570 Biowissenschaften; Biologie
Filtern
Volltext vorhanden
- ja (135)
Gehört zur Bibliographie
- ja (135)
Erscheinungsjahr
- 2019 (135) (entfernen)
Dokumenttyp
Schlagworte
- Tissue Engineering (7)
- Candida albicans (3)
- Genexpression (3)
- In vitro (3)
- Signaltransduktion (3)
- cancer (3)
- leukemic cells (3)
- metagenomics (3)
- 3D Tumormodell (2)
- 3D tissue model (2)
- Annotation (2)
- Bioinformatik (2)
- Blutgerinnung (2)
- Chlamydia trachomatis (2)
- Chronobiologie (2)
- Drosophila (2)
- Drosophila melanogaster (2)
- Ecology (2)
- Fluoreszenzmikroskopie (2)
- Herzmuskelzelle (2)
- Implantat (2)
- Maus (2)
- Mikroskopie (2)
- RNA-seq (2)
- Regenerative Medizin (2)
- Serotonin (2)
- Taufliege (2)
- Vaskularisierung (2)
- Verhalten (2)
- apoptosis (2)
- colorectal cancer (2)
- cytotoxicity (2)
- dSTORM (2)
- evolution (2)
- infection (2)
- ischemic stroke (2)
- microbiome (2)
- optimal drug combination (2)
- rheumatoid arthritis (2)
- ubiquitin (2)
- (hem)ITAM signaling (1)
- 3D (1)
- 3D Modell (1)
- 3D model (1)
- 3D remote sensing (1)
- 3D tumour model (1)
- 3D-Modell (1)
- ABP1 (1)
- ADHD (1)
- ALAN (1)
- AMP-activated kinases (1)
- APOBEC3G (1)
- AUX1 (1)
- Absorbed Doses (1)
- Accurate (1)
- Acids (1)
- Ackerschmalwand (1)
- Adaptation (1)
- Adherens junction (1)
- Administered Activities (1)
- Aggregation (1)
- Algorithmus (1)
- Alkaloid (1)
- Alpine habitats (1)
- Alzheimerkrankheit (1)
- Aminerge Nervenzelle (1)
- Amygdala (1)
- Ancistrocladaceae (1)
- Aneugene (1)
- Angiogenese (1)
- Animales Nervensystem (1)
- Anthropocene (1)
- Anti-infective (1)
- Antigen CD19 (1)
- Apidae (1)
- Apis mellifera (1)
- Apolipoprotein E (1)
- Arabidopsis (1)
- Aspergillus fumigalus (1)
- Associative learning (1)
- Autoaggressionskrankheit (1)
- Automated Image Analysis (1)
- Automatisierung (1)
- Automatisierung der Analyse (1)
- Autophagie <Physiologie> (1)
- Autophagosom (1)
- Autophagozytose (1)
- B-MYB (1)
- BRAF-mutant (1)
- BRAF-mutiert (1)
- Barrier (1)
- Bees (1)
- Behaviour (1)
- Behavioural ecology (1)
- Berberine (1)
- Bildanalyse (1)
- Bildverarbeitung (1)
- Biokinetics (1)
- Biologika (1)
- Biomarker (1)
- Biomaterial (1)
- Biomedical engineering (1)
- Biomedicine (1)
- Biophysics (1)
- Bioreaktor (1)
- Brustkrebs (1)
- C-60 fullerene (1)
- C60 fullerene (1)
- CAR T-Zelltherapie (1)
- C\(_{60}\) fullerene (1)
- Cadherine (1)
- Caenorhabditis elegans (1)
- Callyspongia siphonella (1)
- Cancer Cell (1)
- Cdh13 (1)
- Cell migration (1)
- Cell stainin (1)
- Cellular neuroscience (1)
- Central nervous system (1)
- Channelrhodopsin (1)
- Chondrogenesis (1)
- Chronobiology (1)
- Circular dichroism (1)
- Click Chemie (1)
- CoQ10 (1)
- Cofaktor (1)
- Colonization (1)
- Computational and Systems Biology (1)
- Computer modelling (1)
- Computersimulation (1)
- Confocal microscopy (1)
- Conservation (1)
- Cortex (1)
- CpG (1)
- Cranial sutures (1)
- Cytokine (1)
- Cytologie (1)
- Cytosol (1)
- DC gate (1)
- DLS and AFM measurements (1)
- DNA damage (1)
- DNA-Schäden (1)
- DNS-Doppelstrangbruch (1)
- DNS-Schädigung (1)
- Dendritic cell (1)
- Dendritische Zelle (1)
- Densovirus (1)
- Developmental biology (1)
- Dezellularisierung (1)
- Diagnostic Imaging Exams (1)
- Dickdarmtumor (1)
- Dnaschaden (1)
- Dopamin (1)
- Dopamine (1)
- Dosimetry (1)
- Doxorubicin (1)
- Drug discovery (1)
- Drug targets (1)
- Drug testing (1)
- Dynamics (1)
- E8 symmetry (1)
- EMT (1)
- ERK signaling (1)
- Echinococcosis (1)
- Echinococcus (1)
- Eierstockkrebs (1)
- Einzelmolekülmikroskopie (1)
- Electron Microscopy (1)
- Elektronenmikroskopie (1)
- Embryonic induction (1)
- Embryos (1)
- Endodermis (1)
- Endogene Rhythmik (1)
- Enhancer elements (1)
- Environmental impact (1)
- Epigenetic (1)
- Evolutionary developmental biology (1)
- Evolutionary emergence (1)
- Extracellular matrix (1)
- Eye development (1)
- Eye irritation (1)
- Fear conditioning (1)
- Fgf-signalling (1)
- Flowering plants (1)
- Flowers (1)
- Fluorescence spectroscopy (1)
- Fremdkörpermodell (1)
- G-quadruplex (1)
- Ga-68-labelled Peptides (1)
- Gedächtnis (1)
- Gene by Environment (1)
- Gene expression analysis (1)
- Gene silencing (1)
- Genetik (1)
- Genom (1)
- Genome Annotation (1)
- Genotoxicitiy (1)
- Genotoxizität (1)
- Germline (1)
- Gestational diabetes (1)
- Gestationsdiabetes (1)
- Gewebemodell (1)
- Gliazelle (1)
- Glioblastom (1)
- Glykane (1)
- Haut (1)
- HeLa cells (1)
- Health (1)
- Helicasen (1)
- Hfq (1)
- Hindbrain (1)
- Hippo pathway (1)
- Hippocampus (1)
- Hochauflösende Fluoreszenzmikroskopie (1)
- Host Genome Integrity (1)
- Host-parasite interaction (1)
- Human Herpesvirus 6 (1)
- Humanes Herpesvirus 6 (1)
- Hurwitz theorem (1)
- Hypothalamus (1)
- Hypoxia (1)
- Hypoxie (1)
- Immunologe (1)
- Immunoprecipitation (1)
- Immuntherapie (1)
- Induzierte pluripotente Stammzelle (1)
- Inf-TRAP-Seq (1)
- Inhibitor (1)
- Insect flight (1)
- Insulin (1)
- Invertebrate herbivory (1)
- Isolation (1)
- KDELR2 (1)
- Kardiomyozyt (1)
- Kernspintomografie (1)
- Klassifizierung (1)
- Klastogene (1)
- Knochenimplantat (1)
- Knochenregeneration (1)
- Knorpelbildung (1)
- Kongo (1)
- Kraniosynostose (1)
- Krebs (1)
- Krebs <Medizin> (1)
- LC-HRESIMS (1)
- Leaf traits (1)
- Lee Smolin (1)
- Leichte kognitive Beeinträchtigung (1)
- Lernen (1)
- Lernverhalten (1)
- Light sheet microscopy (1)
- Limb development (1)
- Llullaillaco Volcano (1)
- Lung (1)
- Lunge (1)
- Lungenkrebs (1)
- Lungentumor (1)
- Lysosom (1)
- M14 carboxypeptidasses (1)
- MMB complex (1)
- MRI (1)
- Maculinea butterfly (1)
- Magnetic Resonance Imaging (1)
- Mamma carcinoma (1)
- Mammakarzinom (1)
- Markierungen synaptischer Proteine (1)
- Masern-Virus (1)
- Mass spectrometry (1)
- Massenspektrometrie (1)
- Mc4r (1)
- Measles virus (1)
- Megakaryozyt (1)
- Melanom (1)
- Melanoma (1)
- Meniskus (1)
- Meniskusimplantat (1)
- Metabolomics (1)
- Method development (1)
- Methodenentwicklung (1)
- Methylation (1)
- Microbiology and Infectious Disease (1)
- Mikroarray basierte vergleichende Genomhybridisierung (Array-CGH) (1)
- Mitochondria (1)
- Mitose (1)
- Mobile genetic element (1)
- Modell (1)
- Molekulare Zielstrukturen (1)
- Molekulargenetik (1)
- Molekülsystem (1)
- Motor behaviour (1)
- Multiples Myelom (1)
- Myb-MuvB (1)
- Myrmecology (1)
- Myrmica ant non-equilibrium dynamics (1)
- NIR-Spektroskopie (1)
- Nahrungserwerb (1)
- Naphthylisochinolinalkaloide (1)
- Naphthylisoquinoline (1)
- Neisseria gonorrhoeae (1)
- Neisseria meningitidis (1)
- Neural circuits (1)
- Neurodevelopmental Disorder (1)
- Neurogenese (1)
- Neurons (1)
- Next Generation Sequencing (NGS) (1)
- Non-coding RNA (1)
- Nuclear Medicine (1)
- Object recognition (1)
- Optimal foraging (1)
- Optogenetics (1)
- Optogenetik (1)
- Outer membrane proteins (1)
- PDF neurons (1)
- PI3K/mTOR inhibierung (1)
- Parvovirus (1)
- Paternal age and BMI effects (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)
- Pediatric Nuclear Medicine (1)
- Pediatric Patients (1)
- Phosphatasen (1)
- Phosphoglykolat-Phosphatase (1)
- Phosphoglykolatphosphatase (1)
- Physiologie (1)
- Phytophthora (1)
- Phytosphingosine (1)
- Pigmentdispergierender Faktor (1)
- Piriformospora indica (1)
- Plant signalling (1)
- Plants (1)
- Plasmamembranorganisation (1)
- Plasmozytom (1)
- Polysaccharide (1)
- Prefrontal cortex (1)
- Premna (1)
- ProQ (1)
- Protein crosslinking (1)
- Protein folding (1)
- Protein interactions (1)
- Proteininteraktionen (1)
- Proteinquervernetzungen (1)
- Proteomics Analysis of Complexes (1)
- Proteotype (1)
- Proteus vulgaris (1)
- Präfrontaler Cortex (1)
- Pseudomonas syringae (1)
- Quantifizierung (1)
- Quantitative Mikroskopie (1)
- R package (1)
- REDD1 (1)
- RNA Sequencing (1)
- RNA metabolism (1)
- RNA protein interactions (1)
- RNA secondary structures (1)
- RNA-Seq (1)
- RNA-seq transcriptome (1)
- RNAi (1)
- RNAlater (1)
- RNS (1)
- Radiation Protection (1)
- Radiation-associated Cancer Risk (1)
- Raphe (1)
- Registrierung <Bildverarbeitung> (1)
- Reiz (1)
- Rescue behaviour (1)
- Research Article (1)
- Resistenz (1)
- Rezeptoren (1)
- Rhizodermis (1)
- Risk Assessment (1)
- SREBP (1)
- SSR42 (1)
- Scarabaeidae (1)
- Schlaganfall (1)
- Schmalwand <Arabidopsis> (1)
- Self-renewal (1)
- Sex chromosome (1)
- Sex determination (1)
- Sexual development and function (1)
- Signalweg (1)
- Skull (1)
- Small RNA (1)
- Small interfering RNAs (1)
- Solution-state NMR (1)
- Somites (1)
- Species delimitation (1)
- Species richness (1)
- Sphingobasen (LCB, LCB-P) (1)
- Sphingobases (1)
- Sphingolipide (1)
- Sphingosine-1-phosphate (1)
- Sphingosine-1-phosphats (1)
- Spred-Proteine (1)
- Stammzelle (1)
- Staphylococcus aureus (1)
- Stechameisen (1)
- Stem cell (1)
- Stem cells (1)
- Stem-cell biotechnology (1)
- Stoffwechsel (1)
- Strains (1)
- Structural elucidation (1)
- Subtercola vilae (1)
- Suspensionskultur (1)
- Syap1 knockout (1)
- Synaptische Vesikel (1)
- TLR3 (1)
- TMEM16F (1)
- TNFR1 (1)
- TRAIL (1)
- TWEAK (1)
- Tc-99m-MAG3 Scans (1)
- Therapeutisches System (1)
- Therapie (1)
- Therapiesimulation (1)
- Thrombo-inflammation (1)
- Thrombosis (1)
- Thrombozyt (1)
- Tiermodell (1)
- Tissue engineering (1)
- Todesdomäne (1)
- Trailmaking Test (1)
- Transcription (1)
- Transcriptomic (1)
- Translation (1)
- Transposable element (1)
- Tumor (1)
- UBXD1 (1)
- UV–Vis (1)
- Ubiquitin (1)
- Ultrashort echo time - UTE (1)
- Ustilago maydis (1)
- Vascularized (1)
- Vaskularisation (1)
- Verticillium (1)
- Vesikel (1)
- Wirkstofftestung (1)
- Wundheilung (1)
- Wurzel (1)
- Wurzelzellschichten (1)
- YAP (1)
- ZFAND1 (1)
- Zebrafish (1)
- Zell Migration (1)
- Zellbiologie (1)
- Zellkultur (1)
- Zellmigration (1)
- Zellschichtspezifische Expression (1)
- Zellteilung (1)
- Zelltod (1)
- Zentralzylinder (1)
- Zinc (1)
- accessory medulla (1)
- accumulation (1)
- acetate (1)
- adalimumab (1)
- adapterprotein (1)
- alternative splicing (1)
- altitudinal gradients (1)
- aminergic neurons (1)
- anakinra (1)
- aneugens (1)
- antibacterial (1)
- antibiofilm (1)
- anticancer (1)
- antitrypanosomal (1)
- artifacts (1)
- artificial light at night (1)
- autoimmune disease (1)
- automatisierte Bildanalyse (1)
- autophagocytosis (1)
- autophagosome (1)
- autophagy (1)
- auxin (1)
- bacteria (1)
- bacterial pathogen (1)
- behavioral plasticity (1)
- bioinformatics tool (1)
- bioink (1)
- biological rhythm (1)
- biological scaffolds (1)
- biomarker (1)
- biomarker signature (1)
- biomaterial ink (1)
- bioreactor (1)
- biotic interaction (1)
- blood–brain barrier (1)
- bone (1)
- brain (1)
- brain endothelial cell (1)
- burnt-wood (1)
- calcium (1)
- cancer metabolism (1)
- cancer therapy (1)
- carabid beetles (1)
- cardiac tissue (1)
- cardiomyocytes (1)
- cell biology (1)
- cell therapy (1)
- cell-type specific (1)
- channelrhodopsins (1)
- chlamydia (1)
- chlorophyll fluorescence imaging (1)
- circRNA (1)
- circadian clock (1)
- circadian rhythm (1)
- circular transcriptome sequencing (1)
- classification (1)
- clastogens (1)
- click chemistry (1)
- clinical trial (1)
- closed-loop systems (1)
- co-culture (1)
- cold adaptation (1)
- comparative genomics (1)
- competition (1)
- composition (1)
- conservation (1)
- cosmology (1)
- crystal growth (1)
- crystallization (1)
- cytokinesis (1)
- cytotoxic (1)
- dead-wood enrichment (1)
- decellularization (1)
- definition (1)
- dendritic cells (1)
- designer cell (1)
- developmental forms (1)
- direct muss spectrometric profiling (1)
- disease modelling (1)
- diversity gradients (1)
- domain-specific language (1)
- dopamine (1)
- doxorubicin (1)
- drivers and patterns of diversity and herbivory (1)
- drug delivery (1)
- drug release (1)
- drug resistance evolution (1)
- earlywood (1)
- ecology (1)
- ecosystem service (1)
- efficient intervention points (1)
- elementary body (1)
- enbrel (1)
- endocytosis (1)
- enercy-richness hypothesis (1)
- energy homeostasis (1)
- enhancer (1)
- enzyme mechanism (1)
- etanercept (1)
- expansion microscopy (1)
- external stimuli (1)
- extinction dynamics (1)
- fertility (1)
- fibre length (1)
- flash freezing (1)
- fluxosome (1)
- food resources (1)
- forest ecology (1)
- forest fire (1)
- forest management (1)
- friut fly behaviour (1)
- function (1)
- functional analysis (1)
- fungal rhodopsins (1)
- gangliosides and lipid rafts (1)
- gastrointestinal tract (1)
- gene expression analysis (1)
- gene network (1)
- genetic engineering (1)
- genetic recombination (1)
- genome analysis (1)
- genome annotation (1)
- glia cells (1)
- global change (1)
- green fluorescence protein (GFP) (1)
- ground-dwelling predators (1)
- growth (1)
- growth ring width (1)
- hemostasis (1)
- heuristics (1)
- hiPSC aggregation (1)
- hochauflösende Fluoreszenzmikroskopie (1)
- honeybee (1)
- honeybees (1)
- iPSC (1)
- imaging (1)
- imaging PAM (1)
- immunity (1)
- immunocompetent skin (1)
- immunotherapy (1)
- immunotherapy of cancer (1)
- implant (1)
- in situ microscopy (1)
- in vitro (1)
- indole-3-acetic acid (1)
- induced pluripotent stem cells (1)
- infection biology (1)
- inflation (1)
- insect abundance (1)
- insect collection (1)
- integrative management strategy (1)
- intervention point analyzing (1)
- knockout (1)
- kolorektales Karzinom (1)
- land sharing (1)
- land use (1)
- latewood (1)
- learning (1)
- lignan (1)
- localization microscopy (1)
- lowland beech forests (1)
- mRNA (1)
- machine learning (1)
- macrophages (1)
- mating (1)
- mating preference (1)
- measles virus (1)
- mechanisms of disease (1)
- mechanistic modelling (1)
- medaka (1)
- megakaryopoiesis (1)
- melatonin (1)
- memory (1)
- meningitis (1)
- meniscus implant (1)
- meta-analysis (1)
- metabolic adaptation (1)
- metabolic flux (1)
- metabolic modeling (1)
- metabolic modelling (1)
- metabolite profiling (1)
- metabolomic (1)
- metabolomic profiling (1)
- metaproteomics (1)
- methods (1)
- miR-26 (1)
- microbial rhodopsins (1)
- microbiota (1)
- mitosis (1)
- mitotic gene expression (1)
- mitotic genes (1)
- molecular biology (1)
- multi-photon microscopy (1)
- mutants (1)
- nanocomplex (1)
- native populations (1)
- natural pest control (1)
- neuronal (1)
- next generation sequencing (1)
- next-generation sequencing (1)
- noncoding RNA (1)
- noncovalent complex (1)
- noncovalent nanocomplex (1)
- nuclear envelope (1)
- nuclear export (1)
- oncogenes (1)
- oncology (1)
- oncolysis (1)
- oncolytic vaccinia virus (1)
- oncolytic virus (1)
- optimal drug targeting (1)
- optimal pharmacological modulation (1)
- optimal treatment strategies (1)
- optogenetics (1)
- oxindole alkaloids (1)
- p21-activated kinase Mbt/PAK4 (1)
- p53 (1)
- p97 (1)
- parasexual recombination (1)
- patch-clamp (1)
- peptidomoics (1)
- pharmacophore map (1)
- phenolic compounds (1)
- photodynamic chemotherapy (1)
- piRNA (1)
- pit membrane diameter (1)
- plants (1)
- plant–pathogen interaction (1)
- plasma membrane depolarization (1)
- plasma membrane organization (1)
- platelets (1)
- pollination (1)
- population genetics (1)
- post-fire management (1)
- post-translational modification (1)
- posttranscriptional control (1)
- programmed cell death (1)
- programmierter Zelltod (1)
- protected forests (1)
- protein processing (1)
- proteomics (1)
- puberty (1)
- resonance theory (1)
- restriction factors (1)
- reticulate body (1)
- risk factors (1)
- sample storage (1)
- saproxylic organisms (1)
- secreted effectors (1)
- sentinel prey (1)
- short neuropeptide F (1)
- signalling (1)
- single-molecule tracking (1)
- skin model (1)
- sleep (1)
- small RNA (1)
- small intestinal submucosa scaffold (1)
- small-cell lung cancer (1)
- sodium (1)
- soil fauna (1)
- species richness (1)
- species‐area hypothesis (1)
- sphingolipids (1)
- sporidia (1)
- stem Cells (1)
- stem cells (1)
- storage-pool diseases (1)
- stromal vascular fraction (1)
- structure (1)
- structured illumination microscopy (1)
- super-resolution fluorescence microscopy (1)
- super-resolution microscopy (1)
- superresolution (1)
- suppressor cells (1)
- suppressor mutation (1)
- survival analysis (1)
- synapses (1)
- synergistic effect (1)
- synthetic biology (1)
- systematic affiliation (1)
- systematic drug targeting (1)
- targeted therapies (1)
- targeted therapy (1)
- temperature‐mediated resource exploitation hypothesis (1)
- temperature‐richness hypothesis (1)
- therapy simulation (1)
- thrombosis (1)
- time lag (1)
- tisindoline (1)
- tissue engineering (1)
- transcription (1)
- transcriptome (1)
- transient dynamics (1)
- tree cavities (1)
- trypanosomes (1)
- tumour (1)
- tumour-necrosis factors (1)
- tyloses (1)
- ubiquitin ligase (1)
- ubiquitylation (ubiquitination) (1)
- unmanaged broadleaved forests (1)
- uptake (1)
- vaccinia (1)
- vascularization (1)
- vertical and radial variation (1)
- vessel lumen diameter (1)
- vessel wall resident stem cells (1)
- virotherapy (1)
- virus (1)
- whole-genome sequencing (1)
- wood anatomy (1)
- wound healing (1)
- yH2AX-Foci (1)
- zielgerichtete Behandlung (1)
- zielgerichtete Therapien (1)
Institut
- Theodor-Boveri-Institut für Biowissenschaften (66)
- Graduate School of Life Sciences (33)
- Julius-von-Sachs-Institut für Biowissenschaften (10)
- Lehrstuhl für Tissue Engineering und Regenerative Medizin (9)
- Rudolf-Virchow-Zentrum (6)
- Fakultät für Biologie (4)
- Institut für Hygiene und Mikrobiologie (3)
- Institut für Molekulare Infektionsbiologie (3)
- Institut für Pharmakologie und Toxikologie (3)
- Lehrstuhl für Biochemie (3)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (2)
- Center for Computational and Theoretical Biology (2)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (2)
- Institut für Anatomie und Zellbiologie (2)
- Institut für Humangenetik (2)
- Institut für Medizinische Strahlenkunde und Zellforschung (2)
- Institut für Virologie und Immunbiologie (2)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (2)
- Pathologisches Institut (2)
- Abteilung für Funktionswerkstoffe der Medizin und der Zahnheilkunde (1)
- Comprehensive Cancer Center Mainfranken (1)
- Institut für Geographie und Geologie (1)
- Institut für Klinische Epidemiologie und Biometrie (1)
- Institut für Klinische Neurobiologie (1)
- Institut für Pharmazie und Lebensmittelchemie (1)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (1)
- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (1)
- Klinik und Poliklinik für Nuklearmedizin (1)
- Lehrstuhl für Molekulare Psychiatrie (1)
- Medizinische Klinik und Poliklinik I (1)
- Medizinische Klinik und Poliklinik II (1)
- Urologische Klinik und Poliklinik (1)
Sonstige beteiligte Institutionen
The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.
Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
Animals must slow or halt locomotion to integrate sensory inputs or to change direction. In Caenorhabditis elegans, the GABAergic and peptidergic neuron RIS mediates developmentally timed quiescence. Here, we show RIS functions additionally as a locomotion stop neuron. RIS optogenetic stimulation caused acute and persistent inhibition of locomotion and pharyngeal pumping, phenotypes requiring FLP-11 neuropeptides and GABA. RIS photoactivation allows the animal to maintain its body posture by sustaining muscle tone, yet inactivating motor neuron oscillatory activity. During locomotion, RIS axonal Ca2+ signals revealed functional compartmentalization: Activity in the nerve ring process correlated with locomotion stop, while activity in a branch correlated with induced reversals. GABA was required to induce, and FLP-11 neuropeptides were required to sustain locomotion stop. RIS attenuates neuronal activity and inhibits movement, possibly enabling sensory integration and decision making, and exemplifies dual use of one cell across development in a compact nervous system.
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.
Background
Shotgun metagenomes contain a sample of all the genomic material in an environment, allowing for the characterization of a microbial community. In order to understand these communities, bioinformatics methods are crucial. A common first step in processing metagenomes is to compute abundance estimates of different taxonomic or functional groups from the raw sequencing data.
Given the breadth of the field, computational solutions need to be flexible and extensible, enabling the combination of different tools into a larger pipeline.
Results
We present NGLess and NG-meta-profiler. NGLess is a domain specific language for describing next-generation sequence processing pipelines. It was developed with the goal of enabling user-friendly computational reproducibility. It provides built-in support for many common operations on sequencing data and is extensible with external tools with configuration files.
Using this framework, we developed NG-meta-profiler, a fast profiler for metagenomes which performs sequence preprocessing, mapping to bundled databases, filtering of the mapping results, and profiling (taxonomic and functional). It is significantly faster than either MOCAT2 or htseq-count and (as it builds on NGLess) its results are perfectly reproducible.
Conclusions
NG-meta-profiler is a high-performance solution for metagenomics processing built on NGLess. It can be used as-is to execute standard analyses or serve as the starting point for customization in a perfectly reproducible fashion.
NGLess and NG-meta-profiler are open source software (under the liberal MIT license) and can be downloaded from https://ngless.embl.de or installed through bioconda.
Zn\(^{2+}\) deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn\(^{2+}\)-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn\(^{2+}\) deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn\(^{2+}\) status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn\(^{2+}\) uptake in the gut using different nutritional supplementation of Zn\(^{2+}\) could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn\(^{2+}\) diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn\(^{2+}\) in hemostasis. Storage protein metallothionein maintains or releases Zn\(^{2+}\) in the cytoplasm, and the dynamic change of this cytoplasmic Zn\(^{2+}\) pool is regulated by the redox status of the cell. An increase of labile Zn\(^{2+}\) pool can be toxic for the cells, and therefore cytoplasmic Zn\(^{2+}\) levels are tightly regulated by several Zn\(^{2+}\) transporters located on the cell surface and also on the intracellular membrane of Zn\(^{2+}\) storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn\(^{2+}\) is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn\(^{2+}\) transport and the physiological role of Zn\(^{2+}\) store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn\(^{2+}\) to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn\(^{2+}\) homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases.
Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK\(^{Thr188}\) phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.
Background
ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML).
Methods
Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 106 plaque-forming units (PFU) to 1.8 × 107 PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment.
Results
No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days—an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients’ blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition.
Conclusions
Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility.
Trial registration Retrospectively registered (ISRCTN#10201650) on October 22, 2018.
Background
Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties.
Methods
To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations.
Results
Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor.
Conclusions
Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach.