ΔN-Tp63 mediates Wnt/β-catenin-induced inhibition of differentiation in basal stem cells of mucociliary epithelia

Mucociliary epithelia provide a first line of defense against pathogens. Impaired regeneration and remodeling of mucociliary epithelia are associated with dysregulated Wnt/beta-catenin signaling in chronic airway diseases, but underlying mechanisms remain elusive, and studies yield seemingly contradicting results. Employing the Xenopus mucociliary epidermis, the mouse airway, and human airway Basal cells, we characterize the evolutionarily conserved roles of Wnt/beta-catenin signaling in vertebrates. In multiciliated cells, Wnt is required for cilia formation during differentiation. In Basal cells, Wnt prevents specification of epithelial cell types by activating Delta N-TP63, a master transcription factor, which is necessary and sufficient to mediate the Wnt-induced inhibition of specification and is required to retain Basal cells during development. Chronic Wnt activation leads to remodeling and Basal cell hyperplasia, which are reversible in vivo and in vitro, suggesting Wnt inhibition as a treatment option in chronic lung diseases. Our work provides important insights into mucociliary signaling, development, and disease

Additional file 2 of Small and long RNA transcriptome of whole human cerebrospinal fluid and serum as compared to their extracellular vesicle fractions reveal profound differences in expression patterns and impacts on biological processes

Additional file 2: Read counts of differentially expressed small RNA transcripts listed in table1

Genetic Variants Associated with the Age of Onset Identified by Whole-Exome Sequencing in Fatal Familial Insomnia

Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease with a wide variability in age of onset. Its causes are not known. In the present study, we aimed to analyze genetic risk factors other than the prion protein gene (PRNP), in FFI patients with varying ages of onset. Whole-exome sequencing (WES) analysis was performed for twenty-five individuals with FFI (D178N-129M). Gene ontology enrichment analysis was carried out by Reactome to generate hypotheses regarding the biological processes of the identified genes. In the present study, we used a statistical approach tailored to the specifics of the data and identified nineteen potential gene variants with a potential effect on the age of onset. Evidence for potential disease modulatory risk loci was observed in two pseudogenes (NR1H5P, GNA13P1) and three protein coding genes (EXOC1L, SRSF11 and MSANTD3). These genetic variants are absent in FFI patients with early disease onset (19–40 years). The biological function of these genes and PRNP is associated with programmed cell death, caspase-mediated cleavage of cytoskeletal proteins and apoptotic cleavage of cellular proteins. In conclusions, our study provided first evidence for the involvement of genetic risk factors additional to PRNP, which may influence the onset of clinical symptoms in FFI

Additional file 5 of Small and long RNA transcriptome of whole human cerebrospinal fluid and serum as compared to their extracellular vesicle fractions reveal profound differences in expression patterns and impacts on biological processes

Additional file 5: Transcript sets of mRNA expressed in serum and CSF fractions

Additional file 4 of Small and long RNA transcriptome of whole human cerebrospinal fluid and serum as compared to their extracellular vesicle fractions reveal profound differences in expression patterns and impacts on biological processes

Additional file 4: Read counts of differentially expressed long RNA transcripts listed in table 2 

Additional file 3 of Small and long RNA transcriptome of whole human cerebrospinal fluid and serum as compared to their extracellular vesicle fractions reveal profound differences in expression patterns and impacts on biological processes

Additional file 3: Target sets of miR expressed in serum and CSF fraction

Additional file 1 of Small and long RNA transcriptome of whole human cerebrospinal fluid and serum as compared to their extracellular vesicle fractions reveal profound differences in expression patterns and impacts on biological processes

Additional file 1: Age distribution of patients, volume size, and erythrocyte and leucocyte numbers of CSF and serum samples. Fig. S2 RNA content of 100 KDa column concentrates and filtrates. Fig. S3 Age- and sex-distribution of serum samples. Fig. S4 RNA content of CSF samples in dependence of the storage temperature and RNAse treatment. Fig. S5 RNA content of CSF and serum samples. Fig. S6 Gel analysis of all RNA samples. Fig. S7 Electropherogramms of the RNA samples from serum. Fig. S8 Electropherogramms of the RNA samples from CSF. Fig. S9 Comparison of RNA content and electropherogramms of the RNA samples from CSF and blood-contaminated CSF. Fig. S10 Venn diagrams and UpSet plots form small and long RNA. Fig. S11 Heat maps of small RNA read counts not shown in figure 4. Fig. S12 GO Slim summaries of miR targets from whole CSF, CSF-EV, whole serum, and serum EV. Fig. S13 Heat maps of read counts encompassing all possible comparisons of down- and up-regulated long RNA transcripts. Fig. S14 Venn diagrams of significantly expressed small RNA transcripts, expressed miR, and target transcripts of expressed miR. Fig. S15 Distribution of small RNAs in body fluids and their respective EV

Toxicogenomic differentiation of functional responses to fipronil and imidacloprid in Daphnia magna

Active substances of pesticides, biocides or pharmaceuticals can induce adverse side effects in the aquatic ecosystem, necessitating environmental hazard and risk assessment prior to substance registration. The freshwater crustacean Daphnia magna is a model organism for acute and chronic toxicity assessment representing aquatic invertebrates. However, standardized tests involving daphnia are restricted to the endpoints immobility and reproduction and thus provide only limited insights into the underlying modes-of-action. Here, we applied transcriptome profiling to a modified D. magna Acute Immobilization test to analyze and compare gene expression profiles induced by the GABA-gated chloride channel blocker fipronil and the nicotinic acetylcholine receptor (nAChR) agonist imidacloprid. Daphnids were expose to two low effect concentrations of each substance followed by RNA sequencing and functional classification of affected gene ontologies and pathways. For both insecticides, we observed a concentration-dependent increase in the number of differentially expressed genes, whose expression changes were highly significantly positively correlated when comparing both test concentrations. These gene expression fingerprints showed virtually no overlap between the test substances and they related well to previous data of diazepam and carbaryl, two substances targeting similar molecular key events. While, based on our results, fipronil predominantly interfered with molecular functions involved in ATPase-coupled transmembrane transport and transcription regulation, imidacloprid primarily affected oxidase and oxidoreductase activity. These findings provide evidence that systems biology approaches can be utilized to identify and differentiate modes-of-action of chemical stressors in D. magna as an invertebrate aquatic non-target organism. The mechanistic knowledge extracted from such data will in future contribute to the development of Adverse Outcome Pathways (AOPs) for read-across and prediction of population effects

Genome-wide chromatin and gene expression profiling during memory formation and maintenance in adult mice. [CODE: support files]

This repository contains annotation files for mouse genome assembly mm10, including chromosome sizes, gene and exon annotations, mappability file and the R package chequeR used to generate enrichment statistics for ChIP-seq data. The files are used in the analyses of ChIP-, MeDIP- and RNA-seq data from mouse, as described by the run_scientific_data_analysis.pdf in the scripts repository (https://dx.doi.org/10.6084/m9.figshare.3490613)<br