Refine
Has Fulltext
- yes (118)
Is part of the Bibliography
- yes (118)
Year of publication
- 2019 (118) (remove)
Document Type
- Journal article (94)
- Doctoral Thesis (23)
- Preprint (1)
Keywords
- apoptosis (4)
- infection (3)
- leukemic cells (3)
- p53 (3)
- 3D tissue model (2)
- B-MYB (2)
- Bees (2)
- Chronobiologie (2)
- Drosophila melanogaster (2)
- HeLa cells (2)
- Melanoma (2)
- R package (2)
- Taufliege (2)
- autophagy (2)
- cancer (2)
- cytotoxicity (2)
- dSTORM (2)
- genome annotation (2)
- imaging (2)
- land use (2)
- metagenomics (2)
- microbiome (2)
- optimal drug combination (2)
- pollination (2)
- speciation (2)
- sphingolipids (2)
- transcription (2)
- wild bees (2)
- wound healing (2)
- (classical and atypical) Werner syndrome (1)
- ABP1 (1)
- AUX1 (1)
- Accurate (1)
- Acids (1)
- Algorithmus (1)
- Alpine habitats (1)
- Aminerge Nervenzelle (1)
- Aneugene (1)
- Annotation (1)
- Anthropocene (1)
- Antigen CD19 (1)
- Apidae (1)
- Apis mellifera (1)
- Apoidea (1)
- Aspergillus fumigalus (1)
- Aurora-A (1)
- Automated Image Analysis (1)
- Automatisierung (1)
- Automatisierung der Analyse (1)
- Barrier (1)
- Behavioural ecology (1)
- Berberine (1)
- Bildanalyse (1)
- Bildverarbeitung (1)
- Bioinformatik (1)
- Biomarker (1)
- C-60 fullerene (1)
- C60 fullerene (1)
- CD274 (1)
- CIDP (1)
- COL9A1 (1)
- C\(_{60}\) fullerene (1)
- Caenorhabditis elegans (1)
- Cancer (1)
- Cancer Cell (1)
- Cataglyphis (1)
- Cell stainin (1)
- Central nervous system (1)
- Chemical composition (1)
- Chlamydia trachomatis (1)
- Circular dichroism (1)
- Click Chemie (1)
- CoQ10 (1)
- Colon (1)
- Colonization (1)
- Computational and Systems Biology (1)
- Computer modelling (1)
- Confocal microscopy (1)
- Conifers (1)
- Conservation (1)
- CpG (1)
- Cushing’s disease (1)
- Cyclo-GMP (1)
- Cytosol (1)
- DLS and AFM measurements (1)
- DNA damage (1)
- DNS-Doppelstrangbruch (1)
- DNS-Schädigung (1)
- Dnaschaden (1)
- Dopamine (1)
- Doxorubicin (1)
- Dynamics (1)
- E8 symmetry (1)
- ERK signaling (1)
- Ecology (1)
- Einzelmolekülmikroskopie (1)
- Electron Microscopy (1)
- Elektronenmikroskopie (1)
- Embryonic induction (1)
- Endogene Rhythmik (1)
- Environmental impact (1)
- Evolutionary developmental biology (1)
- Evolutionary emergence (1)
- Extracellular matrix (1)
- FSC (1)
- Fgf-signalling (1)
- Flowering plants (1)
- Flowers (1)
- Fluorescence spectroscopy (1)
- Fluoreszenzmikroskopie (1)
- FoSTeS/MMBIR mechanism (1)
- Forests (1)
- GABA (1)
- GABAA receptors (1)
- GAD1 (1)
- Gastrointestinaltrakt (1)
- Gene expression analysis (1)
- Genome (1)
- Genomics (1)
- Genotoxicitiy (1)
- Genotoxizität (1)
- Germline (1)
- Gliazelle (1)
- Glioblastom (1)
- Glykane (1)
- Haut (1)
- Health (1)
- Herzmuskelzelle (1)
- Hochauflösende Fluoreszenzmikroskopie (1)
- Honey bees (1)
- Host-parasite interaction (1)
- Hurwitz theorem (1)
- Hypothalamus (1)
- Immunoprecipitation (1)
- Immuntherapie (1)
- In vitro (1)
- Inhibitor (1)
- Insect flight (1)
- Invertebrate herbivory (1)
- JAK2 (1)
- K-RAS (1)
- Klassifizierung (1)
- Klastogene (1)
- Knockout-Mäuse (1)
- Laparoscopy (1)
- Lariophagus distinguendus (1)
- Leaf traits (1)
- Learning and memory (1)
- Learning walk (1)
- Lee Smolin (1)
- Limb development (1)
- Llullaillaco Volcano (1)
- Lungenkrebs (1)
- Lymph nodes (1)
- M14 carboxypeptidasses (1)
- MMB (1)
- MYC (1)
- Maculinea butterfly (1)
- Markierungen synaptischer Proteine (1)
- Mc4r (1)
- Melanom (1)
- Methylation (1)
- Microbiology and Infectious Disease (1)
- Mikroskopie (1)
- Minimally invasive surgery (1)
- Mitochondria (1)
- Mitose (1)
- Modell (1)
- Molekülsystem (1)
- Motilität (1)
- Multiples Myelom (1)
- Myb-MuvB (1)
- Myrmica ant non-equilibrium dynamics (1)
- N-Myc (1)
- Neisseria gonorrhoeae (1)
- Neisseria meningitidis (1)
- Neural circuits (1)
- Neuroanatomie (1)
- Neuroblastom (1)
- Neurogenese (1)
- Nicht-kleinzelliges Bronchialkarzinom (1)
- Non-coding RNA (1)
- Oncology (1)
- Outer membrane proteins (1)
- PD-L1 (1)
- PDF neurons (1)
- PI3K/mTOR inhibierung (1)
- PTEN (1)
- Patterns and drivers of invertebrate herbivory (1)
- Patterns and drivers of species diversity of phytophagous beetles (1)
- Patterns and drivers of species richness and community biomass of large mammals (1)
- Phenols (1)
- Pigmentdispergierender Faktor (1)
- Plants (1)
- Plasmamembranorganisation (1)
- Plasmozytom (1)
- Polysaccharide (1)
- Poplars (1)
- Protein folding (1)
- Protein kinase D3 (PKD3) (1)
- Proteomics Analysis of Complexes (1)
- Proteotype (1)
- Proteus vulgaris (1)
- Quantifizierung (1)
- Quantitative Mikroskopie (1)
- RNA metabolism (1)
- RNA polymerase II (1)
- RNA sequencing (1)
- RNA-seq (1)
- RNA-seq transcriptome (1)
- RNAi (1)
- Registrierung <Bildverarbeitung> (1)
- Reiz (1)
- Research Article (1)
- SPT5 (1)
- SPT6 (1)
- SSR42 (1)
- SUPT5H (1)
- Scarabaeidae (1)
- Self-renewal (1)
- Serotonin (1)
- Sex chromosome (1)
- Sex determination (1)
- Sexual development and function (1)
- Small interfering RNAs (1)
- Solid tumors (1)
- Solution-state NMR (1)
- Species delimitation (1)
- Species richness (1)
- Stammzelle (1)
- Staphylococcus aureus (1)
- Stickler syndrome (1)
- Stickstoffoxid (1)
- Stoffwechsel (1)
- Strains (1)
- Subtercola vilae (1)
- Surgical and invasive medical procedures (1)
- Surgical oncology (1)
- Synaptische Vesikel (1)
- Syrphidae (1)
- TNNI3 (1)
- TP53 (1)
- Tagesrhythmus (1)
- Transcription (1)
- Transcriptomic (1)
- Translation (1)
- Transposable element (1)
- Trees (1)
- Tumor (1)
- UV–Vis (1)
- Ustilago maydis (1)
- V-ATPase (1)
- Wundheilung (1)
- YAP (1)
- Zellmigration (1)
- abdominal surgery (1)
- accessory medulla (1)
- accumulation (1)
- acetate (1)
- agriculture (1)
- agroecology (1)
- alternative splicing (1)
- altitudinal gradients (1)
- aminergic neurons (1)
- aneugens (1)
- animal physiology (1)
- anthropogenic disturbance (1)
- anti-contactin-1 (1)
- artifacts (1)
- autoantibody (1)
- automatisierte Bildanalyse (1)
- auxin (1)
- bee conservation (1)
- bee decline (1)
- behavioral plasticity (1)
- biogeography (1)
- bioinformatics (1)
- bioinformatics tool (1)
- biomarker (1)
- biomarker signature (1)
- biophysics (1)
- biotic interaction (1)
- bisulfite pyrosequencing (1)
- bladder (1)
- body size (1)
- boolean modeling (1)
- brain (1)
- brain development (1)
- brain disorders (1)
- burnt-wood (1)
- cancer imaging (1)
- cancer immunotherapy (1)
- cancer metabolism (1)
- cancer therapy (1)
- carabid beetles (1)
- cardiolipin (1)
- cardiomyocytes (1)
- cardiomyopathy (1)
- catheterization (1)
- catheters (1)
- cell biology (1)
- cell growth (1)
- cell migration (1)
- cellular neuroscience (1)
- ceramide (1)
- chaperones (1)
- chlamydia (1)
- cholesterol (1)
- circRNA (1)
- circadian clock (1)
- circadian rhythms (1)
- circular transcriptome sequencing (1)
- cisplatin (1)
- classification (1)
- clastogens (1)
- click chemistry (1)
- cluster analysis (1)
- co-culture (1)
- cold adaptation (1)
- collybistin (1)
- colorectal cancer (1)
- community composition (1)
- comparative genomics (1)
- competition (1)
- complement deposition (1)
- conservation (1)
- copy number variation (1)
- cosmology (1)
- crystal growth (1)
- crystallization (1)
- cytoplasmic incompatibility (1)
- dead-wood enrichment (1)
- dendritic cell (1)
- dendritic cells (1)
- deubiquitinases (1)
- developmental forms (1)
- diacylglycerol (DAG) (1)
- dimeric peptide (1)
- direct muss spectrometric profiling (1)
- directionality (1)
- disease modelling (1)
- diversity gradients (1)
- domain-specific language (1)
- doxorubicin (1)
- drivers and patterns of diversity and herbivory (1)
- drug release (1)
- dry weight (1)
- ecology (1)
- ecosystem function (1)
- ecosystem service (1)
- ecosystem services (1)
- efficient intervention points (1)
- elementary body (1)
- elongation rate (1)
- endocytosis (1)
- endosymbiotic bacteria (1)
- enercy-richness hypothesis (1)
- energy homeostasis (1)
- enhancer (1)
- environmental association (1)
- environmental sciences (1)
- enzymes (1)
- epidural block (1)
- eugenol (1)
- evolution (1)
- evolutionary ecology (1)
- evolutionary genetics (1)
- expansion microscopy (1)
- external stimuli (1)
- extinction dynamics (1)
- fertility (1)
- fission (1)
- fluorescent probes (1)
- fluxosome (1)
- food resources (1)
- foraging patterns (1)
- forest fire (1)
- forest management (1)
- forestry (1)
- friut fly behaviour (1)
- functional analysis (1)
- fungal ecology (1)
- fungal evolution (1)
- fungal rhodopsins (1)
- gangliosides and lipid rafts (1)
- gastrointestinal tract (1)
- gene expression analysis (1)
- genetic engineering (1)
- genetics (1)
- genome analysis (1)
- genome assembly (1)
- genomics (1)
- gephyrin (1)
- glia cells (1)
- glioblastoma multiforme (1)
- global change (1)
- glucose transporter (1)
- ground nesters (1)
- ground-dwelling predators (1)
- growth (1)
- habitat restoration (1)
- heuristics (1)
- histone H2AX (1)
- hochauflösende Fluoreszenzmikroskopie (1)
- honeybee (1)
- honeybees (1)
- human xenografted mouse models (1)
- ichthyology (1)
- immunocompetent skin (1)
- indole-3-acetic acid (1)
- infection biology (1)
- inflation (1)
- insect abundance (1)
- insect collection (1)
- integrative management strategy (1)
- integrative taxonomy (1)
- interstitielle Zellen von Cajal (1)
- intervention point analyzing (1)
- intracellular bacterial pathogens (1)
- irradiation (1)
- knockout (1)
- land sharing (1)
- lipid metabolism (1)
- liver (1)
- localization microscopy (1)
- lowland beech forests (1)
- lung cancer (1)
- lysosome (1)
- mRNA (1)
- mTOR (1)
- machine learning (1)
- macroecology (1)
- macrophages (1)
- mating preference (1)
- measles virus (1)
- mechanisms of disease (1)
- mechanistic modelling (1)
- medaka (1)
- meta-analysis (1)
- metabolic adaptation (1)
- metabolic flux (1)
- metabolic modeling (1)
- metabolic modelling (1)
- metabolism (1)
- metabolism of infected and uninfected host cells (1)
- metabolite profiling (1)
- methods (1)
- methylation array (1)
- miR-26 (1)
- microbial rhodopsins (1)
- migration (1)
- mitochondria (1)
- mitochondrial genome (1)
- mitotic genes (1)
- molecular biology (1)
- mutants (1)
- nanocomplex (1)
- native populations (1)
- natural disturbance (1)
- natural pest control (1)
- nervous system (1)
- nest microbiota (1)
- neural circuits (1)
- neuronal (1)
- next generation sequencing (1)
- next-generation sequencing (1)
- niche differentiation (1)
- non-syndromic hearing loss (1)
- noncovalent complex (1)
- noncovalent nanocomplex (1)
- nuclear envelope (1)
- nuclear export (1)
- oncogenes (1)
- oncology (1)
- oncolytic virus (1)
- optimal drug targeting (1)
- optimal pharmacological modulation (1)
- optimal treatment strategies (1)
- paranodopathy (1)
- parasite biology (1)
- parasitoid wasps (1)
- passive transfer (1)
- patch-clamp (1)
- pathogenesis (1)
- pathogenic bacteria (1)
- pediatrics (1)
- peptide inhibitor design (1)
- peptidomoics (1)
- phenotypic screening (1)
- photodynamic chemotherapy (1)
- piRNA (1)
- plant functional groups (1)
- plant functional types (1)
- plant traits (1)
- plant–microbe–pollinator triangle (1)
- plasma membrane depolarization (1)
- plasma membrane organization (1)
- pollimetry (1)
- pollination network (1)
- population genetics (1)
- population structure (1)
- post-fire management (1)
- predictive models (1)
- premature aging (1)
- processivity (1)
- protected area management (1)
- protected forests (1)
- protein processing (1)
- protein-protein interaction (PPI) (1)
- psychiatric disorders (1)
- puberty (1)
- radiation (1)
- radiation sensitivity (1)
- rectum (1)
- reprogamming of host cell metabolism (1)
- resonance theory (1)
- reticulate body (1)
- rheumatic diseases (1)
- rheumatoid arthritis (1)
- rheumatology (1)
- risk factors (1)
- sanitary logging (1)
- saproxylic organisms (1)
- sarcomere (1)
- secreted effectors (1)
- segmental progeria (1)
- sentinel prey (1)
- sexual isolation (1)
- sexual selection (1)
- signalling (1)
- single cell anatomy (1)
- single-molecule tracking (1)
- skin model (1)
- sleep (1)
- small intestinal submucosa scaffold (1)
- small-cell lung cancer (1)
- software (1)
- soil fauna (1)
- solitary bees (1)
- somatic mutations (1)
- species richness (1)
- species‐area hypothesis (1)
- sphingosine-1-phosphate (1)
- sporidia (1)
- structured illumination microscopy (1)
- super resolution microscopy (1)
- super-resolution fluorescence microscopy (1)
- super-resolution microscopy (1)
- superresolution (1)
- surgical and invasive medical procedures (1)
- survival analysis (1)
- synapses (1)
- synergistic effect (1)
- systematic affiliation (1)
- systematic drug targeting (1)
- targeted therapies (1)
- temperature‐mediated resource exploitation hypothesis (1)
- temperature‐richness hypothesis (1)
- time lag (1)
- topminnow (1)
- transcription deficiency (1)
- transcriptome (1)
- transcriptomics (1)
- transient dynamics (1)
- transposable elements (1)
- tree cavities (1)
- trypanosomes (1)
- tumorigenesis (1)
- tundra biome (1)
- unmanaged broadleaved forests (1)
- uptake (1)
- urinary tract infections (1)
- vegetation change (1)
- vessel wall resident stem cells (1)
- virus (1)
- viruses (1)
- whole-genome sequencing (1)
- yH2AX-Foci (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (118) (remove)
Protein-protein interaction (PPI) studies are gaining momentum these days due to the plethora of various high-throughput experimental methods available for detecting PPIs. Proteins create complexes and networks by functioning in harmony with other proteins and here in silico network biology hold the promise to reveal new functionality of genes as it is very difficult and laborious to carry out experimental high-throughput genetic screens in living organisms. We demonstrate this approach by computationally screening C. elegans conserved homologs of already reported human tumor suppressor and aging associated genes. We select by this nhr-6, vab-3 and gst-23 as predicted longevity genes for RNAi screen. The RNAi results demonstrated the pro-longevity effect of these genes. Nuclear hormone receptor nhr-6 RNAi inhibition resulted in a C. elegans phenotype of 23.46% lifespan reduction. Moreover, we show that nhr-6 regulates oxidative stress resistance in worms and does not affect the feeding behavior of worms. These findings imply the potential of nhr-6 as a common therapeutic target for aging and cancer ailments, stressing the power of in silico PPI network analysis coupled with RNAi screens to describe gene function.
Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.
High-throughput studies of microbial communities suggest that Archaea are a widespread component of microbial diversity in various ecosystems. However, proper quantification of archaeal diversity and community ecology remains limited, as sequence coverage of Archaea is usually low owing to the inability of available prokaryotic primers to efficiently amplify archaeal compared to bacterial rRNA genes. To improve identification and quantification of Archaea, we designed and validated the utility of several primer pairs to efficiently amplify archaeal 16S rRNA genes based on up-to-date reference genes. We demonstrate that several of these primer pairs amplify phylogenetically diverse Archaea with high sequencing coverage, outperforming commonly used primers. Based on comparing the resulting long 16S rRNA gene fragments with public databases from all habitats, we found several novel family- to phylum-level archaeal taxa from topsoil and surface water. Our results suggest that archaeal diversity has been largely overlooked due to the limitations of available primers, and that improved primer pairs enable to estimate archaeal diversity more accurately.
The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.
Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death
(2019)
Background
The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood.
Methods
LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements.
Results
Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells.
Conclusion
This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors.
Die NO-sensitive Guanylyl-Cyclase (NO-GC) ist ein zentrales Enzym der NO/cGMP-Signalkaskade, das über die Aktivierung von NO zur Bildung des second messangers cGMP führt. Die NO-GC setzt sich aus zwei Untereinheiten zusammen, sodass zwei Isoformen des Enzyms gebildet werden können (α1β1 und α2β1). Da die genaue Verteilung der beiden Isoformen im Colon nicht bekannt ist, wurde diese im ersten Teil dieser Arbeit charakterisiert. Immunhistochemie und In-situ-Hybridisierung zeigten die Expression beider Isoformen sowohl in der glatten Muskelschicht als auch in der Submukosa und Lamina propria. Dabei war die α1β1-Isoform ubiquitär, die α2β1-Isoform dagegen hauptsächlich im Bereich des myenterischen Plexus vorzufinden.
In der glatten Muskelschicht des Colons ist die NO-GC in glatten Muskelzellen (SMC), interstitiellen Zellen von Cajal (ICC) sowie Fibroblasten-ähnliche Zellen (FLC) exprimiert und hauptsächlich in die Modulation der gastrointestinalen Motilität involviert. Zur spezifischen Charakterisierung der Funktion der NO-GC in den einzelnen Zelltypen wurden Knockout-Mäuse generiert, denen die NO-GC global (GCKO) oder spezifisch in SMC (SMC-GCKO), ICC (ICC-GCKO) oder beiden Zelltypen (SMC/ICC-GCKO) fehlt. Anhand dieser Mausmodelle sollten im zweiten Teil dieser Arbeit die modulatorischen Effekte der NO-GC auf die spontanen Kontraktionen des Colons bestimmt werden. Zur Charakterisierung der spontanen Kontraktionen der zirkulären Muskelschicht wurden Myographiestudien mit 2,5 mm langen Colonringen durchgeführt. Hierbei konnten drei verschiedene Kontraktionen gemessen werden: Kleine, hochfrequente Ripples, mittlere Kontraktionen und große Kontraktionen. Die detaillierte Analyse der einzelnen Kontraktionen zeigte einerseits eine NO-unabhängige Regulation der Ripples, andererseits eine NO-abhängige Modulation der mittleren und großen Kontraktionen über die NO-GC in SMC und ICC. Die NO-GC in SMC beeinflusst die Kontraktionen vermutlich vor allem über die Regulation des Muskeltonus der zirkulären Muskelschicht. Die NO-GC in ICC dagegen modifiziert die spontanen Kontraktionen möglicherweise über eine Veränderung der Schrittmacheraktivität. Allerdings führt erst ein Funktionsverlust des NO/cGMP-Signalweges in beiden Zelltypen zu einem sichtbar veränderten Kontraktionsmuster, das dem von globalen Knockout-Tieren glich. Dies weist auf eine kompensatorische Wirkung der NO-GC im jeweils anderen Zelltyp hin.
Zur Analyse der propulsiven Kontraktionen entlang des gesamten Colons wurden Videoaufnahmen der Darmbewegungen in Kontraktionsmusterkarten transformiert. Zudem wurde der Darm durchspült und die Ausflusstropfen aufgezeichnet, um die Effektivität der Kontraktionen beurteilen zu können. Hierbei zeigte sich, dass eine Beeinträchtigung des NO/cGMP-Signalweges eine verminderte Effektivität der Kontraktionen zur Folge hat und vermutlich durch eine beeinträchtige Synchronisation der Kontraktionen erklärt werden kann. In diesem Regulationsmechanismus konnte vor allem der NO-GC in SMC eine übergeordnete Rolle zugewiesen werden.
Der dritte Teil der Arbeit thematisierte den Befund, dass SMC-GCKO-Tiere ca. 5 Monate nach Tamoxifen-Behandlung Entartungen der Mukosa entwickelten. Diese Entartung war lediglich in Tamoxifen-induzierten Knockout-Tieren vorzufinden. Histologische Analysen identifizierten die Entartungen als tubulovillöses Adenom. Die Genexpressionsanalyse von Mukosafalten von SMC-GCKO- und heterozygoten Kontrolltieren zeigte eine Vielzahl von Genen, welche spezifisch bei colorectalem Karzinom differenziell exprimiert sind. Einer dieser Faktoren war der BMP-Antagonist Gremlin1. Dieser Faktor erschien von besonderem Interesse, da er in Zellen der Lamina muscularis mucosae und kryptennahen Myofibroblasten exprimiert wird. Immunhistochemische Analysen ließen vermuten, dass diese Zellen sowohl die NO-GC als auch die Cre-Rekombinase unter dem SMMHC-Promotor exprimieren. Diese Arbeit liefert demnach Hinweise darauf, dass die NO-GC einen wichtigen Regulator innerhalb der Stammzellnische bildet. Die Deletion der NO-GC führt vermutlich zu einer verstärkten Bildung bzw. Sekretion von Gremlin1, was die Homöostase der mukosalen Erneuerung stört und somit zur Entwicklung von Adenomen führt.
Life on earth adapted to the daily reoccurring changes in environment by evolving an endogenous circadian clock. Although the circadian clock has a crucial impact on survival and behavior of solitary bees, many aspects of solitary bee clock mechanisms remain unknown. Our study is the first to show that the circadian clock governs emergence in Osmia bicornis, a bee species which overwinters as adult inside its cocoon. Therefore, its eclosion from the pupal case is separated by an interjacent diapause from its emergence in spring. We show that this bee species synchronizes its emergence to the morning. The daily rhythms of emergence are triggered by temperature cycles but not by light cycles. In contrast to this, the bee’s daily rhythms in locomotion are synchronized by light cycles. Thus, we show that the circadian clock of O. bicornis is set by either temperature or light, depending on what activity is timed. Light is a valuable cue for setting the circadian clock when bees have left the nest. However, for pre-emerged bees, temperature is the most important cue, which may represent an evolutionary adaptation of the circadian system to the cavity-nesting life style of O. bicornis.
Predation on pest organisms is an essential ecosystem function supporting yields in modern agriculture. However, assessing predation rates is intricate, and they can rarely be linked directly to predator densities or functions. We tested whether sentinel prey aphid cards are useful tools to assess predation rates in the field. Therefore, we looked at aphid cards of different sizes on the ground level as well as within the vegetation. Additionally, by trapping ground‐dwelling predators, we examined whether obtained predation rates could be linked to predator densities and traits. Predation rates recorded with aphid cards were independent of aphid card size. However, predation rates on the ground level were three times higher than within the vegetation. We found both predatory carabid activity densities as well as community weighted mean body size to be good predictors for predation rates. Predation rates obtained from aphid cards are stable over card type and related to predator assemblages. Aphid cards, therefore, are a useful, efficient method for rapidly assessing the ecosystem function predation. Their use might especially be recommended for assessments on the ground level and when time and resource limitations rule out more elaborate sentinel prey methods using exclosures with living prey animals.
In this work models for molecular networks consisting of ordinary differential equations are extended by terms that include the interaction of the corresponding molecular network with the environment that the molecular network is embedded in. These terms model the effects of the external stimuli on the molecular network. The usability of this extension is demonstrated with a model of a circadian clock that is extended with certain terms and reproduces data from several experiments at the same time.
Once the model including external stimuli is set up, a framework is developed in order to calculate external stimuli that have a predefined desired effect on the molecular network. For this purpose the task of finding appropriate external stimuli is formulated as a mathematical optimal control problem for which in order to solve it a lot of mathematical methods are available. Several methods are discussed and worked out in order to calculate a solution for the corresponding optimal control problem. The application of the framework to find pharmacological intervention points or effective drug combinations is pointed out and discussed. Furthermore the framework is related to existing network analysis tools and their combination for network analysis in order to find dedicated external stimuli is discussed.
The total framework is verified with biological examples by comparing the calculated results with data from literature. For this purpose platelet aggregation is investigated based on a corresponding gene regulatory network and associated receptors are detected. Furthermore a transition from one to another type of T-helper cell is analyzed in a tumor setting where missing agents are calculated to induce the corresponding switch in vitro. Next a gene regulatory network of a myocardiocyte is investigated where it is shown how the presented framework can be used to compare different treatment strategies with respect to their beneficial effects and side effects quantitatively. Moreover a constitutively activated signaling pathway, which thus causes maleficent effects, is modeled and intervention points with corresponding treatment strategies are determined that steer the gene regulatory network from a pathological expression pattern to physiological one again.
Once biological systems are modeled by regulatory networks, the next step is to include external stimuli, which model the experimental possibilities to affect the activity level of certain network’s nodes, in a mathematical framework. Then, this framework can be interpreted as a mathematical optimal control framework such that optimization algorithms can be used to determine external stimuli which cause a desired switch from an initial state of the network to another final state. These external stimuli are the intervention points for the corresponding biological experiment to obtain the desired outcome of the considered experiment. In this work, the model of regulatory networks is extended to controlled regulatory networks. For this purpose, external stimuli are considered which can affect the activity of the network’s nodes by activation or inhibition. A method is presented how to calculate a selection of external stimuli which causes a switch between two different steady states of a regulatory network. A software solution based on Jimena and Mathworks Matlab is provided. Furthermore, numerical examples are presented to demonstrate application and scope of the software on networks of 4 nodes, 11 nodes and 36 nodes. Moreover, we analyze the aggregation of platelets and the behavior of a basic T-helper cell protein-protein interaction network and its maturation towards Th0, Th1, Th2, Th17 and Treg cells in accordance with experimental data.