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For 20 years, the Comparative Toxicogenomics Database (CTD; https://ctdbase.org) has provided high-quality, literature-based curated content describing how environmental chemicals affect human health. Today, CTD includes over 94 million toxicogenomic connections relating chemicals, genes/proteins, phenotypes, anatomical terms, diseases, comparative species, pathways and exposures. In this 20th year anniversary update, we reflect on CTD's remarkable growth and provide an overview of the increased data content and new features, including enhancements to the curation workflow (e.g. new exposure curation tool and expanded use of natural language processing), added functionality (e.g. improvements to CTD Tetramers and Pathway View tools) and significant upgrades to software and infrastructure. Linking lab-based core curation with real-world human exposure curation via the use of controlled vocabularies facilitates analysis of content across the entire environmental health continuum, from molecular toxicological mechanisms to the population level, and vice versa. The 'prototype database' originally described in 2004 has evolved into a premier, sophisticated, highly cited and well-engineered knowledgebase and discoverybase that is utilized by scientists worldwide to design testable hypotheses about environmental health., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In environmental health, the specific molecular mechanisms connecting a chemical exposure to an adverse endpoint are often unknown, reflecting knowledge gaps. At the public Comparative Toxicogenomics Database (CTD; https://ctdbase.org/), we integrate manually curated, literature-based interactions from CTD to compute four-unit blocks of information organized as a potential step-wise molecular mechanism, known as "CGPD-tetramers," wherein a chemical interacts with a gene product to trigger a phenotype which can be linked to a disease. These computationally derived datasets can be used to fill the gaps and offer testable mechanistic information. Users can generate CGPD-tetramers for any combination of chemical, gene, phenotype, and/or disease of interest at CTD; however, such queries typically result in the generation of thousands of CGPD-tetramers. Here, we describe a novel approach to transform these large datasets into user-friendly chord diagrams using R. This visualization process is straightforward, simple to implement, and accessible to inexperienced users that have never used R before. Combining CGPD-tetramers into a single chord diagram helps identify potential key chemicals, genes, phenotypes, and diseases. This visualization allows users to more readily analyze computational datasets that can fill the exposure knowledge gaps in the environmental health continuum., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wyatt, Davis, Wiegers, Wiegers, Abrar, Sciaky, Barkalow, Strong and Mattingly.)

The bacterial cyclic oligonucleotide-based antiphage signaling system (CBASS) is similar to the cGAS-STING system in humans, containing an enzyme that synthesizes a cyclic nucleotide on viral infection and an effector that senses the second messenger for the antiviral response. Cap5, containing a SAVED domain coupled to an HNH DNA endonuclease domain, is the most abundant CBASS effector, yet the mechanism by which it becomes activated for cell killing remains unknown. We present here high-resolution structures of full-length Cap5 from Pseudomonas syringae (Ps) with second messengers. The key to PsCap5 activation is a dimer-to-tetramer transition, whereby the binding of second messenger to dimer triggers an open-to-closed transformation of the SAVED domains, furnishing a surface for assembly of the tetramer. This movement propagates to the HNH domains, juxtaposing and converting two HNH domains into states for DNA destruction. These results show how Cap5 effects bacterial cell suicide and we provide proof-in-principle data that the CBASS can be extrinsically activated to limit bacterial infections., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)