction from \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) to \(3 \times 3\) at 86 K. In this thesis, investigations of the low-temperature phase with high-resolution scanning tunneling microscopy and spectroscopy unveil the formation of a charge-ordered ground state. It is disentangled from a concomitant structural rearrangement which is found to be 2-up/1-down, in contrast to previous predictions. Applying an extended variational cluster approach, a phase diagram of local and nonlocal Coulomb interactions is mapped out. Based on a comparison of theoretical spectral functions with scattering vectors found via quasiparticle interference, Pb/Si(111) is placed in said phase diagram and electronic correlations are found to be the driving force of the charge-ordered state.
In order to realize a doped Mott insulator in a frustrated geometry, potassium was evaporated onto the well-known correlated Sn/Si(111) system. Instead of the expected insulator-to-metal transition, scanning tunneling spectroscopy data indicates that the electronic structure of Sn/Si(111) is only affected locally around potassium atoms while a metallization is suppressed. The potassium atoms were found to be adsorbed on empty \(T_4\) sites of the substrate which eventually leads to the formation of two types of K-Sn alloys with a relative potassium content of 1/3 and 1/2, respectively. Complementary measurements of the spectral function via angle-resolved photoemission reveal that the lower Hubbard band of Sn/Si(111) gradually changes its shape upon potassium deposition. Once the tin and potassium portion on the surface are equal, this evolution is complete and the system can be described as a band insulator without the need to include Coulomb interactions.
The high failure rate of new drug candidates in preclinical or clinical studies due to hepatotoxicity represents a considerable problem in the drug development. Hence, there is an urgent need to develop new approaches for early and reliable prediction of drug-induced hepatotoxicity that enables a better identification of drug candidates with high potential for toxicity at early stages of drug development. Therefore, the aim of this work was to improve the prediction of drug-induced liver injury in preclinical studies through evaluation of more reliable and sensitive biomarkers of hepatotoxicity and a better understanding of the underlying mechanistic basis for drug-induced toxicity. First, the ability of a set of potential markers (NGAL, thiostatin, clusterin, PON1) to detect early signs of liver injury was assessed in rats treated with drug candidates that were dropped from further development, in part due to toxic adverse effects in the liver. In summary, PON1 and clusterin were not consistently altered in response to liver injury and thus provide no additive information to the traditional liver enzymes in detecting drug-induced hepatotoxicity. In contrast, thiostatin and NGAL were increased in serum and urine of treated animals in a time- and dose-dependent manner. These changes correlated well with mRNA expression in the target organ and generally reflected the onset and degree of drug-induced liver injury. Receiver-operating characteristics analyses supported serum thiostatin, but not NGAL, as a better indicator of drug-induced hepatobiliary injury than conventional clinical chemistry parameters, such as ALP, ALT and AST. Although thiostatin, an acute phase protein expressed in a range of tissues, may not be specific for liver injury, our results indicate that thiostatin may serve as a sensitive, minimally-invasive diagnostic marker of inflammation and tissue damage in preclinical safety assessment. In the second part of this work, combined application of genomics profiling technology and RNAi to inhibit the pharmacological target of a drug candidate BAY16, a glucagon receptor (GCGR) antagonist, was used to determine if interference with the pharmacological target plays a role in the toxic response to BAY16, and to narrow down those molecular changes that are associated with toxicity, and not the pharmacological action of BAY16. In contrast to Bay 16, which was found to be cytotoxic at concentrations of 75 µM, silencing of the glucagon receptor did not affect cell viability in primary rat hepatocytes. Thus, it can be concluded that hepatotoxicity of Bay 16 was not related to the drugs inhibitory effect on the glucagon receptor in vitro and in vivo. These findings were supported by the fact that most of BAY16-induced changes in gene expression occurred independently of the pharmacological modulation of GCGR. These off-target effects include altered xenobiotic metabolism, oxidative stress, increased fatty acid synthesis, and alterations in cholesterol and bile acid metabolic processes. Although it was not possible to draw a final conclusion about the mechanism of BAY16 hepatotoxicity, changes in these molecular mechanisms appear contribute to progression of hepatic injury. With regard to drug safety assessment in preclinical studies, the utilization of siRNA technology in vitro represents a new approach to improve mechanistic understanding of the nature of drug’s toxicity, being either chemically mediated or due to primary or secondary pharmacological mode of action.
Bei der vorliegenden Arbeit handelt es sich um eine klinische und radiologische Nachuntersuchung von insgesamt 114 Patientinnen und Patienten, die zwischen 2009 und 2012 in der Poliklinik für Zahnerhaltung und Parodontologie der Universität Würzburg von approbierten Zahnärztinnen und Zahnärzten endodontisch behandelt wurden. Dabei kamen drei verschiedene Obturationsmethoden zum Einsatz.
1. Single-Cone-Technik mit Guttapercha und AH Plus® (SCGP)
2. Single-Cone-Technik mit Guttapercha und GuttaFlow® (SCGF)
3. Adhäsive Obturation in Continuous-Wave-Technik mit Resilon® (CWR)
Die Erhebung der Ausgangsvariablen (zum Behandlungszeitpunkt) erfolgte retrospektiv unter Zuhilfenahme der klinischen und radiologischen Dokumentation. Die Reevaluation des periapikalen Zustands der Zähne und die Erhebung weiterer klinischer Parameter erfolgte im Rahmen eines aktiven Patientenrecalls nach durchschnittlich 6,3 Jahren. Dabei wurden mit möglichst hoher Standardisierung postoperative Einzelzahnaufnah-men angefertigt. Diese wurden anhand der PAI-Klassifikation ausgewertet, um den pe-riapikalen Zustand der Zähne vor und nach Therapie zu bestimmen. PAI-Werte von 1 und 2 galten als Behandlungserfolg, Grad 3 bis 5 als Misserfolg. Im Hinblick auf die de-finierten Arbeitshypothesen wurden die Erfolgsraten innerhalb der Kohorten miteinander verglichen. Das vorrangige Ziel der hier vorliegenden Arbeit war, zu untersuchen, ob der endodontische Behandlungserfolg abhängig von der jeweiligen Obturationsmethode ist und ob technikspezifische Unterschiede sich einerseits auf die Qualität der Obturation und andererseits auf das Auftreten möglicher Komplikationen, wie der periapikalen Extrusion von Wurzelfüllmaterial, auswirken. Ferner sollten diese Aspekte neben weite-ren zahn- und patientenbezogenen Variablen bezüglich ihres Einflusses auf die Erfolgs-rate der endodontischen Therapie analysiert werden.
Es konnten keine signifikanten Unterschiede der endodontischen Erfolgsraten zwischen den hier untersuchten Obturationsmethoden ermittelt werden (p = ,16). In der SCGP-Kohorte lag die Erfolgsrate bei 85 % (34/40) verglichen mit 68,8 % (44/64) für CWR und 80 % (8/10) für SCGF. Die Homogenität der Obturation (p = ,2) und die Extrusion von Wurzelfüllmaterial in das periapikale Gewebe (p = ,93) zeigten keine Abhängigkeit von der gewählten Obturationstechnik. Die Länge der Wurzelkanalfüllung hingegen unter-schied sich signifikant zwischen den Kohorten (p = ,04*). Die Obturation mittels SCGP-Technik erzielte den höchsten Anteil adäquater Wurzelkanalfüllungen (92,5 %, 37/40) gegenüber SCGF (80 %, 8/10) und CWR (71,88 %, 46/64). Die CWR-Methode zeigte mit 18,8 % (12/64) den höchsten Anteil an unterfüllten Obturationen (SCGP: 7,5 %, 3/40; SCGF: 0 %).
Unabhängig von der Obturationsmethodik zeigte sich der endodontische Behandlungs-erfolg im Allgemeinen unbeeinflusst von der Qualität der Wurzelkanalfüllungen. Die Va-riablen Obturationslänge (p = ,12) und -homogenität (p = ,11) sowie die Extrusion von Wurzelfüllmaterial in die periapikale Region (p = 1,00) zeigten keinen signifikanten Ein-fluss auf die Erfolgsrate.
Das Durchschnittsalter im Patientenkollektiv betrug 60 Jahre mit einer tendenziellen Überrepräsentation weiblicher Probandinnen (60,5 %, 69/114). 73 % (81/111, 3 Mis-sings) der Studienteilnehmer/-innen wurden ab einem PSI-Grad von 3 als parodontal erkrankt eingestuft und 23,7 % (27/114) zeigten eine positive Raucheranamnese. Der BMI betrug im Durchschnitt 26,3 kg/m2. 42,3 % (47/111, 3 Missings) der Studienteil-nehmer/-innen wurden anhand der Einnahme von Medikamenten zur Therapie bzw. Prävention von kardiovaskulären Erkrankungen und/oder oraler Antidiabetika als chro-nisch erkrankt klassifiziert (chronic disease medication, CDM). Das Recallintervall be-trug durchschnittlich 6,3 Jahre mit einem Minimum von 4,7 und einem Maximum von 8,7 Jahren. Die patientenbezogenen Variablen Alter (p = ,45), Geschlecht (p = ,67), Pa-rodontitis (p = ,08), BMI (p = ,58), CDM (p = ,19), Recallintervall (p = ,08) und Rauchen (p = ,34) zeigten keinen signifikanten Einfluss auf den endodontischen Behandlungser-folg.
Unter den zahnbezogenen Variablen beeinflusste lediglich der präoperative apikale Sta-tus den endodontischen Erfolg signifikant (p = ,007*). Zähne mit präoperativer apikaler Läsion zeigten eine Erfolgsrate von 66,2 % (47/71) gegenüber 90,7 % (n = 39/43) bei Fällen ohne apikale Läsion. Die Misserfolgswahrscheinlichkeit bei Vorliegen einer präoperativen Läsion war um den Faktor 4,98 erhöht (OR = 4,98, 95 % KI: 1.60, 15,57, p = ,006*). Zwischen Kompositfüllungen, Teilkronen, Vollkronen, Teleskopkronen und Brückenversorgungen konnten keine relevanten Unterschiede in den Erfolgsraten er-mittelt werden (p = ,29). Gleiches galt für adäquate (76,6 %, 82/107) und inadäquate (57,1 %, 4/7) Restaurationen (p = ,36). Ebenso zeigten die Erfolgsraten von Wurzelka-nalrevisionen (70,5 %, 31/44) und Primärbehandlungen (78,6 %, 55/70) keine signifikan-ten Abweichungen voneinander (p = ,45). Molaren waren im Studienkollektiv mit 56,1 % (64/114) gegenüber Prämolaren und Frontzähnen mit je 21,9 % (25/114) überrepräsen-tiert. Der Zahntyp (p = ,07) und die Ausgangsdiagnose (p = ,22) stellten keine relevanten Einflussfaktoren des endodontischen Erfolgs dar.
Context
Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Besides its deleterious impact on cardiovascular target organ damage, PA is considered to cause osteoporosis.
Patients and methods
We assessed bone turnover in a subset of 36 postmenopausal women with PA. 18 patients had unilateral PA and were treated by adrenalectomy, whereas 18 patients had bilateral PA and received mineralocorticoid receptor antagonist (MRA) therapy respectively. 18 age- and BMI-matched females served as controls. To estimate bone remodeling, we measured the bone turnover markers intact procollagen 1 N-terminal propeptide, bone alkaline phosphatase, osteocalcin and tartrate resistant acid phosphatase 5b in plasma by chemiluminescent immunoassays at time of diagnosis and one year after initiation of treatment.
Study design
Observational longitudinal cohort study.
Setting
Tertiary care hospital.
Results
Compared with controls, patients with PA had mildly elevated osteocalcin at baseline (p = 0.013), while the other bone markers were comparable between both groups. There were no differences between the unilateral and the bilateral PA subgroup. One year after initiation of MRA treatment with spironolactone bone resorption and bone formation markers had significantly decreased in patients with bilateral PA. In contrast, patients adrenalectomized because of unilateral PA showed no significant change of bone turnover markers.
Conclusion
This study shows that aldosterone excess in postmenopausal women with PA is not associated with a relevant increase of bone turnover markers at baseline. However, we observed a significant decrease of bone markers in patients treated with spironolactone, but not in patients treated by adrenalectomy.
Das Ziel der vorliegenden Arbeit war es die aktuelle Versorgungskontinuität in der psychotherapeutischen Versorgung hinsichtlich der Zusammenarbeit des (teil-)stationären und des ambulanten Sektors aus Sicht der niedergelassenen Psychotherapeut:innen zu untersuchen, diese in den wissenschaftlichen Kontext einzuordnen und – falls möglich – erste Möglichkeiten zur Verbesserung der derzeitigen Versorgungskontinuität aufzuzeigen.
In Zusammenarbeit mit dem Arbeitsbereich für Medizinische Psychologie und Psychotherapie im Zentrum für psychische Gesundheit des Universitätsklinikums Würzburg wurde hierzu ein Fragebogen entwickelt und acht ausgewählten psychotherapeutischen Fachgesellschaften beziehungsweise Psychotherapeutenkammern mit der Bitte um Weiterleitung an deren Mitglieder zugesandt.
In der vorliegenden Studie wurden – neben einer Globalbeurteilung – im Speziellen die Teil-aspekte des Austauschs, der entsprechenden Rahmenbedingungen und die Bereitstellung des poststationären ambulanten Psychotherapieplatzes betrachtet. Die Studienergebnisse bilden den derzeitigen Status Quo der psychotherapeutischen Versorgungslage aus Sicht der niedergelassenen Psychotherapeut:innen ab und weisen im Zuge dessen auf einige Defizite in den untersuchten Teilaspekten hin. Die aufgestellten Nebenfragestellungen zeigen gleichsam aber auch Ansatzunkte für Lösungen auf.
Aufgrund der besonderen Relevanz der aufgezeigten Ergebnisse, gilt es – zur Ermöglichung einer adäquaten kontinuierlichen psychotherapeutischen Versorgung – eine weitergehende Betrach-tung der aufgezeigten Defizite vorzunehmen. Für ein umfassendes Bild sind zudem kongruente Folgearbeiten mit dem Augenmerk auf der Sichtweise der (teil-)stationären Behandlungseinrichtungen und der Patient:innen notwendig. Insbesondere vor dem Hintergrund der limitierten Möglichkeiten der vorliegenden Arbeit gilt es große repräsentative und nationale Studien anzustreben. Hierzu wäre die Etablierung zentral verwalteter Register zur Bündelung der bisherigen und zukünftigen Forschungsarbeiten im Bereich der Psychotherapie wünschenswert. Vor allem vor dem Hintergrund zahlreicher Modellprojekte erscheint dies sinnvoll und könnte einen wichtigen Beitrag zur Optimierung der derzeitigen psychotherapeutischen Forschungs- und Versorgungslage beitragen.
Background
The dmrt1 and sox9 genes have a well conserved function related to testis formation in vertebrates, and the group of fish presents a great diversity of species and reproductive mechanisms. The lambari fish (Astyanax altiparanae) is an important Neotropical species, where studies on molecular level of sex determination and gonad maturation are scarce.
Methods
Here, we employed molecular cloning techniques to analyze the cDNA sequences of the dmrt1 and sox9 genes, and describe the expression pattern of those genes during development and the male reproductive cycle by qRT-PCR, and related to histology of the gonad.
Results
Phylogenetic analyses of predicted amino acid sequences of dmrt1 and sox9 clustered A. altiparanae in the Ostariophysi group, which is consistent with the morphological phylogeny of this species. Studies of the gonad development revealed that ovary formation occurred at 58 days after hatching (dah), 2 weeks earlier than testis formation. Expression studies of sox9 and dmrt1 in different tissues of adult males and females and during development revealed specific expression in the testis, indicating that both genes also have a male-specific role in the adult. During the period of gonad sex differentiation, dmrt1 seems to have a more significant role than sox9. During the male reproductive cycle dmrt1 and sox9 are down-regulated after spermiation, indicating a role of these genes in spermatogenesis.
Conclusions
For the first time the dmrt1 and sox9 were cloned in a Characiformes species. We show that both genes have a conserved structure and expression, evidencing their role in sex determination, sex differentiation and the male reproductive cycle in A. altiparanae. These findings contribute to a better understanding of the molecular mechanisms of sex determination and differentiation in fish.
Arapaima gigas is one of the largest freshwater fish species of high ecological and economic importance. Overfishing and habitat destruction are severe threats to the remaining wild populations. By incorporating a chromosomal Hi-C contact map, we improved the arapaima genome assembly to chromosome-level, revealing an unexpected high degree of chromosome rearrangements during evolution of the bonytongues (Osteoglossiformes). Combining this new assembly with pool-sequencing of male and female genomes, we identified id2bbY, a duplicated copy of the inhibitor of DNA binding 2b (id2b) gene on the Y chromosome as candidate male sex-determining gene. A PCR-test for id2bbY was developed, demonstrating that this gene is a reliable male-specific marker for genotyping. Expression analyses showed that this gene is expressed in juvenile male gonads. Its paralog, id2ba, exhibits a male-biased expression in immature gonads. Transcriptome analyses and protein structure predictions confirm id2bbY as a prime candidate for the master sex-determiner. Acting through the TGF beta signaling pathway, id2bbY from arapaima would provide the first evidence for a link of this family of transcriptional regulators to sex determination. Our study broadens our current understanding about the evolution of sex determination genetic networks and provide a tool for improving arapaima aquaculture for commercial and conservation purposes.
Sex determination (SD) is a highly diverse and complex mechanism. In vertebrates, one of the first morphological differences between the sexes is the timing of initiation of the first meiosis, where its initiation occurs first in female and later in male. Thus, SD is intimately related to the responsiveness of the germ cells to undergo meiosis in a sex-specific manner. In some vertebrates, it has been reported that the timing for meiosis entry would be under control of retinoic acid (RA), through activation of Stra8. In this study, we used a fish model species for sex determination and lacking the stra8 gene, the Japanese medaka (Oryzias latipes), to investigate the connection between RA and the sex determination pathway. Exogenous RA treatments act as a stress factor inhibiting germ cell differentiation probably by activation of dmrt1a and amh. Disruption of the RA degrading enzyme gene cyp26a1 induced precocious meiosis and oogenesis in embryos/hatchlings of female and even some males. Transcriptome analyzes of cyp26a1–/–adult gonads revealed upregulation of genes related to germ cell differentiation and meiosis, in both ovaries and testes. Our findings show that germ cells respond to RA in a stra8 independent model species. The responsiveness to RA is conferred by sex-related genes, restricting its action to the sex differentiation period in both sexes.
In vertebrates, one of the first recognizable sex differences in embryos is the onset of meiosis, known to be regulated by retinoic acid (RA) in mammals. We investigated in medaka a possible meiotic function of RA during the embryonic sex determination (SD) period and in mature gonads. We found RA mediated transcriptional activation in germ cells of both sexes much earlier than the SD stage, however, no such activity during the critical stages of SD. In adults, expression of the RA metabolizing enzymes indicates sexually dimorphic RA levels. In testis, RA acts directly in Sertoli, Leydig and pre-meiotic germ cells. In ovaries, RA transcriptional activity is highest in meiotic oocytes. Our results show that RA plays an important role in meiosis induction and gametogenesis in adult medaka but contrary to common expectations, not for initiating the first meiosis in female germ cells at the SD stage.
Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies
(2021)
Purpose
Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN.
Methods
Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated.
Results
Median age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found.
Conclusion
No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation.
The main objectives of the KM3NeT Collaboration are (i) the discovery and subsequent observation of high-energy neutrino sources in the Universe and (ii) the determination of the mass hierarchy of neutrinos. These objectives are strongly motivated by two recent important discoveries, namely: (1) the high-energy astrophysical neutrino signal reported by IceCube and (2) the sizable contribution of electron neutrinos to the third neutrino mass eigenstate as reported by Daya Bay, Reno and others. To meet these objectives, the KM3NeT Collaboration plans to build a new Research Infrastructure consisting of a network of deep-sea neutrino telescopes in the Mediterranean Sea. A phased and distributed implementation is pursued which maximises the access to regional funds, the availability of human resources and the synergistic opportunities for the Earth and sea sciences community. Three suitable deep-sea sites are selected, namely off-shore Toulon (France), Capo Passero (Sicily, Italy) and Pylos (Peloponnese, Greece). The infrastructure will consist of three so-called building blocks. A building block comprises 115 strings, each string comprises 18 optical modules and each optical module comprises 31 photo-multiplier tubes. Each building block thus constitutes a three-dimensional array of photo sensors that can be used to detect the Cherenkov light produced by relativistic particles emerging from neutrino interactions. Two building blocks will be sparsely configured to fully explore the IceCube signal with similar instrumented volume, different methodology, improved resolution and
A highly significant excess of high-energy astrophysical neutrinos has been reported by the IceCube Collaboration. Some features of the energy and declination distributions of IceCube events hint at a North/South asymmetry of the neutrino flux. This could be due to the presence of the bulk of our Galaxy in the Southern hemisphere. The ANTARES neutrino telescope, located in the Mediterranean Sea, has been taking data since 2007. It offers the best sensitivity to muon neutrinos produced by galactic cosmic ray interactions in this region of the sky. In this letter a search for an extended neutrino flux from the Galactic Ridge region is presented. Different models of neutrino production by cosmic ray propagation are tested. No excess of events is observed and upper limits for different neutrino flux spectral indices Γ are set. For Γ=2.4 the 90% confidence level flux upper limit at 100 TeV for one neutrino flavour corresponds to Φ\(^{1f}_{0}\) (100 TeV) = 2.0 · 10\(^{−17}\) GeV\(^{−1}\) cm\(^{−2}\)s\(^{−1}\)sr\(^{−1}\). Under this assumption, at most two events of the IceCube cosmic candidates can originate from the Galactic Ridge. A simple power-law extrapolation of the Fermi-LAT flux to account for IceCube High Energy Starting Events is excluded at 90% confidence level.
A search for high-energy neutrino emission correlated with gamma-ray bursts outside the electromagnetic prompt-emission time window is presented. Using a stacking approach of the time delays between reported gamma-ray burst alerts and spatially coincident muon-neutrino signatures, data from the Antares neutrino telescope recorded between 2007 and 2012 are analysed. One year of public data from the IceCube detector between 2008 and 2009 have been also investigated. The respective timing profiles are scanned for statistically significant accumulations within 40 days of the Gamma Ray Burst, as expected from Lorentz Invariance Violation effects and some astrophysical models. No significant excess over the expected accidental coincidence rate could be found in either of the two data sets. The average strength of the neutrino signal is found to be fainter than one detectable neutrino signal per hundred gamma-ray bursts in the Antares data at 90% confidence level.
A search for Secluded Dark Matter annihilation in the Sun using 2007-2012 data of the ANTARES neutrino telescope is presented. Three different cases are considered: a) detection of dimuons that result from the decay of the mediator, or neutrino detection from: b) mediator that decays into a dimuon and, in turn, into neutrinos, and c) mediator that decays directly into neutrinos. As no significant excess over background is observed, constraints are derived on the dark matter mass and the lifetime of the mediator.
A search for muon neutrinos originating from dark matter annihilations in the Sun is performed using the data recorded by the ANTARES neutrino telescope from 2007 to 2012. In order to obtain the best possible sensitivities to dark matter signals, an optimisation of the event selection criteria is performed taking into account the background of atmospheric muons, atmospheric neutrinos and the energy spectra of the expected neutrino signals. No significant excess over the background is observed and 90% C.L. upper limits on the neutrino flux, the spin-dependent and spin-independent WIMP-nucleon cross-sections are derived for WIMP masses ranging from 50 GeV to 5 TeV for the annihilation channels WIMP + WIMP→ b\(\overline{b}\), W\(^{+}\)W\(^{−}\) and τ\(^{+}\)τ\(^{−}\).
Die AML stellt mit einem Anteil von 80 % an den akuten Leukämien bei Erwachsenen eine bedeutende Erkrankung für die Gesellschaft dar. Aufgrund fehlender durchbrechender Erfolge in der Therapieentwicklung liegt die durchschnittliche Fünfjahresüberlebensrate dennoch nur bei etwa 25 %. Der Blick auf die Kraft des Graft-versus-Leukämie-Effekts nach allogener Stammzelltransplantation, eine Langzeitremission der AML erzielen zu können, weist jedoch auf die Immunogenität und Eignung der Erkrankung für neue immuntherapeutische Ansätze hin.
Anhand der Kartierung der in-vivo präsentierten MHC-Klasse-I-Peptidome auf
AML-Blasten sollten in dieser Arbeit potenziell geeignete Therapietargets identifiziert werden, um eine breitere Anwendung immuntherapeutischer Strategien bei AML-Patienten zu ermöglichen. Auf primären Patientenmaterialien, Zelllinien und benignen Zellen wurden hierzu über eine Immunoaffinitätschromatographie mit nachfolgenden Purifizierungsschritten
die MHC-präsentierten Peptide massenspekrometrisch-basiert
identifiziert. Zusätzlich erfolgte eine Quantifizierung der Oberflächen- und intrazellulären MHC-Klasse-I-Moleküle der verwendeten Proben durch einen indirekten Immunfluoreszenz-Assay.
Unter der Gesamtheit von 17.750 identifizierten nicht-redundanten MHC-Klasse-
I-präsentierten Peptiden konnte eine Vielzahl von 5.626 Peptiden mit Präsentationsfrequenzen bis zu 72 % als AML-exklusiv beschrieben werden. Hierunter wurden 240 kryptische Peptide vermeintlich nicht-codierenden Ursprungs identifiziert. Zudem wurden mehrere potenziell CMV-kreuzreaktive AML-Peptide erfasst, die zu der reduzierten Rezidivrate bei CMV-Infektion nach allogener Stammzelltransplantation führen könnten. Bei der MHC-Quantifizierung wiesen die AML-Blasten keine verminderte MHC-Expression auf und stellten sich somit als geeignete Target-Zellen für eine T-Zell-Immuntherapie dar.
With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.
Optimal open-loop control, i.e. the application of an analytically derived control rule, is demonstrated for nanooptical excitations using polarization-shaped laser pulses. Optimal spatial near-field localization in gold nanoprisms and excitation switching is realized by applying a shift to the relative phase of the two polarization components. The achieved near-field switching confirms theoretical predictions, proves the applicability of predefined control rules in nanooptical light–matter interaction and reveals local mode interference to be an important control mechanism.
Radiationless energy transfer is at the core of diverse phenomena, such as light harvesting in photosynthesis\(^1\), energy-transfer-based microspectroscopies\(^2\), nanoscale quantum entanglement\(^3\) and photonic-mode hybridization\(^4\). Typically, the transfer is efficient only for separations that are much shorter than the diffraction limit. This hampers its application in optical communication and quantum information processing, which require spatially selective addressing. Here, we demonstrate highly efficient radiationless coherent energy transfer over a distance of twice the excitation wavelength by combining localized and delocalized\(^5\) plasmonic modes. Analogous to the Tavis-Cummings model, two whispering-gallery-mode antennas\(^6\) placed in the foci of an elliptical plasmonic cavity\(^7\) fabricated from single-crystal gold plates act as a pair of oscillators coupled to a common cavity mode. Time-resolved two-photon photoemission electron microscopy (TR 2P-PEEM) reveals an ultrafast long-range periodic energy transfer in accordance with the simulations. Our observations open perspectives for the optimization and tailoring of mesoscopic energy transfer and long-range quantum emitter coupling.
The aim of the present study was to design different dosage forms as carrier systems to deliver sorafenib to the lung of BXB-23 transgenic mice using different routes of administration. Three dosage forms were used one of them was an oil-in-water emulsion and the oral route was chosen for this experiment. The other delivery system was a liposome preparation for intratracheal instillation. In this case the oral route was considered as a control experiment. The last dosage form was PLGA microspheres. Before sorafenib administration it was important to develop a HPLC method to assess sorafenib absorption after its administration and to determine its concentrations in mouse serum. The HPLC method allowed sorafenib quantification in small volumes (30 µl) of mouse serum and tissues. The developed HPLC method was validated resulting in satisfactory selectivity, good linearity, good accuracy and precision over the concentration range examined. Sorafenib was successfully incorporated in a fat emulsion (o/w) using a traditional method resulting in a white homogenous emulsion and no particle aggregation was observed. Sorafenib exhibited antitumor activity on the lung adenoma in BXB-23 transgenic mice when administered orally (2 mg sorafenib per mouse) in the emulsion preparation. The determined effect was an approximately 29 % reduction in the tumor area of the adenoma foci and a proliferation reduction. In order to improve the pharmacological effects of sorafenib on the lung adenoma in BXB-23 mice, the targeting of sorafenib directly to the site of action (the lung) was an attractive concept. For this purpose the intratracheal route was used. Since sorafenib administration by instillation required incorporation of sorafenib in a dosage form suitable for its lipophilic nature, a liposome suspension was the second dosage form used. A lyophilization method was employed for sorafenib liposome preparation utilizing dilauroylphosphatidylcholine (DLPC) which is safe and tolerable for the lung. Incorporation of sorafenib in the liposomes did not influence the particle size and its distribution. The sorafenib liposomes showed high encapsulation efficiency, good stability at 4 °C for one month and satisfactory in vitro release properties and inhibited Raf-1 mediated activation of ERK in cell culture assay. In a pharmacokinetic experiment sorafenib loaded liposomes were instilled directly into the lung. The results revealed that a significant level of sorafenib was achieved in the lung tissues after 2 hours and then reduced after 48 h and remained nearly constant for one week. On the other hand, only traces of sorafenib were found in the mice serum up to 48 h. Subsequently, the pharmacological activity of sorafenib (1 mg per mouse) was studied when delivered in a liposomal suspension intratracheally to treat the lung adenoma of BXB-23 mice. The data of this experiment demonstrated that sorafenib intratracheal instillation resulted in a reduction of tumor area of adenoma foci (67 %) and an elevation of the percent of apoptotic cells. In contrast, prolongation of the treatment period did not further enhance sorafenib activity on the lung adenoma. This previous finding suggested a development of multidrug resistance (MDR) by the adenoma foci cells against sorafenib instillation, which was examined by immunohistochemistry staining. The percent of MDR positive cells was higher after two and three weeks sorafenib liposome instillation treatment than that after one week treatment. The last dosage form used for sorafenib was microspheres, which were prepared by emulsion-diffusion-evaporation method using biodegradable PLGA 50:50 resulting in a white lyophilized powder. The system was characterized physicochemically and revealed a good microspheres yield, high encapsulation efficiency, a homogenous particle size distribution and slow in vitro release of sorafenib. The other strategy studied in the present research project was gene delivery to target the lung bearing tumor of BXB-23 mice using a non-viral vector (polyethylenimine). Polyethylenimine (PEI) was used to investigate its efficiency in transfecting lung bearing tumor of BXB-23 mice model and its ability to transfect the adenoma foci cells. LacZ, which encodes Beta-galactosidase was used in the present study as a reporter gene and was complexed with PEI before delivered intravenously. A high LacZ expression in the alveolar region with some expression in the adenoma foci was observed. On contrary, a low LacZ expression in the alveoli and in the adenoma foci was achieved after instillation of the same polyplex intratracheally.
Background:
The interaction of eukaryotic host and prokaryotic pathogen cells is linked to specific changes in the cellular proteome, and consequently to infection-related gene expression patterns of the involved cells. To simultaneously assess the transcriptomes of both organisms during their interaction we developed dual 3'Seq, a tag-based sequencing protocol that allows for exact quantification of differentially expressed transcripts in interacting pro-and eukaryotic cells without prior fixation or physical disruption of the interaction.
Results:
Human epithelial cells were infected with Salmonella enterica Typhimurium as a model system for invasion of the intestinal epithelium, and the transcriptional response of the infected host cells together with the differential expression of invading and intracellular pathogen cells was determined by dual 3'Seq coupled with the next-generation sequencing-based transcriptome profiling technique deepSuperSAGE (deep Serial Analysis of Gene Expression). Annotation to reference transcriptomes comprising the operon structure of the employed S. enterica Typhimurium strain allowed for in silico separation of the interacting cells including quantification of polycistronic RNAs. Eighty-nine percent of the known loci are found to be transcribed in prokaryotic cells prior or subsequent to infection of the host, while 75% of all protein-coding loci are represented in the polyadenylated transcriptomes of human host cells.
Conclusions:
Dual 3'Seq was alternatively coupled to MACE (Massive Analysis of cDNA ends) to assess the advantages and drawbacks of a library preparation procedure that allows for sequencing of longer fragments. Additionally, the identified expression patterns of both organisms were validated by qRT-PCR using three independent biological replicates, which confirmed that RELB along with NFKB1 and NFKB2 are involved in the initial immune response of epithelial cells after infection with S. enterica Typhimurium.