Refine
Has Fulltext
- yes (99)
Is part of the Bibliography
- yes (99)
Year of publication
- 2020 (99) (remove)
Document Type
- Journal article (99) (remove)
Keywords
- biodiversity (5)
- autophagy (4)
- Apis mellifera (3)
- diversity (3)
- evolution (3)
- foraging (3)
- forest management (3)
- mutualism (3)
- nutrition (3)
- Acromyrmex fracticornis (2)
- Epichloë (2)
- Expansion microscopy (2)
- Hill numbers (2)
- Lolium perenne (2)
- Staphylococcus aureus (2)
- Surgery (2)
- bee decline (2)
- bees (2)
- body size (2)
- cell death (2)
- circadian clock (2)
- climate change (2)
- colorectal cancer (2)
- deadwood enrichment (2)
- dispersal (2)
- endophyte (2)
- exome sequencing (2)
- identification (2)
- leaf-cutting ants (2)
- molecular docking (2)
- mortality (2)
- natural disturbance (2)
- plant-insect interactions (2)
- saproxylic beetles (2)
- self-organization (2)
- solitary bee (2)
- symbiosis (2)
- toxicity (2)
- wood-inhabiting fungi (2)
- 28 (1)
- 3D reconstruction (1)
- 3D tissue models (1)
- 6-benzylaminopurine (1)
- ATP-adenosine triphosphate (1)
- Acipenser baerii (1)
- Anthropocene (1)
- Aspergillus medium (1)
- Automated analysis (1)
- Axl tyrosine kinase (1)
- BRAF mutation (1)
- Bacillus (1)
- Bembix (1)
- Bienenverhalten (1)
- C. elegans (1)
- CCL3 (1)
- CCL4 (1)
- CCL5 (1)
- CCl\(_4\) (1)
- CDC14A (1)
- CLV3p (1)
- COVID-19 (1)
- COX2 expression (1)
- Cataglyphis-Wüstenameisen (1)
- Cdu1 (1)
- Chagas diagnosis (1)
- Chagas disease (1)
- Chagas monitoring (1)
- Chagas real time PCR (1)
- ChlaDUB1 (1)
- Chlamydia trachomatis (1)
- Chrysididae (1)
- Complex medium (1)
- Costa Rica (1)
- DFNB32 (1)
- DNA barcoding (1)
- DNA double-strand breaks (1)
- DNA metabarcoding (1)
- DUB (1)
- Drosophila melanogaster (1)
- Epichloë spp. (1)
- Fagus orientalis (1)
- Fagus sylvatica (1)
- Fourthcorner analysis (1)
- Gene expression vectors (1)
- Golgi (1)
- HGF (1)
- HIV-1 (1)
- HNSCC (1)
- HPLC/UPLC methods (1)
- High-throughput data (1)
- Himmelskompass (1)
- ICP27 (1)
- ImageJ plugin (1)
- Inoculum production (1)
- Insect symbiois (1)
- Insektennavigation (1)
- Ionizing radiation (1)
- Jena Experiment (1)
- Kenyon cells (1)
- Magnetkompass (1)
- Met (1)
- Microarray analysis (1)
- Mitochondria (1)
- Moleküle (1)
- Multivariate analysis (1)
- NOTCH (1)
- NRF2 (1)
- Open-source tool (1)
- Ordination methods (1)
- Osmia bicornis (1)
- PER (1)
- Paenibacillus (1)
- Pakistan (1)
- Plant growth promotion (1)
- Plant root endophyte (1)
- Polymerase chain reaction (1)
- RFID (1)
- RLQ analysis (1)
- RNA-Seq analysis (1)
- Radiation biology (1)
- Radiochemotherapy (1)
- Rectal cancer (1)
- SARS-CoV-2 (1)
- Sanger sequencing (1)
- Savanna–Forest mosaic (1)
- Seahorse XF (1)
- Serendipita indica (1)
- Shotgun method (1)
- Sporosarcina (1)
- Sunitinib (1)
- Synthetic biology (1)
- T cell receptor (1)
- Temperatur (1)
- Time interval (1)
- Transcriptomics (1)
- TreMs (1)
- Trypanosoma cruzi (1)
- Tyrosine kinase inhibition (1)
- Varroa destructor (1)
- Vegetable juice (1)
- Virtual sequencing (1)
- Visualisierung (1)
- Visualization (1)
- Zellen (1)
- acipenserid minisatellite (1)
- activity rhythm (1)
- activity-based probes (1)
- acylcarnitine (1)
- adipose tissue-derived MSCs (1)
- adult bees (1)
- alkaloid detection methods (1)
- alkaloids (1)
- altitudinal gradient (1)
- ambrosia beetles (1)
- amino acids (1)
- amyotrophic lateral sclerosis (1)
- angiogenesis (1)
- annotation (1)
- ant brain (1)
- antagonists (1)
- antennal lobes (1)
- anthropogenic food subsidies (1)
- anti-cancer drug-like molecules (1)
- antimicrobial (1)
- ants (1)
- aposematism (1)
- architecture (1)
- assembly mechanisms (1)
- autosomal recessive hearing loss (1)
- autotoxicity (1)
- bacterial infection (1)
- bacterial spread (1)
- bacterial transmission (1)
- baited traps (1)
- bark beetle (1)
- bark beetles (1)
- bark-peeling (1)
- bee conservation (1)
- beech forest (1)
- beetle (1)
- behavioral plasticity (1)
- behavioural plasticity (1)
- bet-hedging (1)
- beta-diversity (1)
- binding (1)
- binding protein (1)
- biodiversity threats (1)
- bioinformatics (1)
- biological macromolecules (1)
- biosecurity (1)
- bird communities (1)
- birds (1)
- blood brain barrier (1)
- blood stream (1)
- bombus terrestris (1)
- bottom‐up and top‐down control (1)
- breeding season (1)
- broadleaf tree species (1)
- bryophytes (1)
- building behavior (1)
- bypass (1)
- calcium signaling pathway (1)
- cancer (1)
- cancer metabolism (1)
- canine adipose-derived mesenchymal stem cells (cAdMSCs) (1)
- canine cancer cell lines (1)
- canine cancer therapy (1)
- canine soft tissue sarcoma (CSTS) (1)
- capture (1)
- carbohydrates (1)
- carrion ecology (1)
- cascade (1)
- caspases (1)
- cathepsin (1)
- ceiba pentandra (1)
- cell cycle (1)
- central complex (1)
- cereals (1)
- cerebEND cells (1)
- checkered beetles (1)
- chemical mimicry (1)
- chimpanzee (1)
- circadian rhythms (1)
- click chemistry (1)
- collective building (1)
- collective pattern (1)
- common garden experiment (1)
- community composition (1)
- community data (1)
- community‐weighted mean (1)
- complex behavior (1)
- complications (1)
- comportement des travailleurs (1)
- connectance (1)
- consanguinity (1)
- conservation (1)
- cool-season grass species (1)
- cooperative breeding (1)
- corticosteroids (1)
- cristae (1)
- cross-link repair (1)
- cuticular hydrocarbons (1)
- cycle (1)
- cytokinins (1)
- database (1)
- deadwood (1)
- deadwood experiments (1)
- defense signaling (1)
- definition (1)
- dendritic specializations (1)
- development (1)
- developmental biology (1)
- diapause (1)
- direct drivers (1)
- discharge definition (1)
- dispersal ability (1)
- distance gradient (1)
- domain (1)
- drosophila (1)
- ecological intensification (1)
- ecological network (1)
- ecological niche (1)
- ecosystem services (1)
- electron tomography (1)
- elevational diversity (1)
- elevational gradients (1)
- endocytosis (1)
- environmental filtering (1)
- eugenol (1)
- evolutionary (1)
- exit (1)
- exotic plants (1)
- expression (1)
- extracellular vesicle (1)
- facultatively intracellular pathogens (1)
- feeding (1)
- feeding experiment (1)
- feeding guilds (1)
- fire (1)
- flagellar pocket (1)
- flight behaviour (1)
- flippase (1)
- floral display (1)
- floral resources (1)
- flower-visiting insects (1)
- fluorescence microscopy (1)
- flupyradifurone (1)
- folliculin (1)
- forest (1)
- forest conservation (1)
- forest degradation (1)
- forest pests (1)
- forest physiognomy (1)
- forest succession (1)
- frameshift (1)
- functional network analysis (1)
- functional traits (1)
- fungi (1)
- fungus community (1)
- fungus-farming (1)
- fused in sarcoma (1)
- gamma H2AX-foci (1)
- gene duplications (1)
- gene expression (1)
- generalization (1)
- genetic diagnosis (1)
- genome-wide linkage analysis (1)
- global change (1)
- gonococcal invasion (1)
- gradients (1)
- grass endophytes (1)
- grasslands (1)
- ground‐dwelling predators (1)
- habitat filter (1)
- habitat heterogeneity (1)
- harvesting (1)
- head and neck cancer (1)
- hearing loss (1)
- heat shock response (1)
- hepatic fibrosis (1)
- high-risk Prostate Cancer (1)
- histology (1)
- honey bee (1)
- honey bees (1)
- honeybee (1)
- horses (1)
- human (1)
- hyphae (1)
- hypoxia (1)
- hypthesis (1)
- impact (1)
- in silico simulation (1)
- individual based model (1)
- infected-cell protein (1)
- infection rates (1)
- inflammation (1)
- insect (1)
- insect agriculture (1)
- insect fungal interactions (1)
- insect nutrition (1)
- insect vision (1)
- insecticide (1)
- insects (1)
- integrase (1)
- interaction map (1)
- interactome (1)
- interspecies comparison (1)
- invasion (1)
- invasive species (1)
- isosteviol sodium (1)
- isothiocyanates (1)
- jewel beetles (1)
- land-use change (1)
- land-use intensity (1)
- landscape structure (1)
- lantana canescens (1)
- lentic inland water bodies (1)
- lipid asymmetry (1)
- lipid metabolism (1)
- livestock (1)
- long‐term monitoring (1)
- low fidelity (1)
- lowland rainforest (1)
- lung fibrosis (1)
- lysosome (1)
- management (1)
- material composition (1)
- melanoma malignancy (1)
- membrane occupation (1)
- messenger RNA (1)
- meta-transcriptome (1)
- metabarcoding (1)
- metabolic adaptation (1)
- metabolomics (1)
- miR (1)
- microRNA (1)
- microRNA-221 (1)
- microbiome (1)
- microglomeruli (1)
- microstructure (1)
- migration (1)
- mimicry rings (1)
- mitochondria (1)
- mitochondrial activity (1)
- modularity (1)
- molecular cloning (1)
- molecular dynamics (1)
- molecular modelling (1)
- monitoring (1)
- mortality rate (1)
- mouse (1)
- mushroom bodies (1)
- mushroom body (1)
- mustard oil bomb (1)
- mutualistic interactions (1)
- mycotoxins (1)
- nanoscale imaging (1)
- natural disturbances (1)
- natural killer cell (1)
- naturally occurring polymorphisms (1)
- nature conservation (1)
- necrobiome (1)
- negative density dependence (1)
- neotropical region (1)
- network (1)
- network specialization index (H2′) (1)
- neuromuscular junction (1)
- neuronal network (1)
- neuroprotection (1)
- neutral processes (1)
- neutral sphingomyelinase-2 (1)
- non-sense mediated mRNA decay (1)
- non‐native plants (1)
- number of interactions (1)
- nutrients (1)
- nutritional adaptations (1)
- oil palm plantations (1)
- olfaction (1)
- oncolytic virus (1)
- optical tracts (1)
- oxidative phosphorylation (1)
- pancreatectomy (1)
- pantanal wetland (1)
- paralogs (1)
- parasitoids (1)
- passes (1)
- pathogen (1)
- perennial ryegrass (1)
- pest control (1)
- pest species (1)
- phagocytosis (1)
- phenology (1)
- phosphatidylethanolamine (1)
- phosphatidylserine (1)
- phosphatidylserine transport (1)
- plant bacteria (1)
- plant composition (1)
- plant fresh/dry weight (1)
- plant–bee visitation networks (1)
- platelet (1)
- polarized cell culture (1)
- polarized epithelium (1)
- pollen (1)
- pollen and nectar resources (1)
- pollen provisions (1)
- pollen quality (1)
- pollination (1)
- pollinator attraction (1)
- pollinator friendly plants (1)
- polyploidy (1)
- primeval forest (1)
- productivity hypothesis (1)
- projection neurons (1)
- protein synthesis (1)
- proteome (1)
- proteomics (1)
- quantitative stigmergy (1)
- radiofrequency identification (1)
- rational drug design (1)
- reactive electrophilic species (1)
- recognition nexus domain (1)
- rectal cancer (1)
- rectal resection (1)
- redox homeostasis (1)
- regional species pool (1)
- release (1)
- reliability (1)
- replication (1)
- reproductive performance (1)
- resource use (1)
- resources (1)
- restoration strategy (1)
- reveals (1)
- robustness (1)
- salvage logging (1)
- saproxylic species (1)
- satellite DNA (1)
- seasonal phenology (1)
- seasonality (1)
- secondary invader (1)
- secondary site infection (1)
- self-renewal (1)
- semi‐natural habitats (1)
- senescence (1)
- sequence (1)
- shoot apical meristem (1)
- signaling (1)
- social (1)
- social behavior (1)
- sociality (1)
- solution scattering (1)
- spatial variation (1)
- specialization (1)
- species energy theory (1)
- species richness (1)
- species traits (1)
- species turnover (1)
- sphingolipid expansion microscopy (1)
- sphingolipids (1)
- sphingosine (1)
- sphingosine kinases (1)
- spiders (1)
- splicing (1)
- sporidia (1)
- squamous cell carcinoma (1)
- stem cell transplantation (1)
- stem-cell-triggered immunity (1)
- stratification (1)
- structural synaptic plasticity (1)
- structured illumination microscope (1)
- sturgeon (1)
- sturgeon karyotype (1)
- successional trajectory (1)
- sucrose responsiveness (1)
- sulforaphane (1)
- sun exposure (1)
- superior (1)
- surgical care (1)
- surveillance (1)
- survival (1)
- sustainable (1)
- system inference (1)
- tandem repeats (1)
- target (1)
- targeted therapy (1)
- temperature (1)
- temperature-speciation hypothesis (1)
- temporal variation (1)
- température (1)
- theta (1)
- thin sections (1)
- time series (1)
- transcriptional regulation (1)
- transcriptome (1)
- translation (1)
- translation initiation (1)
- trophic levels (1)
- trophic position (1)
- trypanosoma brucei (1)
- tryptophan (1)
- tumor-associated macrophage (1)
- type 1 (1)
- ultrastructure (1)
- uper-resolution array tomography (1)
- vaccinia virus (1)
- vascular plants (1)
- vertebrate scavenger (1)
- vision (1)
- wasps (1)
- water beetles (1)
- whole genome duplication (1)
- whole-genome duplication (1)
- wild bees (1)
- wildlife management (1)
- windthrow (1)
- woody plant richness (1)
- wood‐inhabiting fungi (1)
- worker behavior (1)
- xenophagy (1)
- β-diversity (1)
- ∆Np63 (1)
Institute
- Theodor-Boveri-Institut für Biowissenschaften (99) (remove)
Sonstige beteiligte Institutionen
EU-Project number / Contract (GA) number
- 765937 (1)
- CoG 721016–HERPES (1)
CDC14A encodes the Cell Division Cycle 14A protein and has been associated with autosomal recessive non-syndromic hearing loss (DFNB32), as well as hearing impairment and infertile male syndrome (HIIMS) since 2016. To date, only nine variants have been associated in patients whose initial symptoms included moderate-to-profound hearing impairment. Exome analysis of Iranian and Pakistani probands who both showed bilateral, sensorineural hearing loss revealed a novel splice site variant (c.1421+2T>C, p.?) that disrupts the splice donor site and a novel frameshift variant (c.1041dup, p.Ser348Glnfs*2) in the gene CDC14A, respectively. To evaluate the pathogenicity of both loss-of-function variants, we analyzed the effects of both variants on the RNA-level. The splice variant was characterized using a minigene assay. Altered expression levels due to the c.1041dup variant were assessed using RT-qPCR. In summary, cDNA analysis confirmed that the c.1421+2T>C variant activates a cryptic splice site, resulting in a truncated transcript (c.1414_1421del, p.Val472Leufs*20) and the c.1041dup variant results in a defective transcript that is likely degraded by nonsense-mediated mRNA decay. The present study functionally characterizes two variants and provides further confirmatory evidence that CDC14A is associated with a rare form of hereditary hearing loss.
Comprehensive bioinformatics identifies key microRNA players in ATG7-deficient lung fibroblasts
(2020)
Background: Deficient autophagy has been recently implicated as a driver of pulmonary fibrosis, yet bioinformatics approaches to study this cellular process are lacking. Autophagy-related 5 and 7 (ATG5/ATG7) are critical elements of macro-autophagy. However, an alternative ATG5/ATG7-independent macro-autophagy pathway was recently discovered, its regulation being unknown. Using a bioinformatics proteome profiling analysis of ATG7-deficient human fibroblasts, we aimed to identify key microRNA (miR) regulators in autophagy. Method: We have generated ATG7-knockout MRC-5 fibroblasts and performed mass spectrometry to generate a large-scale proteomics dataset. We further quantified the interactions between various proteins combining bioinformatics molecular network reconstruction and functional enrichment analysis. The predicted key regulatory miRs were validated via quantitative polymerase chain reaction. Results: The functional enrichment analysis of the 26 deregulated proteins showed decreased cellular trafficking, increased mitophagy and senescence as the major overarching processes in ATG7-deficient lung fibroblasts. The 26 proteins reconstitute a protein interactome of 46 nodes and miR-regulated interactome of 834 nodes. The miR network shows three functional cluster modules around miR-16-5p, miR-17-5p and let-7a-5p related to multiple deregulated proteins. Confirming these results in a biological setting, serially passaged wild-type and autophagy-deficient fibroblasts displayed senescence-dependent expression profiles of miR-16-5p and miR-17-5p. Conclusions: We have developed a bioinformatics proteome profiling approach that successfully identifies biologically relevant miR regulators from a proteomics dataset of the ATG-7-deficient milieu in lung fibroblasts, and thus may be used to elucidate key molecular players in complex fibrotic pathological processes. The approach is not limited to a specific cell-type and disease, thus highlighting its high relevance in proteome and non-coding RNA research.
1.Honeybees Apis mellifera and other pollinating insects suffer from pesticides in agricultural landscapes. Flupyradifurone is the active ingredient of a novel pesticide by the name of ‘Sivanto’, introduced by Bayer AG (Crop Science Division, Monheim am Rhein, Germany). It is recommended against sucking insects and marketed as ‘harmless’ to honeybees. Flupyradifurone binds to nicotinergic acetylcholine receptors like neonicotinoids, but it has a different mode of action. So far, little is known on how sublethal flupyradifurone doses affect honeybees.
2. We chronically applied a sublethal and field‐realistic concentration of flupyradifurone to test for long‐term effects on flight behaviour using radio‐frequency identification. We examined haematoxylin/eosin‐stained brains of flupyradifurone‐treated bees to investigate possible changes in brain morphology and brain damage.
3. A field‐realistic flupyradifurone dose of approximately 1.0 μg/bee/day significantly increased mortality. Pesticide‐treated bees initiated foraging earlier than control bees. No morphological damage in the brain was observed.
4. Synthesis and applications. The early onset of foraging induced by a chronical application of flupyradifurone could be disadvantageous for honeybee colonies, reducing the period of in‐hive tasks and life expectancy of individuals. Radio‐frequency identification technology is a valuable tool for studying pesticide effects on lifetime foraging behaviour of insects.
MORN (Membrane Occupation and Recognition Nexus) repeat proteins have a wide taxonomic distribution, being found in both prokaryotes and eukaryotes. Despite this ubiquity, they remain poorly characterised at both a structural and a functional level compared to other common repeats. In functional terms, they are often assumed to be lipid-binding modules that mediate membrane targeting. We addressed this putative activity by focusing on a protein composed solely of MORN repeats-Trypanosoma brucei MORN1. Surprisingly, no evidence for binding to membranes or lipid vesicles by TbMORN1 could be obtained either in vivo or in vitro. Conversely, TbMORN1 did interact with individual phospholipids. High- and low-resolution structures of the MORN1 protein from Trypanosoma brucei and homologous proteins from the parasites Toxoplasma gondii and Plasmodium falciparum were obtained using a combination of macromolecular crystallography, small-angle X-ray scattering, and electron microscopy. This enabled a first structure-based definition of the MORN repeat itself. Furthermore, all three structures dimerised via their C-termini in an antiparallel configuration. The dimers could form extended or V-shaped quaternary structures depending on the presence of specific interface residues. This work provides a new perspective on MORN repeats, showing that they are protein-protein interaction modules capable of mediating both dimerisation and oligomerisation.
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.
The fruit fly Drosophila melanogaster is an established model organism in chronobiology, because genetic manipulation and breeding in the laboratory are easy. The circadian clock neuroanatomy in D. melanogaster is one of the best-known clock networks in insects and basic circadian behavior has been characterized in detail in this insect. Another model in chronobiology is the honey bee Apis mellifera, of which diurnal foraging behavior has been described already in the early twentieth century. A. mellifera hallmarks the research on the interplay between the clock and sociality and complex behaviors like sun compass navigation and time-place-learning. Nevertheless, there are aspects of clock structure and function, like for example the role of the clock in photoperiodism and diapause, which can be only insufficiently investigated in these two models. Unlike high-latitude flies such as Chymomyza costata or D. ezoana, cosmopolitan D. melanogaster flies do not display a photoperiodic diapause. Similarly, A. mellifera bees do not go into “real” diapause, but most solitary bee species exhibit an obligatory diapause. Furthermore, sociality evolved in different Hymenoptera independently, wherefore it might be misleading to study the social clock only in one social insect. Consequently, additional research on non-model insects is required to understand the circadian clock in Diptera and Hymenoptera. In this review, we introduce the two chronobiology model insects D. melanogaster and A. mellifera, compare them with other insects and show their advantages and limitations as general models for insect circadian clocks.
Aim: Despite increasing interest in β-diversity, that is the spatial and temporal turnover of species, the mechanisms underlying species turnover at different spatial scales are not fully understood, although they likely differ among different functional groups. We investigated the relative importance of dispersal limitations and the environmental filtering caused by vegetation for local, multi-taxa forest communities differing in their dispersal ability, trophic position and body size.
Location: Temperate forests in five regions across Germany.
Methods: In the inter-region analysis, the independent and shared effects of the regional spatial structure (regional species pool), landscape spatial structure (dispersal limitation) and environmental factors on species turnover were quantified with a 1-ha grain across 11 functional groups in up to 495 plots by variation partitioning. In the intra-region analysis, the relative importance of three environmental factors related to vegetation (herb and tree layer composition and forest physiognomy) and spatial structure for species turnover was determined.
Results: In the inter-region analysis, over half of the explained variation in community composition (23% of the total explained 35%) was explained by the shared effects of several factors, indicative of spatially structured environmental filtering. Among the independent effects, environmental factors were the strongest on average over 11 groups, but the importance of landscape spatial structure increased for less dispersive functional groups. In the intra-region analysis, the independent effect of plant species composition had a stronger influence on species turnover than forest physiognomy, but the relative importance of the latter increased with increasing trophic position and body size.
Main conclusions: Our study revealed that the mechanisms structuring assemblage composition are associated with the traits of functional groups. Hence, conservation frameworks targeting biodiversity of multiple groups should cover both environmental and biogeographical gradients. Within regions, forest management can enhance β-diversity particularly by diversifying tree species composition and forest physiognomy.
The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H\(_2\)O\(_2\) or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.
The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of integrase strand transfer inhibitors (INSTIs). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 NOPs within the Cameroonian-derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.