Refine
Has Fulltext
- yes (138) (remove)
Is part of the Bibliography
- yes (138)
Year of publication
Document Type
- Journal article (119)
- Preprint (9)
- Review (8)
- Conference Proceeding (1)
- Working Paper (1)
Language
- English (138) (remove)
Keywords
- metabolism (8)
- apoptosis (7)
- cosmology (6)
- crystallization (6)
- SARS-CoV-2 (5)
- cytokinins (5)
- qubit (5)
- COVID-19 (4)
- decoherence (4)
- evolution (4)
- leukemic cells (4)
- regulation (4)
- transcriptome (4)
- Candida albicans (3)
- bioinformatics (3)
- cisplatin (3)
- cytotoxicity (3)
- database (3)
- expression (3)
- identification (3)
- molecular docking (3)
- mutation (3)
- systems biology (3)
- virulence (3)
- "-omics" (2)
- Aspergillus fumigatus (2)
- Bioinformatik (2)
- Biology (2)
- C-60 fullerene (2)
- Caenorhabditis elegans (2)
- DNA (2)
- DNA storage (2)
- Metabolic pathways (2)
- RNA (2)
- Salmonella-containing vacuole (SCV) (2)
- Staphylococcus aureus (2)
- adaptation (2)
- algorithm (2)
- alignment (2)
- annotation (2)
- cellular signalling networks (2)
- complexity (2)
- dendritic cells (2)
- differentiation (2)
- drug repurposing (2)
- emergent time (2)
- engineering (2)
- infection (2)
- loop quantum gravity (2)
- lung cancer (2)
- machine learning (2)
- metabolic modeling (2)
- modified inflation (2)
- molecular dynamics (2)
- mouse (2)
- oncolytic virus (2)
- oxidative stress (2)
- phase transition (2)
- platelet (2)
- positive selection (2)
- protein folding (2)
- qubit interaction (2)
- recombination (2)
- resistance (2)
- synthetic biology (2)
- transcriptional regulation (2)
- 1st-line treatment (1)
- 3D lung tumor model (1)
- 3D lung tumor tissue models (1)
- 3D tissue models (1)
- 5-Fluorouracil (1)
- 6-benzylaminopurine (1)
- A2a-R receptor (1)
- ACKR4 (1)
- AIModules (1)
- AKT (1)
- Abstandsmessung (1)
- Aspergillus (1)
- Aspergillus fumigalus (1)
- Axl tyrosine kinase (1)
- B-cell (1)
- BRAF mutation (1)
- Bedeutung (1)
- Beobachter (1)
- Berberine (1)
- Berechnungskomplexität (1)
- Beta-catenin (1)
- Biologie (1)
- Boolean function (1)
- Boolean signaling network (1)
- Boolean tree (1)
- C60 fullerene (1)
- CD95 (1)
- CETCH cycle (1)
- CLAVATA3 (1)
- CLV3p (1)
- CO2-sequestration (1)
- C\(_{60}\) fullerene (1)
- Camponotus floridanus (1)
- Carcinoma cells (1)
- Cell surface proteomics (1)
- Cestode (1)
- Chagas diagnosis (1)
- Chagas disease (1)
- Chagas monitoring (1)
- Chagas real time PCR (1)
- Chlamydia trachomatis (1)
- Computer modelling (1)
- Computer software (1)
- Cushing’s disease (1)
- DLS and AFM measurements (1)
- DNA damage (1)
- Doxorubicin (1)
- E8 symmetry (1)
- EMT (1)
- ERK signaling (1)
- Echinococcosis (1)
- Echinococcus (1)
- Einfluss (1)
- Embryonic induction (1)
- Enterobacteriaceae (1)
- Entscheidung (1)
- Entscheidungen (1)
- Enzyme kinetics (1)
- Enzyme metabolism (1)
- Enzyme regulation (1)
- Enzymes (1)
- Epicardium-derived cells (1)
- Evaluation (1)
- Evolution (1)
- FLS2 receptor (1)
- Fibroblasts (1)
- Fluorouracil (1)
- Functional modules (1)
- Fundamentalkonstante (1)
- GPVI (1)
- Gene expression vectors (1)
- Gödel (1)
- H7N9 influenza virus (1)
- HGPS (1)
- HIV (1)
- HPLC-ESI-MS (1)
- HSP90 inhibitor (1)
- HeLa cells (1)
- Host-parasite interaction (1)
- Human atrial stromal cells (1)
- Hurwitz theorem (1)
- Hurwitz-Theorem (1)
- ICEP (1)
- ICP27 (1)
- IGFBP2 (1)
- Insulin (1)
- Integrated network analysis (1)
- Invasion (1)
- IronChip Evaluation Package (1)
- KRAS biomarker signatures (1)
- KRAS mutation signature (1)
- Ki67 (1)
- Kinase inhibitor (1)
- Kolmogorov-Komplexität (1)
- Komplex <Algebra> (1)
- Komplexität (1)
- Kosmologie (1)
- LEDs (1)
- LS-MIDA (1)
- Lee Smolin (1)
- MHC I (1)
- MHC II (1)
- MITE (1)
- Matrix (1)
- Metabolic profiles (1)
- Microarray (1)
- Mikroarray (1)
- Milnesium tardigradum (1)
- Multicenter randomized-trial (1)
- Mycoplasma (1)
- Natur (1)
- Nature constants (1)
- Naturgesetz (1)
- Natürliche Auslese (1)
- Neuromuscular junctions (1)
- Olea (1)
- Phylogenie (1)
- PknB (1)
- Polymerase chain reaction (1)
- Predictive toxicology (1)
- Prognose (1)
- Proteasen (1)
- Proteine (1)
- Quantenschleifen-Gravitation (1)
- Qubits (1)
- R0 (1)
- RNA secondary structure (1)
- RNA sequencing (1)
- RNA-SEQ (1)
- RNAi (1)
- Receptor kinase (1)
- Salmonella enterica (1)
- Salmonella-containing vacuole (1)
- Sanger sequencing (1)
- Septins (1)
- Shotgun method (1)
- Spumaviren (1)
- Stp (1)
- Strukturanalyse (1)
- Synapses (1)
- Synaptic vesicles (1)
- Synthetic biology (1)
- T-cell (1)
- T-cell epitope (1)
- Tapeworm (1)
- Tissue (1)
- Toxicity (1)
- Transcriptional control (1)
- Trend test (1)
- Trypanosoma (1)
- Trypanosoma cruzi (1)
- UV–Vis (1)
- V1–V9 (1)
- V4 (1)
- V7/V8 (1)
- VASP (1)
- Vasodilatator-stimuliertes Phosphoprotein (1)
- Verschränkung (1)
- Vesicles (1)
- Virtual sequencing (1)
- WNT (1)
- Yolk protein (1)
- Zebrafish (1)
- Zika virus (1)
- abscisic acid (ABA) (1)
- accumulation (1)
- adaption (1)
- agent-based model (1)
- aging (1)
- air-liquid interface (1)
- alveolar fibrosis (1)
- alveolar regeneration (1)
- alzheimer's disease (1)
- alzheimers disease (1)
- animals (1)
- anti-cancer drug-like molecules (1)
- anti-thrombotic therapies (1)
- anticancer activity (1)
- antimicrobial peptides (1)
- antimycotics (1)
- antioxidants (1)
- antiproliferative (1)
- approved drugs (1)
- arabidopsis thaliana (1)
- arabidpsis thaliana (1)
- artificial membrane-permeability (1)
- asthmatic bronchial epithelium (1)
- auxin (1)
- bacterial invasion (1)
- bacterial pathogens (1)
- bacteriology (1)
- beta-lactamase inhibition (1)
- binary decision diagram (1)
- binding pocket (1)
- binding protein (1)
- biofilm formation (1)
- biofuel (1)
- bioinformatics and computational biology (1)
- biological activities (1)
- biomanufacturing (1)
- biomarker (1)
- biomaterial surfaces (1)
- bioreactor culture (1)
- bit (1)
- blood platelets (1)
- boolean in silico models (1)
- boolean modeling (1)
- brain (1)
- caenorhabditis elegans (1)
- calcium (1)
- calcium signaling pathway (1)
- camponotus floridanus (1)
- cancer therapy (1)
- candida genome database (1)
- carboxylation (1)
- carpenter ant (1)
- cascade (1)
- caspase-3 (1)
- cell death (1)
- cell staining (1)
- cell wall (1)
- centrality (1)
- cerebral ischemia (1)
- chemical similarity (1)
- chemoresistance (1)
- chondrosarcoma (1)
- cluster (1)
- collagen (1)
- colony-stimulating factor (1)
- colorectal cancer (1)
- combinatorial drug predictions (1)
- comparative sequence analysis (1)
- complex networks (1)
- computational (1)
- computational biology and bioinformatics (1)
- computational modelling (1)
- computational prediction (1)
- computational systems biology (1)
- computer modelling (1)
- computer-assisted (1)
- connector (1)
- control group (1)
- control profiles (1)
- controllability (1)
- corticotropin-releasing hormone (1)
- crosstalk (1)
- cryptic (1)
- crystal growth (1)
- culture (1)
- cycle (1)
- cyclic nucleotide signaling (1)
- cytokines (1)
- cytokinin (1)
- cytokinin kinetin (1)
- data mining/methods (1)
- data storage (1)
- decision (1)
- defense and evasion strategies (1)
- defense signaling (1)
- defenses (1)
- design (1)
- deubiquitinases (1)
- differentially expressed genes (1)
- discovery (1)
- disease (1)
- docking (1)
- domain (1)
- doxorubicin (1)
- drosophila (1)
- drug design (1)
- drug release (1)
- drug resistance (1)
- drug-minded protein (1)
- dynamic protein-protein interactions (1)
- early cosmology (1)
- early diagnosis (1)
- efficient intervention points (1)
- elementary body (1)
- elementary modes (1)
- embryonic stem cells (1)
- emergent gravity (1)
- encapsulation (1)
- encephalitis dementia (1)
- entanglement (1)
- enteric pathogens (1)
- enterica serovar Typhimurium (1)
- enzyme (1)
- epithelial cell culture (1)
- epitope mapping (1)
- epitope prediction (1)
- error (1)
- error-transfer (1)
- eugenol (1)
- evolutionary (1)
- exome (1)
- explainability of machine learning (1)
- expressed sequence tag (1)
- extracellular matrix (1)
- facultatively intracellular pathogens (1)
- feature analysis (1)
- feature selection (1)
- fine-tuning (1)
- flg22 (1)
- fluorescence recovery after photobleaching (1)
- flux balance analysis (1)
- format (1)
- fostamatinib (1)
- free energy (1)
- functional modules (1)
- fungal pathogens (1)
- fungicide (1)
- gamma (1)
- gene expression (1)
- gene ontology (1)
- genes (1)
- genetic regulatory network (1)
- genetic variation (1)
- genetics (1)
- genome browser (1)
- genus Aspergillus (1)
- guard cells (1)
- heart (1)
- hepatotoxicity (1)
- heuristics (1)
- histidine kinase (1)
- homology modeling (1)
- host-pathogen adaption (1)
- host-pathogen interaction (1)
- human (1)
- human immune system (1)
- human immunodeficiency virus (1)
- human pathogenic fungi (1)
- human xenografted mouse models (1)
- humans (1)
- image processing (1)
- imaging (1)
- immune system (1)
- immune-informatics (1)
- immunity (1)
- immunocytochemistry (1)
- immunological cross-talk (1)
- immunotherapies (1)
- in silico simulation (1)
- in vitro (1)
- in vitro models (1)
- in vivo toxicity (1)
- in-vitro (1)
- infected-cell protein (1)
- infection biology (1)
- infection spread (1)
- inflammation (1)
- inflation (1)
- inhibitor (1)
- insilico drug screening too (1)
- interaction (1)
- interaction map (1)
- interaction networks (1)
- interactome (1)
- intermediate host (1)
- internal transcribed spacer 2 (1)
- interolog (1)
- interpolation (1)
- interspecies comparison (1)
- invasion (1)
- invasiveness (1)
- ion signaling (1)
- isotopolog profiling (1)
- kinase signaling (1)
- kinetin (1)
- lactate dehydrogenase (1)
- lethality rate (1)
- life-span regulation (1)
- light-gated proteins (1)
- lncRNAs (1)
- lymphocytes (1)
- lymphotoxicity (1)
- mammalian system (1)
- meaning (1)
- messenger RNA (1)
- meta-data (1)
- meta-transcriptome (1)
- metabolic flux (1)
- metabolic modelling (1)
- metabolic pathways (1)
- metabolomic profiling (1)
- miRNAs (1)
- microRNAs (1)
- microRNA–target interaction (1)
- microarray (1)
- microbes (1)
- model reduction (1)
- modeling (1)
- models (1)
- modular tumor tissue models (1)
- modulatory effects (1)
- molecular cloning (1)
- molecular dynamics simulation (1)
- molecular evolution (1)
- molecular modeling (1)
- molecular systematics (1)
- mortality (1)
- mosquito (1)
- mouse model (1)
- multiverse (1)
- myocardial infarction (1)
- myocardium (1)
- nanocarrier (1)
- nanocellulose (1)
- nanocomplex (1)
- natural language processing (1)
- natural processing (1)
- neisseria meningitidis (1)
- network (1)
- network analysis (1)
- network biology (1)
- network inference (1)
- network simulation (1)
- neuraminidase (1)
- neutrophils (1)
- next generation sequencing (1)
- nitric oxide (1)
- non-invasive biomarkers (1)
- noncovalent complex (1)
- noncovalent nanocomplex (1)
- nucleic acid motifs (1)
- observer (1)
- olive (1)
- omics (1)
- on-a-chip (1)
- optimal drug combination (1)
- optimal drug targeting (1)
- optimal pharmacological modulation (1)
- optimal treatment strategies (1)
- optogenetics (1)
- organogenesis (1)
- origin (1)
- pH (1)
- pangolin (1)
- parasite (1)
- pathogen-host interaction (PHI) (1)
- pathogenesis (1)
- pathogenicity (1)
- pathways (1)
- patient data (1)
- permeability (1)
- pharmacology (1)
- phase space (1)
- phosphoproteome (1)
- phosphorylation (1)
- photodanamic therapy (1)
- photodynamic chemotherapy (1)
- photorespiration (1)
- phylogenetic analysis (1)
- phylogenetic tree (1)
- phylogenetics (1)
- phylogeny (1)
- phytohormones (1)
- plant hormones (1)
- plant system (1)
- pollen tube (1)
- population coverage (1)
- potential role (1)
- principal (1)
- pro-oxidant (1)
- progeria (1)
- promoter (1)
- protease; Indinavir; lead expansion; docking; pharmacophore (1)
- protein (1)
- protein analysis (1)
- protein chip (1)
- protein familiy (1)
- protein interaction database (1)
- protein-protein interaction (1)
- protein-protein interaction network (1)
- proteins (1)
- proteome (1)
- pseudomas-syringae (1)
- pulmonary drug-delivery (1)
- pyrazolo[3,4-d]pyrimidine (1)
- quantum computing (1)
- radiation (1)
- rational drug design (1)
- re-annotation (1)
- receptor (1)
- reconstructed human epidermis (1)
- regulatory networks (1)
- relA (1)
- reliability (1)
- reproductive toxicity (1)
- respiratory syncytial virus (1)
- response regulator (1)
- reticulate body (1)
- ribosomal RNA (1)
- riboswitch (1)
- richtersius coronifer (1)
- scaffold search (1)
- secondary structure (1)
- selection (1)
- sensor (1)
- sequence (1)
- sequence alignment (1)
- shoot apical meristem (1)
- signaling (1)
- signaling network (1)
- signaling pathway (1)
- signalling (1)
- signalling pathways (1)
- silico model (1)
- simulation (1)
- single cell analysis (1)
- single-electron transistors (1)
- sky kinases (1)
- software (1)
- somatic mutations (1)
- spanlastic (1)
- splicing factors (1)
- stable state (1)
- stable-isotope (1)
- stem cell niche (1)
- stem-cell-triggered immunity (1)
- stemness (1)
- stratification (1)
- stringent response (1)
- structure (1)
- structure-activity relationship (1)
- sun exposure (1)
- superoxide-dismutase (1)
- synaptic vesicles (1)
- synergistic effect (1)
- synthetic pathways (1)
- system inference (1)
- tardigrada (1)
- target (1)
- targeted combination therapy (1)
- targeted therapy (1)
- targets (1)
- therapeutic strategy (1)
- thrombosis (1)
- tolerance (1)
- tools overview (1)
- transcription (1)
- translation (1)
- transmission (1)
- transport studies (1)
- tumors (1)
- type 1 (1)
- unified theories (1)
- uptake (1)
- variable regions (1)
- variants (1)
- vesicle-based barrier (1)
- virulenceregulatory evolution (1)
- viruses (1)
- vitellogenin (1)
- water stress (1)
- wrong labelling (1)
- xanthurenic acid (1)
- yeast U3 localization (1)
- yvcK/glmR operon (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (134)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin (8)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (6)
- Institut für Molekulare Infektionsbiologie (5)
- Center for Computational and Theoretical Biology (4)
- Institut für Experimentelle Biomedizin (4)
- Institut für Pharmakologie und Toxikologie (4)
- Institut für Virologie und Immunbiologie (4)
- Kinderklinik und Poliklinik (3)
- Institut für Humangenetik (2)
Sonstige beteiligte Institutionen
EU-Project number / Contract (GA) number
- 031A408B (1)
- CoG 721016–HERPES (1)
- ESF-ZDEX 4.0 (1)
The signal modelling framework JimenaE simulates dynamically Boolean networks. In contrast to SQUAD, there is systematic and not just heuristic calculation of all system states. These specific features are not present in CellNetAnalyzer and BoolNet. JimenaE is an expert extension of Jimena, with new optimized code, network conversion into different formats, rapid convergence both for system state calculation as well as for all three network centralities. It allows higher accuracy in determining network states and allows to dissect networks and identification of network control type and amount for each protein with high accuracy. Biological examples demonstrate this: (i) High plasticity of mesenchymal stromal cells for differentiation into chondrocytes, osteoblasts and adipocytes and differentiation-specific network control focusses on wnt-, TGF-beta and PPAR-gamma signaling. JimenaE allows to study individual proteins, removal or adding interactions (or autocrine loops) and accurately quantifies effects as well as number of system states. (ii) Dynamical modelling of cell–cell interactions of plant Arapidopsis thaliana against Pseudomonas syringae DC3000: We analyze for the first time the pathogen perspective and its interaction with the host. We next provide a detailed analysis on how plant hormonal regulation stimulates specific proteins and who and which protein has which type and amount of network control including a detailed heatmap of the A.thaliana response distinguishing between two states of the immune response. (iii) In an immune response network of dendritic cells confronted with Aspergillus fumigatus, JimenaE calculates now accurately the specific values for centralities and protein-specific network control including chemokine and pattern recognition receptors.
To improve and focus preclinical testing, we combine tumor models based on a decellularized tissue matrix with bioinformatics to stratify tumors according to stage-specific mutations that are linked to central cancer pathways. We generated tissue models with BRAF-mutant colorectal cancer (CRC) cells (HROC24 and HROC87) and compared treatment responses to two-dimensional (2D) cultures and xenografts. As the BRAF inhibitor vemurafenib is—in contrast to melanoma—not effective in CRC, we combined it with the EGFR inhibitor gefitinib. In general, our 3D models showed higher chemoresistance and in contrast to 2D a more active HGFR after gefitinib and combination-therapy. In xenograft models murine HGF could not activate the human HGFR, stressing the importance of the human microenvironment. In order to stratify patient groups for targeted treatment options in CRC, an in silico topology with different stages including mutations and changes in common signaling pathways was developed. We applied the established topology for in silico simulations to predict new therapeutic options for BRAF-mutated CRC patients in advanced stages. Our in silico tool connects genome information with a deeper understanding of tumor engines in clinically relevant signaling networks which goes beyond the consideration of single drivers to improve CRC patient stratification.
MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.
Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRAS\(^{G12C}\) or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRAS\(^{G12C}\) inhibitor in KRAS\(^{G12C}\) mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.
High attrition-rates entailed by drug testing in 2D cell culture and animal models stress the need for improved modeling of human tumor tissues. In previous studies our 3D models on a decellularized tissue matrix have shown better predictivity and higher chemoresistance. A single porcine intestine yields material for 150 3D models of breast, lung, colorectal cancer (CRC) or leukemia. The uniquely preserved structure of the basement membrane enables physiological anchorage of endothelial cells and epithelial-derived carcinoma cells. The matrix provides different niches for cell growth: on top as monolayer, in crypts as aggregates and within deeper layers. Dynamic culture in bioreactors enhances cell growth. Comparing gene expression between 2D and 3D cultures, we observed changes related to proliferation, apoptosis and stemness. For drug target predictions, we utilize tumor-specific sequencing data in our in silico model finding an additive effect of metformin and gefitinib treatment for lung cancer in silico, validated in vitro. To analyze mode-of-action, immune therapies such as trispecific T-cell engagers in leukemia, as well as toxicity on non-cancer cells, the model can be modularly enriched with human endothelial cells (hECs), immune cells and fibroblasts. Upon addition of hECs, transmigration of immune cells through the endothelial barrier can be investigated. In an allogenic CRC model we observe a lower basic apoptosis rate after applying PBMCs in 3D compared to 2D, which offers new options to mirror antigen-specific immunotherapies in vitro. In conclusion, we present modular human 3D tumor models with tissue-like features for preclinical testing to reduce animal experiments.
Patient-tailored therapy based on tumor drivers is promising for lung cancer treatment. For this, we combined in vitro tissue models with in silico analyses. Using individual cell lines with specific mutations, we demonstrate a generic and rapid stratification pipeline for targeted tumor therapy. We improve in vitro models of tissue conditions by a biological matrix-based three-dimensional (3D) tissue culture that allows in vitro drug testing: It correctly shows a strong drug response upon gefitinib (Gef) treatment in a cell line harboring an EGFR-activating mutation (HCC827), but no clear drug response upon treatment with the HSP90 inhibitor 17AAG in two cell lines with KRAS mutations (H441, A549). In contrast, 2D testing implies wrongly KRAS as a biomarker for HSP90 inhibitor treatment, although this fails in clinical studies. Signaling analysis by phospho-arrays showed similar effects of EGFR inhibition by Gef in HCC827 cells, under both 2D and 3D conditions. Western blot analysis confirmed that for 3D conditions, HSP90 inhibitor treatment implies different p53 regulation and decreased MET inhibition in HCC827 and H441 cells. Using in vitro data (western, phospho-kinase array, proliferation, and apoptosis), we generated cell line-specific in silico topologies and condition-specific (2D, 3D) simulations of signaling correctly mirroring in vitro treatment responses. Networks predict drug targets considering key interactions and individual cell line mutations using the Human Protein Reference Database and the COSMIC database. A signature of potential biomarkers and matching drugs improve stratification and treatment in KRAS-mutated tumors. In silico screening and dynamic simulation of drug actions resulted in individual therapeutic suggestions, that is, targeting HIF1A in H441 and LKB1 in A549 cells. In conclusion, our in vitro tumor tissue model combined with an in silico tool improves drug effect prediction and patient stratification. Our tool is used in our comprehensive cancer center and is made now publicly available for targeted therapy decisions.
The ITS2 Database
(2012)
The internal transcribed spacer 2 (ITS2) has been used as a phylogenetic marker for more than two decades. As ITS2 research mainly focused on the very variable ITS2 sequence, it confined this marker to low-level phylogenetics only. However, the combination of the ITS2 sequence and its highly conserved secondary structure improves the phylogenetic resolution1 and allows phylogenetic inference at multiple taxonomic ranks, including species delimitation.
The ITS2 Database presents an exhaustive dataset of internal transcribed spacer 2 sequences from NCBI GenBank accurately reannotated. Following an annotation by profile Hidden Markov Models (HMMs), the secondary structure of each sequence is predicted. First, it is tested whether a minimum energy based fold (direct fold) results in a correct, four helix conformation. If this is not the case, the structure is predicted by homology modeling. In homology modeling, an already known secondary structure is transferred to another ITS2 sequence, whose secondary structure was not able to fold correctly in a direct fold.
The ITS2 Database is not only a database for storage and retrieval of ITS2 sequence-structures. It also provides several tools to process your own ITS2 sequences, including annotation, structural prediction, motif detection and BLAST search on the combined sequence-structure information. Moreover, it integrates trimmed versions of 4SALE and ProfDistS for multiple sequence-structure alignment calculation and Neighbor Joining tree reconstruction. Together they form a coherent analysis pipeline from an initial set of sequences to a phylogeny based on sequence and secondary structure.
In a nutshell, this workbench simplifies first phylogenetic analyses to only a few mouse-clicks, while additionally providing tools and data for comprehensive large-scale analyses.
Cyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified three plasmodial SR proteins, PfSRSF12, PfSFRS4 and PfSF-1, which are predominantly present in the nucleus of blood stage trophozoites, PfSRSF12 and PfSF-1 are further detectable in the nucleus of gametocytes. We found that recombinantly expressed SR proteins comprising the Arginine/Serine (RS)-rich domains were phosphorylated by the four PfCLKs in in vitro kinase assays, while a recombinant PfSF-1 peptide lacking the RS-rich domain was not phosphorylated. Since it was hitherto not possible to knock-out the pfclk genes by conventional gene disruption, we aimed at chemical knock-outs for phenotype analysis. We identified five human CLK inhibitors, belonging to the oxo-beta-carbolines and aminopyrimidines, as well as the antiseptic chlorhexidine as PfCLK-targeting compounds. The six inhibitors block P. falciparum blood stage replication in the low micromolar to nanomolar range by preventing the trophozoite-to-schizont transformation. In addition, the inhibitors impair gametocyte maturation and gametogenesis in in vitro assays. The combined data show that the four PfCLKs are involved in phosphorylation of SR proteins with essential functions for the blood and sexual stages of the malaria parasite, thus pointing to the kinases as promising targets for antimalarial and transmission blocking drugs.
Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin, regulating important platelet functions such as platelet adhesion and thrombus growth. Although the blockade of GPVI function is widely recognized as a potent anti-thrombotic approach, there are limited studies focused on site-specific targeting of GPVI. Using computational modeling and bioinformatics, we analyzed collagen- and CRP-binding surfaces of GPVI monomers and dimers, and compared the interacting surfaces with other mammalian GPVI isoforms. We could predict a minimal collagen-binding epitope of GPVI dimer and designed an EA-20 antibody that recognizes a linear epitope of this surface. Using platelets and whole blood samples donated from wild-type and humanized GPVI transgenic mice and also humans, our experimental results show that the EA-20 antibody inhibits platelet adhesion and aggregation in response to collagen and CRP, but not to fibrin. The EA-20 antibody also prevents thrombus formation in whole blood, on the collagen-coated surface, in arterial flow conditions. We also show that EA-20 does not influence GPVI clustering or receptor shedding. Therefore, we propose that blockade of this minimal collagen-binding epitope of GPVI with the EA-20 antibody could represent a new anti-thrombotic approach by inhibiting specific interactions between GPVI and the collagen matrix.
The predicted 80 open reading frames (ORFs) of herpes simplex virus 1 (HSV-1) have been intensively studied for decades. Here, we unravel the complete viral transcriptome and translatome during lytic infection with base-pair resolution by computational integration of multi-omics data. We identify a total of 201 transcripts and 284 ORFs including all known and 46 novel large ORFs. This includes a so far unknown ORF in the locus deleted in the FDA-approved oncolytic virus Imlygic. Multiple transcript isoforms expressed from individual gene loci explain translation of the vast majority of ORFs as well as N-terminal extensions (NTEs) and truncations. We show that NTEs with non-canonical start codons govern the subcellular protein localization and packaging of key viral regulators and structural proteins. We extend the current nomenclature to include all viral gene products and provide a genome browser that visualizes all the obtained data from whole genome to single-nucleotide resolution. Here, using computational integration of multi-omics data, the authors provide a detailed transcriptome and translatome of herpes simplex virus 1 (HSV-1), including previously unidentified ORFs and N-terminal extensions. The study also provides a HSV-1 genome browser and should be a valuable resource for further research.
The opportunistic human pathogen Staphylococcus aureus causes serious infectious diseases that range from superficial skin and soft tissue infections to necrotizing pneumonia and sepsis. While classically regarded as an extracellular pathogen, S. aureus is able to invade and survive within human cells. Host cell exit is associated with cell death, tissue destruction, and the spread of infection. The exact molecular mechanism employed by S. aureus to escape the host cell is still unclear. In this study, we performed a genome-wide small hairpin RNA (shRNA) screen and identified the calcium signaling pathway as being involved in intracellular infection. S. aureus induced a massive cytosolic Ca\(^{2+}\) increase in epithelial host cells after invasion and intracellular replication of the pathogen. This was paralleled by a decrease in endoplasmic reticulum Ca\(^{2+}\) concentration. Additionally, calcium ions from the extracellular space contributed to the cytosolic Ca2+ increase. As a consequence, we observed that the cytoplasmic Ca\(^{2+}\) rise led to an increase in mitochondrial Ca\(^{2+}\) concentration, the activation of calpains and caspases, and eventually to cell lysis of S. aureus-infected cells. Our study therefore suggests that intracellular S. aureus disturbs the host cell Ca\(^{2+}\) homeostasis and induces cytoplasmic Ca\(^{2+}\) overload, which results in both apoptotic and necrotic cell death in parallel or succession.
IMPORTANCE Despite being regarded as an extracellular bacterium, the pathogen Staphylococcus aureus can invade and survive within human cells. The intracellular niche is considered a hideout from the host immune system and antibiotic treatment and allows bacterial proliferation. Subsequently, the intracellular bacterium induces host cell death, which may facilitate the spread of infection and tissue destruction. So far, host cell factors exploited by intracellular S. aureus to promote cell death are only poorly characterized. We performed a genome-wide screen and found the calcium signaling pathway to play a role in S. aureus invasion and cytotoxicity. The intracellular bacterium induces a cytoplasmic and mitochondrial Ca\(^{2+}\) overload, which results in host cell death. Thus, this study first showed how an intracellular bacterium perturbs the host cell Ca\(^{2+}\) homeostasis."
Metabolic adaptation to the host cell is important for obligate intracellular pathogens such as Chlamydia trachomatis (Ct). Here we infer the flux differences for Ct from proteome and qRT-PCR data by comprehensive pathway modeling. We compare the comparatively inert infectious elementary body (EB) and the active replicative reticulate body (RB) systematically using a genome-scale metabolic model with 321 metabolites and 277 reactions. This did yield 84 extreme pathways based on a published proteomics dataset at three different time points of infection. Validation of predictions was done by quantitative RT-PCR of enzyme mRNA expression at three time points. Ct’s major active pathways are glycolysis, gluconeogenesis, glycerol-phospholipid (GPL) biosynthesis (support from host acetyl-CoA) and pentose phosphate pathway (PPP), while its incomplete TCA and fatty acid biosynthesis are less active. The modeled metabolic pathways are much more active in RB than in EB. Our in silico model suggests that EB and RB utilize folate to generate NAD(P)H using independent pathways. The only low metabolic flux inferred for EB involves mainly carbohydrate metabolism. RB utilizes energy -rich compounds to generate ATP in nucleic acid metabolism. Validation data for the modeling include proteomics experiments (model basis) as well as qRT-PCR confirmation of selected metabolic enzyme mRNA expression differences. The metabolic modeling is made fully available here. Its detailed insights and models on Ct metabolic adaptations during infection are a useful modeling basis for future studies.
C60 fullerene as an effective nanoplatform of alkaloid Berberine delivery into leukemic cells
(2019)
A herbal alkaloid Berberine (Ber), used for centuries in Ayurvedic, Chinese, Middle-Eastern, and native American folk medicines, is nowadays proved to function as a safe anticancer agent. Yet, its poor water solubility, stability, and bioavailability hinder clinical application. In this study, we have explored a nanosized carbon nanoparticle—C60 fullerene (C60)—for optimized Ber delivery into leukemic cells. Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios were prepared. UV–Vis spectroscopy, dynamic light scattering (DLS), and atomic force microscopy (AFM) evidenced a complexation of the Ber cation with the negatively charged C60 molecule. The computer simulation showed that π-stacking dominates in Ber and C\(_{60}\) binding in an aqueous solution. Complexation with C\(_{60}\) was found to promote Ber intracellular uptake. By increasing C\(_{60}\) concentration, the C\(_{60}\)-Ber nanocomplexes exhibited higher antiproliferative potential towards CCRF-CEM cells, in accordance with the following order: free Ber < 1:2 < 1:1 < 2:1 (the most toxic). The activation of caspase 3/7 and accumulation in the sub-G1 phase of CCRF-CEM cells treated with C\(_{60}\)-Ber nanocomplexes evidenced apoptosis induction. Thus, this study indicates that the fast and easy noncovalent complexation of alkaloid Ber with C\(_{60}\) improved its in vitro efficiency against cancer cells.
Cosmology often uses intricate formulas and mathematics to derive new theories and concepts. We do something different in this paper: We look at biological processes and derive from these heuristics so that the revised cosmology agrees with astronomical observations but does also agree with standard biological observations. We show that we then have to replace any type of singularity at the start of the universe by a condensation nucleus and that the very early period of the universe usually assumed to be inflation has to be replaced by a period of rapid crystal growth as in Weiss magnetization domains.
Impressively, these minor modifications agree well with astronomical observations including removing the strong inflation perturbations which were never observed in the recent BICEP2 experiments. Furthermore, looking at biological principles suggests that such a new theory with a condensation nucleus at start and a first rapid phase of magnetization-like growth of the ordered, physical laws obeying lattice we live in is in fact the only convincing theory of the early phases of our universe that also is compatible with current observations.
We show in detail in the following that such a process of crystal creation, breaking of new crystal seeds and ultimate evaporation of the present crystal readily leads over several generations to an evolution and selection of better, more stable and more self-organizing crystals. Moreover, this explains the “fine-tuning” question why our universe is fine-tuned to favor life: Our Universe is so self-organizing to have enough offspring and the detailed physics involved is at the same time highly favorable for all self-organizing processes including life.
This biological theory contrasts with current standard inflation cosmologies. The latter do not perform well in explaining any phenomena of sophisticated structure creation or self-organization. As proteins can only thermodynamically fold by increasing the entropy in the solution around them we suggest for cosmology a condensation nucleus for a universe can form only in a “chaotic ocean” of string-soup or quantum foam if the entropy outside of the nucleus rapidly increases. We derive an interaction potential for 1 to n-dimensional strings or quantum-foams and show that they allow only 1D, 2D, 4D or octonion interactions. The latter is the richest structure and agrees to the E8 symmetry fundamental to particle physics and also compatible with the ten dimensional string theory E8 which is part of the M-theory. Interestingly, any other interactions of other dimensionality can be ruled out using Hurwitz compositional theorem. Crystallization explains also extremely well why we have only one macroscopic reality and where the worldlines of alternative trajectories exist: They are in other planes of the crystal and for energy reasons they crystallize mostly at the same time, yielding a beautiful and stable crystal. This explains decoherence and allows to determine the size of Planck´s quantum h (very small as separation of crystal layers by energy is extremely strong).
Ultimate dissolution of real crystals suggests an explanation for dark energy agreeing with estimates for the “big rip”. The halo distribution of dark matter favoring galaxy formation is readily explained by a crystal seed starting with unit cells made of normal and dark matter.
That we have only matter and not antimatter can be explained as there may be right handed mattercrystals and left-handed antimatter crystals. Similarly, real crystals are never perfect and we argue that exactly such irregularities allow formation of galaxies, clusters and superclusters. Finally, heuristics from genetics suggest to look for a systems perspective to derive correct vacuum and Higgs Boson energies.
The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure–activity relationships.
New antimycotic drugs are challenging to find, as potential target proteins may have close human orthologs. We here focus on identifying metabolic targets that are critical for fungal growth and have minimal similarity to targets among human proteins. We compare and combine here: (I) direct metabolic network modeling using elementary mode analysis and flux estimates approximations using expression data, (II) targeting metabolic genes by transcriptome analysis of condition-specific highly expressed enzymes, and (III) analysis of enzyme structure, enzyme interconnectedness (“hubs”), and identification of pathogen-specific enzymes using orthology relations. We have identified 64 targets including metabolic enzymes involved in vitamin synthesis, lipid, and amino acid biosynthesis including 18 targets validated from the literature, two validated and five currently examined in own genetic experiments, and 38 further promising novel target proteins which are non-orthologous to human proteins, involved in metabolism and are highly ranked drug targets from these pipelines.
Central nervous system dysfunction is an important cause of morbidity and mortality in patients with human immunodeficiency virus type 1 (HIV-1) infection and acquired immunodeficiency virus syndrome (AIDS). Patients with AIDS are usually affected by HIV-associated encephalitis (HIVE) with viral replication limited to cells of monocyte origin. To examine the molecular mechanisms underlying HIVE-induced dementia, the GSE4755 Affymetrix data were obtained from the Gene Expression Omnibus database and the differentially expressed genes (DEGs) between the samples from AIDS patients with and without apparent features of HIVE-induced dementia were identified. In addition, protein–protein interaction networks were constructed by mapping DEGs into protein–protein interaction data to identify the pathways that these DEGs are involved in. The results revealed that the expression of 1,528 DEGs is mainly involved in the immune response, regulation of cell proliferation, cellular response to inflammation, signal transduction, and viral replication cycle. Heat-shock protein alpha, class A member 1 (HSP90AA1), and fibronectin 1 were detected as hub nodes with degree values >130. In conclusion, the results indicate that HSP90A and fibronectin 1 play important roles in HIVE pathogenesis.
Over recent years next generation sequencing (NGS) technologies evolved from costly tools used by very few, to a much more accessible and economically viable technology. Through this recently gained popularity, its use-cases expanded from research environments into clinical settings. But the technical know-how and infrastructure required to analyze the data remain an obstacle for a wider adoption of this technology, especially in smaller laboratories. We present GensearchNGS, a commercial DNAseq software suite distributed by Phenosystems SA. The focus of GensearchNGS is the optimal usage of already existing infrastructure, while keeping its use simple. This is achieved through the integration of existing tools in a comprehensive software environment, as well as custom algorithms developed with the restrictions of limited infrastructures in mind. This includes the possibility to connect multiple computers to speed up computing intensive parts of the analysis such as sequence alignments. We present a typical DNAseq workflow for NGS data analysis and the approach GensearchNGS takes to implement it. The presented workflow goes from raw data quality control to the final variant report. This includes features such as gene panels and the integration of online databases, like Ensembl for annotations or Cafe Variome for variant sharing.
Modulating key dynamics of plant growth and development, the effects of the plant hormone cytokinin on animal cells gained much attention recently. Most previous studies on cytokinin effects on mammalian cells have been conducted with elevated cytokinin concentration (in the μM range). However, to examine physiologically relevant dose effects of cytokinins on animal cells, we systematically analyzed the impact of kinetin in cultured cells at low and high concentrations (1nM-10μM) and examined cytotoxic and genotoxic conditions. We furthermore measured the intrinsic antioxidant activity of kinetin in a cell-free system using the Ferric Reducing Antioxidant Power assay and in cells using the dihydroethidium staining method. Monitoring viability, we looked at kinetin effects in mammalian cells such as HL60 cells, HaCaT human keratinocyte cells, NRK rat epithelial kidney cells and human peripheral lymphocytes. Kinetin manifests no antioxidant activity in the cell free system and high doses of kinetin (500 nM and higher) reduce cell viability and mediate DNA damage in vitro. In contrast, low doses (concentrations up to 100 nM) of kinetin confer protection in cells against oxidative stress. Moreover, our results show that pretreatment of the cells with kinetin significantly reduces 4-nitroquinoline 1-oxide mediated reactive oxygen species production. Also, pretreatment with kinetin retains cellular GSH levels when they are also treated with the GSH-depleting agent patulin. Our results explicitly show that low kinetin doses reduce apoptosis and protect cells from oxidative stress mediated cell death. Future studies on the interaction between cytokinins and human cellular pathway targets will be intriguing.
Lung cancer is currently the leading cause of cancer related mortality due to late diagnosis and limited treatment intervention. Non-coding RNAs are not translated into proteins and have emerged as fundamental regulators of gene expression. Recent studies reported that microRNAs and long non-coding RNAs are involved in lung cancer development and progression. Moreover, they appear as new promising non-invasive biomarkers for early lung cancer diagnosis. Here, we highlight their potential as biomarker in lung cancer and present how bioinformatics can contribute to the development of non-invasive diagnostic tools. For this, we discuss several bioinformatics algorithms and software tools for a comprehensive understanding and functional characterization of microRNAs and long non-coding RNAs.