Claudia Mengoni

Microbial genomes are available at an ever-increasing pace, as cultivation and sequencing become cheaper and obtaining metagenome-assembled genomes (MAGs) becomes more effective. Phylogenetic placement methods to contextualize hundreds of thousands of genomes must thus be efficiently scalable and sensitive from closely related strains to divergent phyla. We present PhyloPhlAn 3.0, an accurate, rapid, and easy-to-use method for large-scale microbial genome characterization and phylogenetic analysis at multiple levels of resolution. PhyloPhlAn 3.0 can assign genomes from isolate sequencing or MAGs to species-level genome bins built from >230,000 publically available sequences. For individual clades of interest, it reconstructs strain-level phylogenies from among the closest species using clade-specific maximally informative markers. At the other extreme of resolution, it scales to large phylogenies comprising >17,000 microbial species. Examples including Staphylococcus aureus isolates, gut metagenomes, and meta-analyses demonstrate the ability of PhyloPhlAn 3.0 to support genomic and metagenomic analyses.

Most cell type-specific genes are regulated by the interaction of enhancers with their promoters. The identification of enhancers is not trivial as enhancers are diverse in their characteristics and dynamic in their interaction partners. We present Esearch3D, a new method that exploits network theory approaches to identify active enhancers. Our work is based on the fact that enhancers act as a source of regulatory information to increase the rate of transcription of their target genes and that the flow of this information is mediated by the folding of chromatin in the three-dimensional (3D) nuclear space between the enhancer and the target gene promoter. Esearch3D reverse engineers this flow of information to calculate the likelihood of enhancer activity in intergenic regions by propagating the transcription levels of genes across 3D genome networks. Regions predicted to have high enhancer activity are shown to be enriched in annotations indicative of enhancer activity. These include: enhancer-associated histone marks, bidirectional CAGE-seq, STARR-seq, P300, RNA polymerase II and expression quantitative trait loci (eQTLs). Esearch3D leverages the relationship between chromatin architecture and transcription, allowing the prediction of active enhancers and an understanding of the complex underpinnings of regulatory networks. The method is available at: https://github.com/InfOmics/Esearch3D and https://doi.org/10.5281/zenodo.7737123.

INTRODUCTION: Studies have correlated living close to major roads with Alzheimer's disease (AD) risk. However, the mechanisms responsible for this link remain unclear. METHODS: We exposed olfactory mucosa (OM) cells of healthy individuals and AD patients to diesel emissions (DE). Cytotoxicity of exposure was assessed, mRNA, miRNA expression, and DNA methylation analyses were performed. The discovered altered pathways were validated using data from the human population-based Rotterdam Study. RESULTS: DE exposure resulted in an almost four-fold higher response in AD OM cells, indicating increased susceptibility to DE effects. Methylation analysis detected different DNA methylation patterns, revealing new exposure targets. Findings were validated by analyzing data from the Rotterdam Study cohort and demonstrated a key role of nuclear factor erythroid 2-related factor 2 signaling in responses to air pollutants. DISCUSSION: This study identifies air pollution exposure biomarkers and pinpoints key pathways activated by exposure. The data suggest that AD individuals may face heightened risks due to impaired cellular defenses. HIGHLIGHTS: Healthy and AD olfactory cells respond differently to DE exposure. AD cells are highly susceptible to DE exposure. The NRF2 oxidative stress response is highly activated upon air pollution exposure. DE-exposed AD cells activate the unfolded protein response pathway. Key findings are also confirmed in a population-based study.

interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation.