Refine
Year of publication
- 2018 (250) (remove)
Document Type
- Doctoral Thesis (141)
- Article (108)
- Report (1)
Language
- English (152)
- German (97)
- Multiple languages (1)
Has Fulltext
- yes (250)
Is part of the Bibliography
- no (250)
Keywords
- - (91)
- Staphylococcus aureus (5)
- Depression (4)
- climate change (4)
- Mecklenburg-Vorpommern (3)
- SHIP (3)
- Sepsis (3)
- Simulation (3)
- Study of Health in Pomerania (3)
- dendrochronology (3)
- innate immunity (3)
- platelets (3)
- <i>Burkholderia pseudomallei</i> (2)
- Brain-derived neurotrophic factor (2)
- Bürgerkrieg (2)
- CASP model (2)
- China (2)
- Clinical guideline (2)
- Cystitis (2)
- Digitale Volumentomographie (2)
- Epidemiologie (2)
- Fettsucht (2)
- Flavivirus (2)
- Fournier’s gangrene (2)
- GWAS (2)
- Germany (2)
- Hyperbaric oxygenation (2)
- Kernspintomografie (2)
- Klimawandel (2)
- Magen (2)
- Morphologic changes (2)
- Necrotizing fasciitis (2)
- Necrotomy (2)
- Obesity (2)
- Oxidoreduktase (2)
- Plasma (2)
- Plasmaphysik (2)
- Proteine (2)
- Pyelonephritis (2)
- Sepsis score (2)
- Small animal MRI (2)
- Soft tissue infection (2)
- Spiroergometrie (2)
- Streptococcus pneumoniae (2)
- Systematic review (2)
- Therapy (2)
- Tollwut (2)
- Urinary tract infection (2)
- Uterus (2)
- Verhalten (2)
- Vitamin D (2)
- Wirkstofffreisetzung (2)
- Wundheilung (2)
- antibiotics (2)
- antimicrobial peptides (2)
- ascariasis (2)
- bias (2)
- biofilm (2)
- causal inference (2)
- dendroecology (2)
- environment (2)
- epidemiology (2)
- helminth (2)
- intestinal nematode (2)
- lectin (2)
- melioidosis (2)
- mendelian randomization (2)
- metabolomics (2)
- microbiota (2)
- phenotypic plasticity (2)
- proteomics (2)
- public awareness (2)
- statistical methods (2)
- tree-ring width (2)
- 1,2,3-benzotriazoles (1)
- 1,2,4-triazoles (1)
- 1999-2009 (1)
- 2,4-diamino-1,3,5-triazines (1)
- 2-imino-2<i>H</i>-chromen-3-yl-1,3,5-triazines (1)
- 2-imino-coumarins (1)
- 2<i>H</i>-chromen-3-yl-1,3,5-triazines (1)
- 2D PAGE (1)
- 3D-Druck (1)
- 4015016-1 (1)
- 4042270-7 (1)
- 4042278-1 (1)
- 4049722-7 (1)
- 4121138-8 (1)
- 4121944-2 (1)
- 4137913-5 (1)
- 4165547-3 (1)
- 4175999-0 (1)
- 4185874-8 (1)
- 4188802-9 (1)
- 4216345-6 (1)
- 4251573-7 (1)
- <i>Clostridiodes difficile</i> (1)
- <i>Hermite</i>-polynomials (1)
- <i>Kolmogorov</i>-backward-equation (1)
- <i>N</i>-acylhydrazones (1)
- <i>N</i>-sulfonylhydrazones (1)
- <i>S. aureus</i> (1)
- ACT-209905 (1)
- AFLP, microsatellite SSR, ITS, DNA isolation (1)
- AMC DCBA (1)
- AQT90 FLEX (1)
- ATP-binding cassette transporters (1)
- Acne inversa (1)
- Adaptation (1)
- Adenosarkom (1)
- Aerobe Leistungsfähigkeit (1)
- Africa (1)
- African swine fever virus (1)
- Afrikanische Schweinepest Virus (1)
- Afrikanisches Schweinepest-Virus (1)
- Aggravation (1)
- Akne inversa (1)
- Alaska (1)
- Alfvén Waves (1)
- Allgemeinbevölkerung (1)
- Alpha-Winkel (1)
- Amymetacresol (1)
- Anatomie (1)
- Angiogenese (1)
- Angiopoietine (1)
- Angiotensin-(1-7) (1)
- Animal behavior (1)
- Annual rings (1)
- Anthropometrie (1)
- Antibiotika (1)
- Antibiotikum (1)
- Antioxidans (1)
- Antisense-Transkription (1)
- Anxiety sensitivity (1)
- Aorta (1)
- Aortenwanddicke (1)
- Apolipoprotein E (1)
- Arbovirus (1)
- Architektur (1)
- Arsen (1)
- Arzneistofftransporter (1)
- Asymmetric synthesis (1)
- Atherosklerose (1)
- Aufbereitung (1)
- Aufbissschiene (1)
- Austria (1)
- B cell class switch (1)
- B1 B cells (1)
- Bathymodiolus (1)
- Bathymodiolus symbiosis (1)
- Bauchspeicheldrüse (1)
- Bauleitplanung (1)
- Baumgrenze (1)
- Baurecht (1)
- Bayley scales (1)
- Befragung (1)
- Belastungshypertonus (1)
- Benign breast tumours (1)
- Beringung (1)
- Berufsausbildung (1)
- Bicyclomycin (1)
- Bildqualität (1)
- Biochemie (1)
- Biodiesel (1)
- Biokatalyse , Organische Synthese , Enzym , Prozessoptimierung (1)
- Biomathematik , Bioinformatik (1)
- Biopharmazie (1)
- Biorelevante Wirkstofffreisetzung (1)
- Biosphärenreservat (1)
- Blue Intensity (1)
- Bodentemperatur (1)
- Bronchialkarzinom (1)
- Bronchopulmonary dysplasia (1)
- Brust MRT (1)
- Buche (1)
- CA–Markov (1)
- CCD-Winkel (1)
- CD40L (1)
- CD8+ T-Zellantwort (1)
- CFTR Cl (1)
- CKD (1)
- CM-Wire (1)
- CPET (1)
- CRMP2 (1)
- Canalis (1)
- Canalis nasolacrimalis (1)
- Candida albicans (1)
- Capillary blood glucose; Diabetes mellitus; Glucose concentration measurement; Impaired glucose tolerance; Oral glucose tolerance test; OGTT; Point-of-care-testing; POCT; Plasma-referenced blood glucose; Unit use (1)
- Cardiopulmonary bypass (1)
- Center-Edge Winkel (1)
- Cerebral Palsy Kinder (1)
- Cerebral cavernous malformations (1)
- Chemo-enzymatic synthesis (1)
- Chinin (1)
- Chiral amines (1)
- Civil conflicts (1)
- Clade Annotation (1)
- Claudicatio spinalis (1)
- Climate Change (1)
- ClinROM, Clinician reported outcome measures (1)
- Clusteranalyse (1)
- Cochlea-Implantat (1)
- Cochrane–Orcutt procedure (1)
- Cold Atmospheric Pressure Plasma (1)
- Collisions (1)
- Comparative Gene Finding (1)
- Comparative Genomics (1)
- Cowpox virus (1)
- Craniomandibuläre Dysfunktion (1)
- Cronbach's alpha (1)
- CyberKnife robotic radiosurgery (1)
- Cybermobbing (1)
- Cystatin C (1)
- Cytochrome P-450 (1)
- DHEAS (1)
- DIN-Norm (1)
- DISQOVER (1)
- DLX proteins (1)
- DNA-microarray (1)
- Dach1 (1)
- Dark Blood Sequenz (1)
- Darm (1)
- Darstellung (1)
- Deep-sea hydrothermal vents (1)
- Democracy (1)
- Demokratie (1)
- Dendrochronologie (1)
- Depressivität (1)
- Dermatochirurgie (1)
- Desinfektion (1)
- Deutschland (1)
- Deutschland <DDR> (1)
- Diabetes mellitus , Blutzucker , Messgerät , Kapillarblut , Messgenauigkeit (1)
- Diagnosis (1)
- Diastolische Dysfunktion (1)
- Differenzierung (1)
- Dispersal (1)
- Diversität (1)
- Doppelkronen (1)
- Doxorubicin (1)
- Drug recall (1)
- Drygala (1)
- Dual Decomposition (1)
- Dysfunktionale Kognitionen (1)
- EBERA (1)
- ECAP (1)
- EEG (1)
- EMSA (1)
- Ecosystem Dynamics (1)
- Efflux (1)
- Einstellung (1)
- Einzelhandel (1)
- Elektrochemischer Sensor (1)
- Empfindlichkeit (1)
- Endometriumkarzinom (1)
- Endothel (1)
- Entdifferenzierung (1)
- Entropium (1)
- Entwicklungszusammenarbeit (1)
- Environmental conditions (1)
- Epidemiology (1)
- Epigenetik (1)
- Erwartungsbilder (1)
- Evolution (1)
- Evolutionsbiologie , Tierökologie , Sexuelle Selektion , Sexualverhalten (1)
- Exosomen (1)
- FMD (1)
- FRET (1)
- FRS (1)
- Facettengelenksinjektion (1)
- Facettensyndrom (1)
- Fachkräfte akquirieren (1)
- False-Belief-Test (1)
- Fast Particles (1)
- Faszikularisgruppe (1)
- Feldversuch (1)
- Femurkopfdurchmesser (1)
- Feste Arzneiform (1)
- Fettfreie Masse (1)
- Fettstoffwechsel (1)
- Flight ability (1)
- Flug (1)
- Fluoreszenz-Resonanz-Energie-Transfer (1)
- Folgekosten (1)
- Foreign aid (1)
- Fossa pterygopalatina (1)
- Fourier analysis (1)
- Friedensvertrag (1)
- Frühkindliche Lebensereignisse (1)
- Full Anticoagulation (1)
- Funktionsfragebogen Hannover-Rückenschmerz (1)
- Fusarium solani (1)
- Fused Deposition Modeling (1)
- Förster-Resonanzenergietransfer (1)
- G-Quadruplex (1)
- GAPDH, ALDH (1)
- GHG emissions (1)
- GPU computing (1)
- Gastrointestinal oncology (1)
- Gastrointestinal stromal tumor (1)
- Gastrointestinal symptoms (1)
- Gastrointestinal tract (1)
- Gastroretentive Arzneiform (1)
- Gefäßstenose (1)
- Gehstrecke (1)
- Gender Mainstreaming (1)
- Gene Structure Prediction (1)
- Genetic counselling (1)
- Genetic diversity (1)
- Genome Annotation (1)
- Genotyping (1)
- Geräuschreduktion (1)
- Gesamtüberleben (1)
- Geschichte (1)
- Geschlechterforschung (1)
- Gesunde (1)
- Gewaltopfer, Gewaltambulanz, Unfallchirurgie, Dokumentationsqualität (1)
- Glazitektonik (1)
- Global South regional policy (1)
- Global change (1)
- Glomeruläre Filtrationsrate (1)
- Glutaredoxin (1)
- Glutaredoxine (1)
- Glutathion (1)
- Glutathione (1)
- Glycoprotein B (1)
- Gorilla (1)
- Graphen (1)
- Greifvögel (1)
- Gyro-kinetic Theory (1)
- Güstrow Parchim (1)
- HACA (1)
- HCMV (1)
- HCO (1)
- HEV (1)
- HFpEF (1)
- HIT (1)
- HSP27 (1)
- Halsschmerz (1)
- Hangzhou International Airport (1)
- Harris Hip Score (1)
- Haupttestgütekriterien von Assessments (1)
- Heart failure (1)
- Heat-flux (1)
- Henipavirus-ähnliche Partikel (1)
- Hepatitis-E-Virus , Polymerase-Kettenreaktion , Microarray , West-Nil-Virus , Flaviviren , RNS-Viren , Genotypisierung (1)
- Hermeneutik (1)
- Herpesviren (1)
- Herpesvirus suis (1)
- Herz-Lungen-Maschine (1)
- Herzchirurgie (1)
- Herzinsuffizienz (1)
- Heterostrukturen (1)
- Himalayan Silver Fir (<i>Abies spectabilis</i>), Nepal Himalaya (1)
- Hirninfarkt (1)
- Histon-Demethylase (1)
- Hitzeschockprotein (1)
- Hominidae (1)
- Homo sapiens (1)
- Homöopathie (1)
- Humanmedizin (1)
- Humanphysiologie (1)
- Hydrozephalus (1)
- Hyperspectral Imaging (1)
- Hyperventilation (1)
- Hüft- und Knie-Totalendoprothese (TEP) (1)
- Hüftgelenk (1)
- IDD in pregnant women (1)
- IL-10 (1)
- Ili River delta (1)
- Imaging features (1)
- Immunologie (1)
- Immuntoxizität (1)
- Impfeinstellung (1)
- Impfen (1)
- Impfstoff (1)
- Impfverhalten (1)
- Implantate (1)
- In vitro (1)
- In vitro-Freisetzungsmodell (1)
- In vivo (1)
- Individual phenotype (1)
- Indolochinolin (1)
- Insulin-like Growth Factor (1)
- Integrins (1)
- Intelligenzstörung (1)
- Interoception (1)
- Interozeption (1)
- Intrastate conflicts (1)
- Intraventricular hemorrhage (1)
- Iodine (1)
- Iodine deficiency disorders (1)
- Ionthruster (1)
- Isopropylamine (1)
- Isothermale Titrationskalorimetrie (1)
- JSNZ (1)
- Jahresring (1)
- Japanische (1)
- Japanische Makaken (1)
- Juniperus communis (1)
- Jurkat (1)
- Kaltplasma (1)
- Kardiopulmonale Fitness (1)
- Kardiorespiratorische Fitness (1)
- Kartografie (1)
- Kartographiegeschichte (1)
- Karzinom (1)
- Karzinosarkom (1)
- Kephalometrie (1)
- Kephalometrische Analyse (1)
- Keratin 15 (1)
- Ketamin (1)
- Kieferorthopädie (1)
- Kindergarten (1)
- Kindesalter (1)
- Kinetic simulation (1)
- Klinische Studie (1)
- Knee Society Score (1)
- Knochendicke (1)
- Kohärenzgefühl (1)
- Kolonkarzinom (1)
- Komplexes Plasma (1)
- Komplikationen (1)
- Konfliktregelung (1)
- Kontaktlinsen (1)
- Kontaktlinsendesinfektion (1)
- Kontaktlinsenreinigung (1)
- Konuskronenprothesen (1)
- Korrespondenzprinzip (1)
- Kosten (1)
- Kreatinin (1)
- Kritische Lebensereignisse (1)
- Kuhpockenvirus (1)
- Kupffer-Zellen (1)
- Kupfferzellen (1)
- Körperzellmasse (1)
- Körperzusammensetzung (1)
- LAVH (1)
- LED (1)
- LIGHT (1)
- LPS (1)
- LUCC (1)
- Lagrangian Relaxation (1)
- Lake Balkhash (1)
- Landformanalyse (1)
- Landolt-Ring (1)
- Landsat (1)
- Lebensereignis (1)
- Leber (1)
- Lebermetastasen (1)
- Leistungsphysiologie (1)
- Lemnaceae (1)
- LiDAR (1)
- Ligand-DNA-Interaktion (1)
- Lipide (1)
- Liposomen (1)
- Local adaptation (1)
- Lord's Resistance Army (1)
- Low temperature plasma (1)
- Lumbale Fusionsoperationen (1)
- Lumbale Spinalkanalstenose (1)
- Lungentumor (1)
- Lycaena tityrus (1)
- Lymphknotensilikose (1)
- Lymphozyt (1)
- M-Wire (1)
- MTIP planning (1)
- Macaca (1)
- Macaca fuscata (1)
- Machtteilungsregierungen (1)
- Magenmotilität (1)
- Magnetfeld (1)
- Magnetfeldinduktion (1)
- Magnetismus (1)
- Makaken (1)
- Makrophagen (1)
- Makrophagendepletion (1)
- Maligner Müller Mischtumor (1)
- Mantelgas (1)
- Manuelle Muskelkrafttestung (1)
- Mas-Rezeptor (1)
- Master-Gleichung (1)
- Mathematik (1)
- Maximale Sauerstoffaufnahme (1)
- Mediation (1)
- Medienbildung (1)
- Mediennutzungsethik (1)
- Medikamentenkonsum (1)
- Medizin (1)
- Membranfusion (1)
- Mensch (1)
- Mentale Retardierung (1)
- Metastasis (1)
- Methoden der Philosophie (1)
- Middle East (1)
- Migration (1)
- Mikrobiologie (1)
- Minimally invasive diagnostics (1)
- Mitochondrium (1)
- Mixed methods (1)
- Modellverbindungen (1)
- Molarenwurzel (1)
- Molecular biology (1)
- Molecular genetics (1)
- Molekularbiologie (1)
- Molekularbiologie, Genotypisierung, Genetische Diversität (1)
- Molybdenum (1)
- Molybdopterin (1)
- Molybdän-Cofaktor (1)
- Molybdän-Cofaktor-Defizienz (1)
- Monitoring IDD (1)
- Monte Carlo (1)
- Motivation (1)
- Movement (1)
- NF-Y (1)
- NUTS2-Regionen (1)
- Naturstoff (1)
- NeT (1)
- Nerve Root Sedimentation Sign (1)
- Neurodevelopmental Disorders (1)
- Neurodevelopmental outcome (1)
- Neuroimmunologie (1)
- Neurologie (1)
- Neuronale Differenzierung (1)
- Neuronale Plastizität (1)
- Neurowissenschaften (1)
- Neutral-Null-Methode (1)
- Nichtlineare Dynamik (1)
- Nickel-Titan-Systeme (1)
- Nickel-titanium (1)
- Nierenfunktionsparameter (1)
- Nipahvirus (1)
- OATP2B1 (1)
- OCT1 (1)
- Olga Maria Drygala (1)
- Online Befragung (1)
- Optomechanik (1)
- Oral health, Cerebral palsy, Children, Prevention (1)
- Orale Gesundheit (1)
- Orang-Utan (1)
- Organo-Anionen-Transporter (1)
- Organo-Anionen-Transporter 2B1 (1)
- Osmoregulation (1)
- Osteocalcin (1)
- Osteoporose (1)
- Osteosarkom (1)
- Outcomes research (1)
- Ovarialkarzinom (1)
- Overview (1)
- Oxidativer Stress (1)
- P300 (1)
- PCLake (1)
- PD-L1 (1)
- PEI,PDADMA,PSS,surface forces,atomic force microscopy, colloidal probe (1)
- PF4 (1)
- POCT (1)
- PP2 (1)
- PROM, Patient reported outcome measures (1)
- Pantoprazol (1)
- Parietale Epithelzellen (1)
- Parkinson's disease (1)
- Partial migration (1)
- Pathogenität (1)
- Patientennahe Sofortdiagnostik (1)
- Pearson Korrelation (1)
- Pediatric (1)
- Permissive hypercapnia (1)
- Pflege (1)
- Pflegepraktikum (1)
- Pharmakokinetik (1)
- Pharmakologie (1)
- Pharmazeutische Technologie (1)
- Physiotherapie (1)
- Picea glauca (1)
- Plasma , Plasmaphysik , Tokamak , Stellarator , Magnetohydrodynamik , Kinetische Theorie , Simulation , Alfvén-Welle , Energiereiches Teilchen (1)
- Plasma Physics (1)
- Plasmamedizin (1)
- Plastizität (1)
- Podocyte (1)
- Political Economy (1)
- Politische Ökonomie (1)
- Polymere (1)
- Polyneuropathie (1)
- Polyphenole (1)
- Pongiden (1)
- Postoperatives Schmerzempfinden nach Wirbelsäulenoperationen (1)
- Potamopyrgus antipodarum (1)
- Potentiale (1)
- Power-Sharing (1)
- Prevalence (1)
- Prevention (1)
- Primaten (1)
- Printmedien (1)
- Profilbilanzierung (1)
- Proliferation (1)
- Protease-aktivierter Rezeptor-2 (1)
- Protein engineering (1)
- Proteom (1)
- Proteomanalyse (1)
- Prädikate (1)
- Prädikatoren (1)
- Prävention (1)
- Pseudomonas aeruginosa (1)
- Psychiatrie (1)
- Psychopathologie (1)
- Psychosomatik (1)
- Pt(II) complexes (1)
- Pterin (1)
- Pulswelle (1)
- Pulswellenanalyse (1)
- Pädiater (1)
- Qualitätsmanagement Akutschmerz (1)
- Quantenoptik (1)
- Quantenpunkt (1)
- Quantifizierung (1)
- Quarz (1)
- Querschnittserhebung (1)
- RT-qPCR (1)
- Rabies (1)
- Rabies virus (1)
- Radikalfänger (1)
- Radiologische Diagnostik (1)
- Radon (1)
- Range shift (1)
- Rapsanbau (1)
- Raumbedeutsamkeit (1)
- Raumordnung (1)
- Raumordnungsrecht (1)
- Reaktive Sauerstoffspezies (1)
- Recurrence (1)
- Redoxplasmid (1)
- Referenzwerte (1)
- Relativismus (1)
- Relativistische Quantenmechanik (1)
- RenBP (1)
- Renin (1)
- Renin Binding Protein (1)
- Reservoirwirt (1)
- Rezidivfreies Intervall (1)
- Risk Assessment (1)
- Rocker switch (1)
- Rotbuche (1)
- S. aureus (1)
- SFC-MS (1)
- SHIP- Studie (1)
- SIRT2 (1)
- SLCO2B1 (1)
- SNP (1)
- STED microscopy (1)
- SaeRS (1)
- Salztoleranz (1)
- Sarkom (1)
- Sarkomatös entdifferenziertes Endometriumkarzinom (1)
- Schamethik (1)
- Scheindissense (1)
- Scherstress (1)
- Schimpanse (1)
- Schlaganfall (1)
- Schlaganfall induzierte Immunschwäche (1)
- Schmetterling (1)
- Schnecke (1)
- Schwangerschaft (1)
- Schweinekrankheit (1)
- Schweineleberesterase (1)
- SedSign (1)
- Sekretion (1)
- Selbstmanagement (1)
- Serratia marcescens (1)
- Sexting (1)
- Short Form 36 Health Questionnaire (SF-36) (1)
- Shrubs (1)
- Shunt (1)
- Silikose (1)
- Sinlge port (1)
- Sinus maxillaris (1)
- Sirt2 (1)
- Sirtuin (1)
- Solute Carrier (1)
- Sonographie (1)
- Sonography (1)
- Sowjetisch-Deutsche Aktiengesellschaft Wismut (1)
- Soziale Unterstützung (1)
- Sozialität (1)
- Sphingosine-1-Phosphate (1)
- Spinalkanalstenose (1)
- Spinnen (1)
- Spintronik (1)
- Splitomicin (1)
- SrGAP3 (1)
- Src Tyrosinkinase (1)
- Stadtentwicklung (1)
- Staffelstein-Score Version Hüfte und Knie (1)
- Starch (1)
- Stark gekoppelte Systeme (1)
- Statine (1)
- Stellarator (1)
- Stelligkeitserhöhung (1)
- Sterilisation (1)
- Stickland reactions (1)
- Stickstoffdüngung (1)
- Stimmungen (1)
- Streutheorie (1)
- Study of Healt in Pomerania (1)
- Stumpfes Bauchtrauma (1)
- Stärke (1)
- T cell maturation (1)
- THP-1 (1)
- TRPC (1)
- Tabletten (1)
- Teilzug (1)
- Tetrahydroindolon (1)
- Tetrazol (1)
- Theodoxus fluviatilis (1)
- Theory of Mind (1)
- Thiole (1)
- Thioredoxine (1)
- Third-party intervention (1)
- Thorakale Periduralanästhesie (1)
- Thrombospondin (1)
- Tierphysiologie (1)
- Tierseuche (1)
- Tigecyclin (1)
- Tokamak (1)
- Tollwutvirus (1)
- Topografie (1)
- Touristische Karten der DDR (1)
- Toxizität (1)
- Transaminases (1)
- Transfektion (1)
- Transkriptionstermination (1)
- Transporter (1)
- Treibhausgasemissionen (1)
- Triangulärer Index (1)
- Troponin (1)
- Tumor (1)
- Two component systems (1)
- Tyrosinkinase-Rezeptor 2 (1)
- UNESCO (1)
- UV-Strahlung (1)
- UVC-Bestrahlung (1)
- Uganda (1)
- Ultraschalldiagnostik (1)
- Umwelt (1)
- Uncoupling (1)
- VEEV (1)
- Vagusnerv (1)
- Validierung (1)
- Vascular malformation (1)
- Vegetation Ecology (1)
- Verbreitung (1)
- Verlag (1)
- Verlagsgeschichte (1)
- Videodefiziteffekt (1)
- Vietnam (1)
- Virologie (1)
- Virus (1)
- Virus evolution (1)
- Virusinfektion (1)
- Visustest (1)
- Vogelzug (1)
- Vollheparinisierung (1)
- Vorpommern (1)
- WNV (1)
- WOMAC® (1)
- Wachstum (1)
- Waldgrenze (1)
- Waldökologie (1)
- Waldökosystem (1)
- Weichselvereisung (1)
- Weißfichte (1)
- Windenergieanlagen (1)
- Winter (1)
- Wirbelsäulendeformität (1)
- Wohnungsbau (1)
- Wound Healing (1)
- Wurzelkanalmodelle (1)
- Wurzellänge (1)
- Yeast (1)
- Zahnentwicklung (1)
- Zahnkeimvolumina (1)
- Zahnwurzel (1)
- Zellkultur (1)
- Zitterbewegung (1)
- Zoonose (1)
- Zufriedenheit (1)
- Zukunftspläne (1)
- Zweikomponentensystem (1)
- Zytoskelett (1)
- Zytosolisches Renin (1)
- [Fe-S] Cluster (1)
- absolute (1)
- adaptation (1)
- adaptive immunity (1)
- age (1)
- agroecosystems (1)
- airport cases (1)
- alanine scanning (1)
- alcohol risk drinking (1)
- alexithymia (1)
- ambulante muskuloskeletale Rehabilitation (1)
- amino acids (1)
- anaerobic metabolism (1)
- animal (1)
- anthropometrics (1)
- anti-GD<sub>2</sub> immunotherapy (1)
- anticoagulants (1)
- anticonvulsants (1)
- antiseptic stewardship (1)
- aquaporins (1)
- aquatic plants (1)
- arable wild plants (1)
- arid river basins (1)
- arm (1)
- arm ability training (1)
- asymmetric synthesis (1)
- asymptotic expansion (1)
- atomic force microscopy (1)
- attention (1)
- autoimmunity (1)
- autoregressive conditional heteroskedasticity (1)
- averaging (1)
- bacterial meningitis (1)
- beech (1)
- berufliche Entwicklung (1)
- berufliche Spezialisierung (1)
- berufliche Ziele (1)
- big-fish-little-pond-effect (1)
- bile acids (1)
- binding force (1)
- binding land-use plan (1)
- biocide (1)
- biodiversity offsets (1)
- biomanipulation (1)
- biorelevant dissolution (1)
- blood–brain barrier (1)
- body cell mass (1)
- body composition (1)
- boreal forest (1)
- brain stimulation (1)
- brownfields (1)
- cancer therapy (1)
- carbon–carbon lyase (1)
- carboplatin (1)
- cardiac surgery (1)
- cardiac troponin (1)
- cardiopulmonary fitness (1)
- cardiorespiratory exercise capacity (1)
- catalytic activity (1)
- caudal epidural morphin (1)
- ch14.18/CHO (1)
- chaperones (1)
- child development (1)
- chromoplexy (1)
- chromosomal translocations (1)
- chromosome conformation capture (1)
- chronic pancreatitis (1)
- chronotypes (1)
- cine SSFP- Sequenz (1)
- cisplatin (1)
- climate elasticity (1)
- climate regime (1)
- climate sensitivity (1)
- climate signal age effects (1)
- climate variability (1)
- climate warming (1)
- climate-growth relationships (1)
- climate–growth relationships (1)
- clinical wound healing (1)
- cloud removal (1)
- clustering (1)
- cognition (1)
- cognitive control (1)
- colonization (1)
- combination assay (1)
- comorbidity (1)
- complement dependent cytotoxicity (1)
- composite ridges (1)
- computational fluid dynamics (1)
- concussion (1)
- cone beam computed tomography (1)
- corridor development strategies (1)
- coumarins (1)
- counterfactual analysis (1)
- criterial (1)
- cross-reactivity (1)
- cross-resistance (1)
- cross-tolerance (1)
- crystallized intelligence (1)
- cutaneous T-cell lymphoma (1)
- cyberbullying (1)
- cytosolic Renin (1)
- damage-associated molecular patterns (1)
- deep sequencing (1)
- dehydroepiandrosterone (1)
- dendritic cells (1)
- deutschlandweit (1)
- developmental screening (1)
- diffusion tensor imaging (1)
- diffusion tractography (1)
- diffusion weighted imaging (1)
- digital elevation models (1)
- digitale Volumentomographie (1)
- dreidimenional (1)
- dreidimensional (1)
- dual task (1)
- duckweed (1)
- ductal closure (1)
- ductal epithelium (1)
- early competencies (1)
- echocardiography (1)
- ecology (1)
- ecosystem dynamics (1)
- education (1)
- elektrische Stimulation (1)
- embodied cognition (1)
- embodiment (1)
- empathy (1)
- endothelfunktion (1)
- entry (1)
- environmental offsets (1)
- epilepsy (1)
- epileptic encephalopathies (1)
- epithelial fluid secretion (1)
- ethics of media use (1)
- ethics of shame (1)
- eutrophication (1)
- evozierte Potentiale (1)
- exercise (1)
- exercise physiology (1)
- experimental pancreatitis (1)
- experimental plant ecology (1)
- expression (1)
- fagus sylvatica (1)
- fat-free mass (1)
- fatty acids (1)
- fetal and adult neurogenesis (1)
- fisheries (1)
- flow tank (1)
- fluid intelligence (1)
- forest ecology (1)
- forest understory vegetation (1)
- free amino acids (1)
- fuscata (1)
- fusion loops (1)
- gH/gL complex (1)
- gastroretentive dosage form (1)
- genetic adaptation (1)
- genomics (1)
- genotyping (1)
- geometric morphometrics (1)
- gestural-verbal association (1)
- gewebeverträgliches Plasma (1)
- glacier skiing (1)
- glacitectonics (1)
- glioblastoma multiforme (1)
- global production networks (1)
- glutaredoxins (1)
- gradient-design field experiment (1)
- granuloma (1)
- greenfields (1)
- gross tumor volume optimization (1)
- gutachterlich (1)
- habituation (1)
- health risk behaviors (1)
- healthcare (1)
- heat-shock proteins (1)
- heparin- and antibody-induced thrombocytopenia (1)
- heparins (1)
- herpesvirus (1)
- high thoracic peridural anaesthesie (1)
- high-ability tracked students (1)
- high-frequency heart rate variability (1)
- homoarginine (1)
- host-symbiont (1)
- human (1)
- humanized mice (1)
- hybrid molecules (1)
- hydrazones (1)
- hydrological regimes (1)
- hypertension (1)
- häusliche Gewalt (1)
- ibuprofen (1)
- image reconstruction (1)
- imagery (1)
- immune evasion (1)
- immunogenicity (1)
- impact mitigation regulation (1)
- implied volatility surface (1)
- in vitro anticancer activity (1)
- in vitro antitumor activity (1)
- inactivity (1)
- incidence (1)
- individual academic self-concept (SESSKO) (1)
- individual based (1)
- indoleamine 2,3-dioxygenase (1)
- indomethacin (1)
- industrielle Biokatalyse (1)
- infants (1)
- infection (1)
- inflammation (1)
- infrastructure (1)
- inner urban development (1)
- insurance claims (1)
- interactions (1)
- intrakraniell (1)
- invasive (1)
- iodine deficiency disorders (1)
- iron surrogates (1)
- isoprenoid degradation (1)
- jep Gene (1)
- junge Erwachsene (1)
- kINPenMed (1)
- kaltes Atmosphärendruck-Argon-Plasma (1)
- kardiopulmonale Belastbarkeit (1)
- kardiovaskuläre Risikofaktoren (1)
- katalytische Aktivität (1)
- kephalometrisch (1)
- knowledge-is-power (1)
- kognitive Entwicklungspsychologie (1)
- kynurenine pathway (1)
- lake restoration. nutrient load reduction (1)
- land conversion (1)
- land use change (1)
- landcover reconstruction (1)
- language disorders (1)
- language processing (1)
- levetiracetam (1)
- light-sheet imaging (1)
- linear discriminant analyses (1)
- lipoprotein (1)
- lipoprotein profiling (1)
- locus coeruleus (1)
- long-term infusion (1)
- longitudinal (1)
- luciferase reporter gene assay (1)
- lung metastases (1)
- lymphocyte trafficking (1)
- mTHPC (1)
- maligner Mischtumor (1)
- mass spectrometry (1)
- mast cell (1)
- matrix metalloproteinase (1)
- maximum latewood density (1)
- mechanism (1)
- media education (1)
- medical assistants (1)
- membrane fusion (1)
- mental representations (1)
- mental rotation (1)
- mental transformations (1)
- metabolic interactions (1)
- metabolism (1)
- methyltryptophan (1)
- micro-site (1)
- mikrobielle Reinigung (1)
- mineral soil (1)
- mixed model (1)
- mode comparison (1)
- monoterpene (1)
- mortality (1)
- motility (1)
- mouse model (1)
- mucosal immunity (1)
- mucus (1)
- multiphoton imaging (1)
- multitasking (1)
- myeloid-derived suppressor cells (1)
- myxomycetes (1)
- nasolacrimalis (1)
- near-hand space (1)
- neuroactive steroids (1)
- neuroblastoma (1)
- neuroendokrin (1)
- neuropsychiatric diseases (1)
- night shift work (1)
- no-net-loss (1)
- noXrayceph® (1)
- non-small cell lung cancer (1)
- norepinephrine (1)
- objektive Diagnostik (1)
- objektivierter Sehschärfevalidierungstest (1)
- oil palm plantation (1)
- optical imaging analyses (1)
- osmoregulation (1)
- osmotolerance (1)
- overfishing (1)
- overweight (1)
- oxaliplatin (1)
- oxidoreductase (1)
- pain (1)
- palynology (1)
- pancreas (1)
- patent ductus arteriosus (1)
- patientennahe und klinische Erhebungsverfahren (1)
- peak oxygen uptake (1)
- pediatric thrombosis (1)
- peptidases (1)
- peptide sharing (1)
- peripersonal space (1)
- peritoneal B cells (1)
- photodynamic therapy (1)
- phylogenetic (1)
- physiological responses (1)
- phytosterols (1)
- pig (1)
- plant traits (1)
- plasticity (1)
- poaching (1)
- podocyte nephropathy (1)
- point-of-care testing (1)
- pollen accumulation rates (1)
- pollen productivity estimates (1)
- poly(hydroxyalkanoates) (1)
- polycrystalline gold (1)
- population-based (1)
- population-based study (1)
- post-translational modifications (1)
- postnatales Wachstum (1)
- pregnenolone sulfate (1)
- preschool (1)
- preterm infant (1)
- prevalence (1)
- prevention (1)
- principal component analyses (1)
- production-integrated compensation (1)
- promoter (1)
- protection (1)
- protein (1)
- protein synthesis (1)
- proteins (1)
- psychological refractory period (PRP) (1)
- pterygopalatine fossa (1)
- pyramidal tract integrity (1)
- quinolines (1)
- rabies (1)
- radical polishing (1)
- radiometric interpolation (1)
- raumbedeutsam (1)
- re-epithelialization (1)
- reactivation (1)
- recruitment curve steepness (1)
- redox regulation (1)
- regime shift (1)
- rehabilitation (1)
- ring-opening reactions (1)
- rotary (1)
- rubber plantation (1)
- rule changes (1)
- röntgenfrei (1)
- s-förmig (1)
- s-shaped (1)
- salinity (1)
- salivary alpha-amylase (1)
- secondary plantmetabolites (1)
- seizure (1)
- self assembled monolayer (1)
- serial block-face scanning electron microscopy (SBFSEM) (1)
- serious adverse reaction (1)
- sex (1)
- sex differences (1)
- sexting (1)
- shaping ability (1)
- simulated (1)
- smoking (1)
- snail (1)
- snow cover manipulation (1)
- social (1)
- social cognition (1)
- social interaction (1)
- soil organic carbon stock (1)
- solute carriers (1)
- spatial analysis (1)
- spatial cognition (1)
- spectral matching (1)
- sphingosine-1-phosphate (S1P) (1)
- starvation (1)
- statistical analysis (1)
- stereotactic body radiation therapy (1)
- stomach (1)
- stream ecology (1)
- stroke (1)
- structure (1)
- structured illumination microscopy (1)
- subacute stroke (1)
- summer skiing (1)
- superresolution microscopy (1)
- surface forces (1)
- symbiosis (1)
- synergism (1)
- synthesis (1)
- tVNS (1)
- temporal dynamics (1)
- temporal fitting (1)
- terahertz emission spectroscopy (1)
- terahertz transmission spectroscopy (1)
- thrombosis (1)
- tiling, self-similarity, fractal, aperiodic, iterated function system (1)
- topography (1)
- toxin formation (1)
- training (1)
- transfusion (1)
- tree growth–climate correlation (1)
- tree size (1)
- tree-growth patterns (1)
- treeline (1)
- treeline ecotone (1)
- tropical forest conversion (1)
- tuberculosis (1)
- turbulente Verdünnungsströmung (1)
- turbulenzarme Verdrängungsströmung (1)
- uACR (1)
- ultrafast spincaloritronics (1)
- ultrafast spintronics (1)
- upper limb motor function (1)
- urine normalization (1)
- vagus nerve (1)
- vegetation history (1)
- venous thromboembolism (1)
- vent (1)
- vertebrobasiläre Stenosen (1)
- viral diagnosis (1)
- viral infections (1)
- virulence (1)
- vocational education and training (1)
- volatility (1)
- voxel-based morphometry (1)
- white spruce (1)
- winter ecology (1)
- women’s’ health (1)
- wood anatomy (1)
- wound healing (1)
- zellautonome Immunität (1)
- Änderungssensitivität (1)
- Ärzte (1)
- Überblähung (1)
- β-amino acid (1)
- β-phenylalanine ethyl ester (1)
- ω-transaminase (1)
Institute
- Institut für Botanik und Landschaftsökologie & Botanischer Garten (16)
- Kliniken und Polikliniken für Innere Medizin (15)
- Institut für Community Medicine (13)
- Institut für Pharmazie (13)
- Abteilung für Mikrobiologie und Molekularbiologie (11)
- Institut für Biochemie (10)
- Institut für Physik (10)
- Institut für Diagnostische Radiologie (9)
- Klinik und Poliklinik für Neurologie (8)
- Institut für Pharmakologie (7)
- Institut für Psychologie (7)
- Klinik für Psychiatrie und Psychotherapie (7)
- Zoologisches Institut und Museum (7)
- Institut für Anatomie und Zellbiologie (6)
- Institut für Geographie und Geologie (6)
- Institut für Klinische Chemie und Laboratoriumsmedizin (6)
- Klinik und Poliklinik für Frauenheilkunde u. Geburtshilfe (6)
- Institut für Epidemiologie u. Sozialmedizin (5)
- Institut für Mikrobiologie - Abteilung für Genetik & Biochemie (5)
- Interfakultäres Institut für Genetik und Funktionelle Genomforschung (MNF) (5)
- Institut für Hygiene und Umweltmedizin (4)
- Institut für Mathematik und Informatik (4)
- Klinik für Anästhesiologie und Intensivmedizin (4)
- Klinik und Poliklinik für Orthopädie und Orthopädische Chirurgie (4)
- Poliklinik für Kieferorthopädie, Präventive Zahnmedizin und Kinderzahnheilkunde (4)
- Institut für Erziehungswissenschaft (3)
- Institut für Immunologie u. Transfusionsmedizin - Abteilung Immunologie (3)
- Institut für Politik- und Kommunikationswissenschaft (3)
- Klinik und Poliklinik für Augenheilkunde (3)
- Klinik und Poliklinik für Chirurgie Abt. für Unfall- und Wiederherstellungschirurgie (3)
- Klinik und Poliklinik für Chirurgie Abt. für Viszeral-, Thorax- und Gefäßchirurgie (3)
- Klinik und Poliklinik für Kinder- und Jugendmedizin (3)
- Klinik und Poliklinik für Kinderchirurgie (3)
- Friedrich-Loeffler-Institut für Medizinische Mikrobiologie (2)
- Institut für Immunologie u. Transfusionsmedizin - Abteilung Transfusionsmedizin (2)
- Institut für Med. Biochemie u. Molekularbiologie (2)
- Klinik und Poliklinik für Hautkrankheiten (2)
- Poliklinik für Zahnerhaltung, Parodontologie und Endodontologie (2)
- Wirtschaftswissenschaften (2)
- Caspar-David-Friedrich-Institut (1)
- Historisches Institut (1)
- Institut für Ethik und Geschichte der Medizin (1)
- Institut für Fennistik und Skandinavistik (1)
- Institut für Medizinische Psychologie (1)
- Institut für Philosophie (1)
- Institut für Physiologie (1)
- Institut für Slawistik (1)
- Klinik und Poliklinik für Hals-, Nasen-, Ohrenkrankheiten (1)
- Klinik und Poliklinik für Innere Medizin Abt. Gastroenterologie, Endokrinologie und Ernährungsmedizin (1)
- Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie/Plastische Operationen (1)
- Klinik und Poliklinik für Neurochirurgie (1)
- Klinik und Poliklinik für Strahlentherapie (1)
- Klinik und Poliklinik für Urologie (1)
- Mathematisch-Naturwissenschaftliche Fakultät (1)
- Philosophische Fakultät (1)
- Poliklinik für zahnärztliche Prothetik und Werkstoffkunde (1)
- Rechts- und Staatswissenschaftliche Fakultät (1)
- Rechtswissenschaften (1)
- Theologie (1)
- Universitätsmedizin (1)
Publisher
- Frontiers Media S.A. (37)
- MDPI (37)
- S. Karger AG (17)
- De Gruyter (7)
- BioMed Central (BMC) (4)
- Akadémiai Kiadó (1)
- De Gruyter Mouton (1)
- Hindawi (1)
- IOP Publishing (1)
- Nature Publishing Group (1)
Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis
(2018)
Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP), therefore we aimed to (i) investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii) to correlate the mucus phenotype with epithelial ion transport function.
Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP) and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production.
Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression.
Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.
Introduction
We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean dose optimized stereotactic body radiation therapy (SBRT) for primary and secondary lung tumors with and without robotic real-time motion compensation.
Materials and methods
Between 2011 and 2017, 208 patients were treated with SBRT for 111 primary lung tumors and 163 lung metastases with a median GTV of 8.2 cc (0.3–174.0 cc). Monte Carlo dose optimization was performed prioritizing GTV mean dose at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The median GTV mean biological effective dose (BED)10 was 162.0 Gy10 (34.2–253.6 Gy10) and the prescribed PTV BED10 ranged 23.6–151.2 Gy10 (median, 100.8 Gy10). Motion compensation was realized through direct tracking (44.9%), fiducial tracking (4.4%), and internal target volume (ITV) concepts with small (≤5 mm, 33.2%) or large (>5 mm, 17.5%) motion. The local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity were analyzed.
Results
Median follow-up was 14.5 months (1–72 months). The 2-year actuarial LC, PFS, and OS rates were 93.1, 43.2, and 62.4%, and the median PFS and OS were 18.0 and 39.8 months, respectively. In univariate analysis, prior local irradiation (hazard ratio (HR) 0.18, confidence interval (CI) 0.05–0.63, p = 0.01), GTV/PTV (HR 1.01–1.02, CI 1.01–1.04, p < 0.02), and PTV prescription, mean GTV, and maximum plan BED10 (HR 0.97–0.99, CI 0.96–0.99, p < 0.01) were predictive for LC while the tracking method was not (p = 0.97). For PFS and OS, multivariate analysis showed Karnofsky Index (p < 0.01) and tumor stage (p ≤ 0.02) to be significant factors for outcome prediction. Late radiation pneumonitis or chronic rip fractures grade 1–2 were observed in 5.3% of the patients. Grade ≥3 side effects did not occur.
Conclusion
Robotic SBRT is a safe and effective treatment for lung tumors. Reducing the PTV prescription and keeping high GTV mean doses allowed the reduction of toxicity while maintaining high local tumor control. The use of real-time motion compensation is strongly advised, however, well-performed ITV motion compensation may be used alternatively when direct tracking is not feasible.
on-healing wounds continue to be a clinical challenge for patients and medical staff.
These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is
therefore important to decipher molecular signatures that reflect the macroscopic process of wound
healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy
after surgical trauma to generate wound-derived protein profiles via global mass spectrometry.
We confidently identified 311 proteins in exudates. Among them were expected targets belonging to
the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to
several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates
presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including
for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200
post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine
trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually
collected exudates, we confirmed presence of neutrophils and their products, such as microparticles
and fragments containing myeloperoxidase and DNA. These data confirmed known and identified
less known wound proteins and their PTMs, which may serve as resource for future studies on
human wound healing
Zusammenfassung
Die Wundheilung stellt einen komplexen und sensiblen Prozess dar, wobei neben Keratinozyten auch besonders Immunzellen eine wesentliche Rolle spielen. Besonders in der Medizin ist die Behandlung von Wunden eine zentrale Aufgabe und erfordert immer mehr Techniken, um diesen Prozess effizienter ablaufen zu lassen. Seit einigen Jahren steht die Behandlung von Wunden mittels Niedertemperatur Plasma immer mehr im Fokus der Wissenschaft. Dabei besteht Plasma aus zahlreichen Komponenten, wobei jede Komponente die Zelle unterschiedlich beeinflussen kann. Da auch jede Wunde einzigartig im Hinblick auf Beschaffenheit und Erregerspektrum ist, sollte dies auch mit einer individuellen Abstimmung der Plasamkomponenten einhergehen um so die Wundheilung noch effizienter zu gestallten. Ziel dieser Arbeit ist die Modifizierung der Plasma-Komponenten durch einen Gasmantel, um herauszufinden, welche Modifizierung am effektivsten auf Immunzellen und somit auch auf die Wundheilung wirkt.Dafür wurde in der vorliegenden Arbeit die Auswirkungen von fünf Gaszumischungen im Mantelgas eines argonbetriebenen kalten Atmosphärendruckplasmajets (kINPen 11) auf die Generierung von reaktiven Spezies in Flüssigkeiten und auf Monozyten in vitro untersucht. Der kINPen (ein Gerät der Firma neoplas,zur Erzeugung von Niedertemperatur-Plasma) war dabei auf 5slm(Standardliter pro Minute Argon) und Burstmodus eingestellt. Die Gaszusammensetzung variiert von 100% Stickstoff (N2) und 0% Sauerstoff (O2) in 25íger Schritten zu 100% O2 und 0% N2. Dabei entstehen abhängig von der O2- und N2-Zufuhr im Gasmantel unterschiedliche reaktive Spezies. Als repräsentativ für die Bildung von reaktiven Sauerstoffspezies (ROS) wird Wasserstoffperoxid (H2O2) und für reaktiven Stickstoffspezies (RNS) werden Nitrit (NO2–) und Nitrat (NO3–) erfasst. Die Experimente wurden nach Flüssigkeitsanalytik und zellphysiologischen Aspekten gegliedert. Es wurde die THP-1-Monozytenzelllinie verwendet. Zu den Methoden der Flüssigkeitsanalytik gehören die Bestimmung des pH-Werts, die Detektion der NO2–-, NO3–- und H2O2-Konzentration. Zellphysiologisch wurde die Zellviabillität,die Apoptoserate,der Wachstumsfaktor HB-EGF,sowie die Zytokinsekretion detektiert. Zudem wurde die direkte und indirekte Plasma-Behandlung verglichen.Bei derdirekten Plasma-Behandlung stehen die Zellen mit dem Plasmaeffluenten im direkten, kontinuierlich Kontakt, wohingegen bei der indirekten Behandlung nur das Zellkulturmedium behandelt wird und anschließend auf die Zellen gelangt. Die Zellen haben keinen Kontakt mit dem Plasmaeffluenten. Zu der Flüssigkeitsanalytik gehört die gezielte Messung der durch das Plasma entstehenden ROS und RNS in phosphatgepufferte Salzlösung (PBS) und Zellkulturmedium (RPMI-Medium, Roswell Park Memorial Institute). Es konnten keine pH-Wert-Veränderungen durch die Plasma-Behandlung gemessen werden, aber mit Zunahme der Behandlungszeit stieg die Menge an reaktiven Spezies. Der Gasmantel hat besonders Auswirkungen auf den Gehalt der Flüssigkeiten an reaktiven Spezies. Die niedrigsten Nitrat-Anion (NO3–)- und Nitrit-Anion (NO2–)-Konzentrationen ergaben sich bei der 100% und 0%N2-Mantelgaszumischung. Die75%N2-Mantelgaszumischung zeigte die höchste NO3–-Konzentration in PBS. Die H2O2-Konzentration nahm mit dem Anteil an O2 im Mantelgas zu und erreicht ihr Maximum bei Mantelgaszumischung gezeigt werden. Alle anderen Mantelgaszumischungen zeigten zwar bei der Flüssigkeitsanalytik deutliche Unterschiede, doch durch die Anwesenheit von THP-1-Zellen wurde der Einfluss deutlich geringer. Die Gaszumischungen hatten trotz unterschiedlicher Bildung von reaktiven Stickstoff- und Sauerstoffspezies keinen großen Effekt auf die Zelltoxizität. Die 50%-N2-Mantelgaszumischung bewirkte die höchsten Konzentrationen an reaktive Sauerstoff- und Stickstoffspezies (RONS), was mit einer erhöhten frühen und späten Apoptose einherging und mit niedrigen IL-8-Werten. Die 100% N2-Mantelgaszumischung zeigte die größten Effekte auf die Zytokinsekretion. Die IL-6-Konzentration sank sowohl bei den direkt als auch indirekt mit Plasma behandelten und mit Lipopolysaccharid (LPS)-stimulierten Proben. Gleichzeitig wurde für die unstimulierte, indirekte Plasma-Behandlung ein deutlicher Anstieg der IL-8-Konzentration gemessen. Neben den erwähnten Ergebnissen konnten weitere zelluläre Effekte unabhängig von den Mantelgaszumischungen gemessen werden. Zum Einen zeigten sich deutliche Unterschiede zwischen der direkten und indirekten Plasma-Behandlung. Die indirekte Plasma-Behandlung,d.h.diePlasma-Behandlung von Zellkulturmedium und die anschließende Inkubation der Zellen, zeigte eine starke Erhöhung der IL-8-Konzentration, die mit der N2-Konzentration im Mantelgas anstieg. Auch für die IL-6- und IL-8-Konzentrationen nach LPS-Stimulation zeigten sich Unterschiede zwischen der direkten und indirekten Behandlung. Die indirekte Plasma-Behandlung zeigte eine stark reduzierte Zellviabilität gegenüber der direkten Plasma-Behandlung (1 min), die eher aktivierend wirkte. Zum Zweiten zeigte sich nach der Plasma-Behandlung, dass die Zellen im Durchflusszytometer eine Erhöhung des Volumens und der Granularität nach langen Behandlungszeiten aufwiesen und scheinbar erhöhte Zellviabilität. Eine Detektion des Wachstumsfaktors HB-EGF mit Hilfe der FACS-Analyse konnte nicht gezeigt werden. Drittens, konnte durch Zugabe von Katalase ein Anstieg der NO2–-Konzentration im RPMI im Vergleich zur Behandlung ohne Katalase gezeigt werden. Somit spiegelt die Flüssigkeitsanalytik nicht die Stituation in Gegenwart von Zellen in vitro wieder. Erstmalig konnte in dieser Arbeit gezeigt werden, dass die Modifizierung der Umgebungsgase bei der Plasma-Behandlung einen Einfluss auf die Bildung von ROS, RNS und Zytokinen hat. Besonders die 50% N2-Mantelgaszumischung hat mit der Reduktion der IL-8-Konzentration und damit der Reduktion eines für die Angionese relevanten Faktors möglicherweise einen negativen Effekt auf die Wundheilung. Im Gegensatz dazu bewirkt die 100% N2-Mantelgaszumischung durch Abnahme von IL-6 eine Verringerung der Entzündungsmediatoren und durch die Erhöhung von IL-8 eine Zunahme eines für die Angiogenese in Wunden wichtigen Parameters. Gleichzeitig konnte gezeigt werden, dass der Einfluss durch die Behandlungszeit und der direkten und indirekten Behandlung einen weitaus größeren Effekt auf Monozyten haben könnte als bisher angenommen. Somit leistet diese Arbeit einen zusätzlichen Beitrag für das weitere Verständnis bei der Aufklärung der zellulären Effekte durch die Plasma-Behandlung. Es kamen aber auch neue Fragen auf, die noch nicht hinreichend geklärt wurden: Erstens, welcher Mechanismus steht hinter der Zunahme der Granularität und des Volumens nach langen Plasma-Behandlungen. Zweitens, in wie weit sind die ohne Katalase-Behandlung gemessenen NO2–-Konzentrationen aussagekräftig. Drittens, haben die indirekte und direkte Plasma-Behandlung den gleichen Effekt in vivo wie in vitro. Um diese Fragen weiter zu klären ist weitere Forschung nötig.
Currently, plastic materials are an integral part of our lives, but their production mostly bases on fossil fuels or derivatives, which resources are decreasing. Extraction and processing of non-renewable resources have also negative impact on environment. One of the most promising and environmentally friendly approaches is use of microorganism. This PhD dissertation presents the non-conventional yeast Arxula adeninivorans as a host for production of bio-based and biodegradable poly(hydroxyalkanoates) plastics poly(hydroxybutyrate) and co-polymer poly(hydroxybutyrate-co-hydroxyvalerate). Additionally, the constructed yeast strain was able to secrete enantiomerically pure (R)-3-hydroxybutyric acid.
The production of PHAs requires three enzymes: β-ketothiolase, acetoacetyl-CoA reductase and PHA synthase. The strategy followed in this project was divided into two parts. While all three enzymes are responsible for intracellular production of PHA polymer, first two only lead to secretion of (R)-3-HB into culture media, which was used in a first stage of work to establish and optimize polymer production. Both, different bacterial strains and yeast A. adeninivorans were taken into account in screening of the genes encoding aforementioned enzymes. Bacterial genes were chemically synthesized using codon optimization pattern and endogenous genes were obtained using PCR and genomic DNA template from A. adeninivorans LS3 wild-type strain. Each gene was cloned into Xplor2 vector between TEF1 constitutive promoter and PHO5 terminator. Vector containing both thiolase and reductase genes was used for A. adeninivorans transformation.
The best combination of heterologous genes was overexpression of β-ketothiolase gene from Clostridium acetobutylicum and acetoacetyl-CoA reductase gene from Cupriavidus necator which led to secretion of 4.84 g L−1 (R)-3-HB, at a rate of 0.023 g L−1 h−1 over 214 h in shaking flask cultivation. Further optimization by fed-batch culturing with glucose as a carbon source did not improve (R)-3-HB secretion, but the rate of production was doubled to 0.043 g L−1 h−1 [3.78 g L−1 of (R)-3-HB at 89 h].
The product of acetoacetyl-CoA reductase is (R)-3-HB-CoA and further removing of CoA moiety is needed for acid secretion into culture media. A. adeninivorans is able to conduct this process without any additional modification but the conversion rate is unknown. Two thioesterases, cytosolic TesBp encoded by TesB gene from E. coli and mitochondrial ATes1p encoded by ATES1 gene from A. adeninivorans, were analysed to enhance secretion process. Additionally, a cytosolic version of ATES1 gene (ATES1cyt) was tested. All three genes were expressed in A. adeninivorans cells under TEF1 constitutive promoter together with thiolase and reductase genes. Despite detected enzymatic activity the yield of (R)-3-HB synthesis and secretion was not increased. Moreover, overexpressed thioesterases negatively influenced cell growth, indicating that they act on other metabolic components. The results provided two sets of information, first, the endogenous secretion system is sufficient for (R)-3-HB production; second, further screening of suitable genes needs to be performed.
Based on optimization of (R)-3-HB synthesis, thiolase gene (thl) from C. acetobutylicum and reductase gene (phaB) from C. necator were chosen to combine with PHA synthase gene (phaC) for creating the PHB-V producing strain. The PHA synthase expression module, containing TEF1 promoter and PHO5 terminator, was cloned into Xplor2 vector together with thiolase and reductase expression modules and used for A. adeninivorans transformation. The engineered strain accumulated up to 7.47% PHB of dcw. During the set of cells passaging A. adeninivorans lost the ability to accumulate polymer with maximal 23.1 % of primary accumulation level. Additionally, use of a vector including hygromycin B antibiotic resistance marker (instead of auxotrophic marker in Xplor2) did not improve polymer accumulation and stability.
To counteract the effect of loss of accumulation stability, phasin gene (phaP1), originated from C. necator, was introduce together with PHA pathway genes. First screening cultivations resulted in stabilizing of polymer production reaching 9.58 % PHB of dcw and only 12.0 % loss of production ability. Further experiments increased PHB content with 19.9% PHB of dcw (3.85 g L-1) after 180 h of cultivation using rich medium. Use of another thiolase gene, the second thiolase from C. necator (bktB), which theoretically should induce production of PHBV copolymer, led to accumulation only 11.4% PHB of dcw after 139 h and no PHV fraction was detected.
Variation of the ratio between flask volume and amount of media influences the level of aeration. Importantly, decrease of aeration level significantly increased polymer synthesis. Additionally, PHB-V copolymer accumulation has been induced by use of different carbon source co-substrates. Use of rich media supplemented with ethanol allow the strain with thl thiolase to accumulate up to 42.9 % PHB of dcw without PHV fraction and with bktB thiolase to 30.5 % PHB of dcw. Nevertheless, despite of lower total amount of polymer, supplementation with 1-propanol allow both strains to accumulate PHB-V copolymer with 7.30 %mol and 22.5 %mol of PHV for thl and bktB strains, respectively.
Optimization based on genetic engineering further enhanced polymer production yield led to exceeding of 50 % PHB-V of dcw. For doubling the gene dosage, PHA synthesizing strains of A. adeninivorans were again transformed with Xplor2 vector containing PHA pathway genes. Resulting strains exhibited twice the level of enzymatic activities of thiolase and reductase compared with strains transformed once with expression vector. In a shaking flask experiment the strain transformed twice with vector containing bktB thiolase reached after 240 h 52.1% PHB-V of dcw (10.8 g L-1) with 12.3 %mol of PHV fraction which is the highest level found in yeast. As another genetic approach, a fusion strain has been created. Two different strains have been established and merged using protoplast fusion technique. Doubling of genetic material resulted in similar level of copolymer produced by Arxula as in former experiments (50.2% of dcw, 10.7 g L-1).
Culture conditions were optimized in controllable cultivation using fed-batch mode. Although optimal oxygen and pH level and continuous carbon source and nitrogen feeding were maintained, final polymer level in % of dry mass was around three times lower than for shaking flask experiment. Nevertheless, efficient growth of Arxula in fed-batch mode led to increase of total copolymer level in g L-1 (16.5 g L-1 compare to 10.8 g L-1 for shaking flasks) showing the feasibility of using Arxula strain for up-scaling production of copolymer.
Acetyl-CoA is a main precursor in synthesis of PHB-V copolymer and change of its pool was investigated. ATP citrate lyase is a cytosolic enzyme converting citrate into oxaloacetate and acetyl-CoA, supporting the biosynthesis of fatty acids. Two genes encoding Acl subunits from Aspergillus nidulans (AnAcl1 and AnAcl2) were again cloned into Xplor2 vector and transformed into A. adeninivorans PHA producing strain. Despite of higher enzymatic activity of AnAclp, accumulation of polymer was around three times higher for control without expression of lyase genes. Expectedly, the strain expressing AnAcl1/2 genes accumulated larger amount of each stearic, palmitic and oleic acid in both standard and fatty acid inducing conditions (lower nitrogen level). Thus, overexpression of AnAcl1/2 genes in A. adeninevorans cells may improve biosynthesis of fatty acids but is ineffective for PHB polymer accumulation.
The aim of the project was use of starch-based media, manufactured as by-products, for polymer production. Genetically engineered Arxula strains were cultivated using these media instead of glucose-based media. Although yeast cells were both able to secrete (R)-3-HB and to accumulate PHB, the yield was lower than for previous media. Additionally, only trace of PHV was found at the end of cultivation time when 1-propanol was supplemented. Obtained results showed that use of cheaper media is a promising approach to decrease production costs but further optimization needs to be performed especially for extended scale of production.
Determination of produced copolymer has been done based on microscopic analysis and studies of physical and chemical properties. Results revealed that Arxula accumulated PHA polymer in cytosolic granules with a similar size range compared to the ones produced by bacteria. The physicochemical study showed that produced polymer exhibited slightly different properties in comparison to bacterial polymer with similar content of PHV, i.e. very-low molecular mass, higher melting and glass transition temperature.
All above results showed that A. adeninivorans is a promising host for PHB-V production. Expression of phasin greatly increased production and stability of polymer, which led to an accumulation level never found before in yeast. Further optimization in higher production scale using cheap starch-based media may establish Arxula strain as a valuable tool for industrial production of PHB-V copolymer.
Streptococcus pneumoniae (pneumococci) and Staphylococcus aureus (S. aureus) are human-specific commensals of the upper respiratory tract. Every individual is asymptomatically colonized with both bacteria at least once in their life-time. The opportunistic pathogens can affect further organs and invade into deeper tissue. The occupation of normally sterile niches of the human body with the bacteria can lead to local infections such as sinusitis, otitis media and abscesses, or to life-threatening diseases like pneumonia, meningitis or sepsis. A strong interaction between the bacterium and the respiratory epithelial cells is a prerequisite for a successful colonization. This interaction is ensured by bacterial surface proteins, so called adhesins. The binding of the adhesins to the epithelial lineage occurs predominantly indirectly via components of the extracellular matrix (ECM), but also directly to cellular receptors. Pneumococci and S. aureus bind to various ECM glycoproteins, amongst others: fibronectin, fibrinogen, vitronectin, and collagen. Also binding of both pathogens to human thrombospondin-1 has been described. Thrombospondin-1 is mainly stored in the α-granula of thrombocytes (platelets) and released into the circulation upon activation. However, thrombospondin-1 is also produced and secreted by other cell types like endothelial cells, macrophages, and fibroblasts, which gets subsequently incorporated as component into the ECM. So far, no thrombosponin-1-binding adhesins of pneumococci were identified. PspC, Hic, and PavB are important surface-localized virulence factors, which were shown to interact with human ECM and plasma proteins. PspC and Hic bind to vitronectin and factor H, which inhibits the complement cascade of the human immune system. PavB interacts with fibronectin and plasminogen, and a pavB-deficient mutant of S. pneumoniae showed diminished capacity in colonization in a mouse model. Among the surface proteins of S. aureus, only Eap was identified as thrombospondin-1-binding adhesin. Beyond colonization, pneumococci and S. aureus can enter the blood circulation, interact with platelets, and cause their activation. The aggregation of platelets, especially initiated by S. aureus, plays an important role in the clinic, because most of the septic patients develop thrombocytopenia. Surface localized factors of
S. pneumoniae triggering platelet activation are unknown to date. In contrast, few proteins of S. aureus with potential to activate platelets, including Eap, were identified previously.
This study identified the surface proteins PavB, PspC, and Hic of S. pneumoniae as specific ligands of the human thrombospondin-1. Flow cytometric, surface plasmon resonance spectroscopic and immunological analyses revealed interactions between the pneumococcal proteins and soluble as well as immobilized thrombospondin-1. The use of specific pneumococcal deletion mutants verified the importance of the three virulence factors as binding partners of soluble thrombospondin-1. The results suggest that pneumococci are capable of acquiring soluble thrombospondin-1 from blood as well as utilizing immobilized glycoprotein of the ECM as substrate for adhesion. Furthermore, the thrombospondin-1-binding domain within the pneumococcal proteins was analyzed by use of recombinant fragments of PavB, PspC, and Hic. The binding capacity of thrombospondin-1 increased proportionally with the amount of repetitive sequences in PavB and PspC, and the length of the α-helical region within the Hic molecule. The binding behavior of thrombospondin-1 towards PavB and PspC is comparable with that of the ECM proteins vitronectin and fibronectin, but is unique towards Hic.
The localization of the binding domain of the adhesins within the thrompospondin-1 molecule occurred via use of glycosaminoglycans as competitive inhibitors for the interaction. The results suggest that the pneumococcal proteins Hic and PspC target the identical binding region within thrombospondin-1, which differs from the binding domain for PavB. However, all three virulence factors seem to bind in the N-terminal part of thrombospondin-1.
Two-dimensional gel electrophoresis, thrombospondin-1 overlay assay and subsequent mass spectrometric analysis identified AtlA of S. aureus as a surface localized interaction partner of human thrombospondin-1. Moreover, a vitronectin binding activity for AtlA was determined. Immunological and surface plasmon resonance binding studies with recombinant AtlA fragments revealed that interactions with both matrix proteins is mediated via the C-terminal located repeats R1R2 of the AtlA amidase domain. Binding of thrombospondin-1 and vitronectin occurred not simultaneously, due to a competitive inhibition.
The second part of the study focused on the activation of human platelets by recombinant pneumococcal and staphylococcal proteins. In total, 28 proteins of S. pneumoniae and 52 proteins of S. aureus were incubated with human platelets. The activation of the cells was detected by flow cytometry using the activation markers P-selectin and the dimerization of the integrin αIIbβIII. The proteins CbpL, PsaA, PavA, and SP_0899 of S. pneumoniae induced platelet activation, however, the detailed mechanism has to be deciphered in further studies. Furthermore, the secreted proteins CHIPS, FLIPr, and AtlA of S. aureus were discovered as inductors for the activation of platelets. In addition, the domains of AtlA and Eap, crucial for platelet activation, were narrowed down. Interestingly, CHIPS, FLIPr, and Eap were described as inhibitors of neutrophil recruitment. Platelets are recently recognized as immune cells, due to the expression of immune receptors. The data obtained in this study highlight a comprehensive spectrum of effects of the S. aureus proteins towards different type of immune cells. Besides the activation of platelets in suspension buffer and plasma, the aggregation of platelets in whole blood was triggered by the proteins CHIPS, AtlA, and Eap. These results suggest a contribution of the proteins during the S. aureus-induced infectious endocarditis. Secretion of the platelet activating virulence factors, which were identified within this study, might represent a pathogenic strategy during S. aureus infection in which a direct contact between S. aureus and platelets is not required or even avoided.
In conclusion, PavB, PspC, and Hic of S. pneumoniae and AtlA of S. aureus were identified as interaction partners of human thrombospondin-1. Furthermore, CHIPS, FLIPr, AtlA, and Eap were characterized as platelet activators. This study provides candidates for the development of protein-based vaccines, to prevent bacterial colonization and to neutralize secreted pathogenic factors.
Der Einsatz von Glukose Point-Of-Care-Testung- (POCT) Geräten zur Diagnose von Diabetes mellitus (DM) ist derzeit nicht allgemein akzeptiert. In der Patientenversorgung werden bei einzelnen Patienten unterschiedliche Messsysteme mit verschiedenen prä-analytischen Prozessen regelhalft parallel angewandt. POCT-Glukose aus Kapillarblut wird oft zur Verlaufskontrolle, venöses Plasma im Zentrallabor eher zu diagnostischen Zwecken verwendet. Behandelnde Ärzte müssen dementsprechend Messwerte verschiedener Probetypen und Messsysteme einordnen können. In dieser Arbeit wurden Glukosemessungen in Kapillarblut sowie venösem Blut mittels POCT- und Zentrallaborgeräten durchgeführt mit dem Ziel, typische Szenarien der Patientenversorgung nachzubilden. Die resultierenden Diagnoseraten von gestörter Glukosetoleranz (IGT) und DM wurden bestimmt und verglichen. Dafür wurden zwei Kohorten wurden einem OGTT unterzogen. In den Proben wurde die P-Glukosekonzentration mit zwei POCT-Methoden untersucht: einem Handgerät mit Teststreifen sowie einem kleinen Tischgerät mit Batch-Reagenzien, das oft patientennah eingesetzt wird. Daneben wurden zwei Messsysteme im Zentrallabor eingesetzt. Es wurden Vollblutproben sowie Kapillarproben untersucht. Zusätzlich wurde glykolisiertes Hämoglobin (HbA1c) aus Vollblut bestimmt.
Insgesamt wurden 231 Probanden untersucht. Die Zweistunden-OGTT-Glukosekonzentrationen der Kapillarproben wiesen eine systematische positive Messabweichung von 0,8 mmol/L auf, verglichen mit den Messungen an Plasmaproben im Kernlabor. Daraus resultierte eine höhere Diagnoserate von IGT und DM wenn die Messergebnisse der Kapillarproben zugrunde gelegt werden. Die Messabweichung reduzierte sich auf 0,2 mmol/L, wenn an allen Messsystemen venöses Blut untersucht wurde. Ein Methodenwechsel im Kernlabor hingegen führte zu einer negativen systematischen Messabweichung von 0,5 mmol/L und damit verbunden zu geringeren Diagnoseraten.
Venöse Proben, die patientennah gemessen werden, sind am besten geeignet zur Diagnose von DM im Rahmen eines OGTT. Die untersuchte Teststreifen-basierte POCT-Methode erscheint geeignet zur Diagnose von IGT und DM, wenn venöse Proben eingesetzt werden. Wechsel von Kernlabormethoden können systematische Messunterschiede in der P-Glukose-Messung verursachen, die die Diagnoserate von IGT und DM beeinflussen. Dies unterstreicht die Notwendigkeit zur Engerfassung der Kriterien für die externe Qualitätssicherung.