From papers to RDF-based integration of physicochemical data and adverse outcome pathways for nanomaterials.

Adverse Outcome Pathways (AOPs) have been proposed to facilitate mechanistic understanding of interactions of chemicals/materials with biological systems. Each AOP starts with a molecular initiating event (MIE) and possibly ends with adverse outcome(s) (AOs) via a series of key events (KEs). So far, the interaction of engineered nanomaterials (ENMs) with biomolecules, biomembranes, cells, and biological structures, in general, is not yet fully elucidated. There is also a huge lack of information on which AOPs are ENMs-relevant or -specific, despite numerous published data on toxicological endpoints they trigger, such as oxidative stress and inflammation. We propose to integrate related data and knowledge recently collected. Our approach combines the annotation of nanomaterials and their MIEs with ontology annotation to demonstrate how we can then query AOPs and biological pathway information for these materials. We conclude that a FAIR (Findable, Accessible, Interoperable, Reusable) representation of the ENM-MIE knowledge simplifies integration with other knowledge. SCIENTIFIC CONTRIBUTION: This study introduces a new database linking nanomaterial stressors to the first known MIE or KE. Second, it presents a reproducible workflow to analyze and summarize this knowledge. Third, this work extends the use of semantic web technologies to the field of nanoinformatics and nanosafety.

Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals.

The adverse outcome pathway (AOP) framework plays a crucial role in the paradigm shift of tox­icity testing towards the development and use of new approach methodologies. AOPs developed for chemicals are in theory applicable to nanomaterials (NMs). However, only initial efforts have been made to integrate information on NM-induced toxicity into existing AOPs. In a previous study, we identified AOPs in the AOP-Wiki associated with the molecular initiating events (MIEs) and key events (KEs) reported for NMs in scientific literature. In a next step, we analyzed these AOPs and found that mitochondrial toxicity plays a significant role in several of them at the molecular and cellular levels. In this study, we aimed to generate hypothesis-based AOPs related to NM-induced mitochondrial toxicity. This was achieved by integrating knowledge on NM-induced mitochondrial toxicity into all existing AOPs in the AOP-Wiki, which already includes mitochondrial toxicity as a MIE/KE. Several AOPs in the AOP-Wiki related to the lung, liver, cardiovascular and nervous system, with extensively defined KEs and key event relationships (KERs), could be utilized to develop AOPs that are relevant for NMs. However, the majority of the studies included in our literature review were of poor quality, particularly in reporting NM physicochemical characteristics, and NM-relevant mitochondrial MIEs were rarely reported. This study highlights the potential role of NM-induced mitochondrial toxicity in human-relevant adverse outcomes and identifies useful AOPs in the AOP-Wiki for the development of AOPs for NMs.

This article investigates commonalities in the toxicity pathways of chemicals and nanomaterials. Nanomaterials have been found to affect the function of mitochondria, the powerhouses within every human cell. Mitochondrial dysfunction may cause harmful effects such as cellular damage and inflammation. By linking these findings to existing adverse outcome pathways for chemicals, the research provides valuable insights for assessing the risks associated with nanomaterial exposure. This work is crucial for understanding the potential health implications of nanomaterials and can contribute to informed decision-making in regulatory and risk assessment processes without the use of animals.

WikiPathways 2024: next generation pathway database.

WikiPathways (wikipathways.org) is an open-source biological pathway database. Collaboration and open science are pivotal to the success of WikiPathways. Here we highlight the continuing efforts supporting WikiPathways, content growth and collaboration among pathway researchers. As an evolving database, there is a growing need for WikiPathways to address and overcome technical challenges. In this direction, WikiPathways has undergone major restructuring, enabling a renewed approach for sharing and curating pathway knowledge, thus providing stability for the future of community pathway curation. The website has been redesigned to improve and enhance user experience. This next generation of WikiPathways continues to support existing features while improving maintainability of the database and facilitating community input by providing new functionality and leveraging automation.

Artificial intelligence for natural product drug discovery.

Developments in computational omics technologies have provided new means to access the hidden diversity of natural products, unearthing new potential for drug discovery. In parallel, artificial intelligence approaches such as machine learning have led to exciting developments in the computational drug design field, facilitating biological activity prediction and de novo drug design for molecular targets of interest. Here, we describe current and future synergies between these developments to effectively identify drug candidates from the plethora of molecules produced by nature. We also discuss how to address key challenges in realizing the potential of these synergies, such as the need for high-quality datasets to train deep learning algorithms and appropriate strategies for algorithm validation.

Extending inherited metabolic disorder diagnostics with biomarker interaction visualizations.

BACKGROUND: Inherited Metabolic Disorders (IMDs) are rare diseases where one impaired protein leads to a cascade of changes in the adjacent chemical conversions. IMDs often present with non-specific symptoms, a lack of a clear genotype-phenotype correlation, and de novo mutations, complicating diagnosis. Furthermore, products of one metabolic conversion can be the substrate of another pathway obscuring biomarker identification and causing overlapping biomarkers for different disorders. Visualization of the connections between metabolic biomarkers and the enzymes involved might aid in the diagnostic process. The goal of this study was to provide a proof-of-concept framework for integrating knowledge of metabolic interactions with real-life patient data before scaling up this approach. This framework was tested on two groups of well-studied and related metabolic pathways (the urea cycle and pyrimidine de-novo synthesis). The lessons learned from our approach will help to scale up the framework and support the diagnosis of other less-understood IMDs. METHODS: Our framework integrates literature and expert knowledge into machine-readable pathway models, including relevant urine biomarkers and their interactions. The clinical data of 16 previously diagnosed patients with various pyrimidine and urea cycle disorders were visualized on the top 3 relevant pathways. Two expert laboratory scientists evaluated the resulting visualizations to derive a diagnosis. RESULTS: The proof-of-concept platform resulted in varying numbers of relevant biomarkers (five to 48), pathways, and pathway interactions for each patient. The two experts reached the same conclusions for all samples with our proposed framework as with the current metabolic diagnostic pipeline. For nine patient samples, the diagnosis was made without knowledge about clinical symptoms or sex. For the remaining seven cases, four interpretations pointed in the direction of a subset of disorders, while three cases were found to be undiagnosable with the available data. Diagnosing these patients would require additional testing besides biochemical analysis. CONCLUSION: The presented framework shows how metabolic interaction knowledge can be integrated with clinical data in one visualization, which can be relevant for future analysis of difficult patient cases and untargeted metabolomics data. Several challenges were identified during the development of this framework, which should be resolved before this approach can be scaled up and implemented to support the diagnosis of other (less understood) IMDs. The framework could be extended with other OMICS data (e.g. genomics, transcriptomics), and phenotypic data, as well as linked to other knowledge captured as Linked Open Data.

Guiding the choice of informatics software and tools for lipidomics research applications.

Progress in mass spectrometry lipidomics has led to a rapid proliferation of studies across biology and biomedicine. These generate extremely large raw datasets requiring sophisticated solutions to support automated data processing. To address this, numerous software tools have been developed and tailored for specific tasks. However, for researchers, deciding which approach best suits their application relies on ad hoc testing, which is inefficient and time consuming. Here we first review the data processing pipeline, summarizing the scope of available tools. Next, to support researchers, LIPID MAPS provides an interactive online portal listing open-access tools with a graphical user interface. This guides users towards appropriate solutions within major areas in data processing, including (1) lipid-oriented databases, (2) mass spectrometry data repositories, (3) analysis of targeted lipidomics datasets, (4) lipid identification and (5) quantification from untargeted lipidomics datasets, (6) statistical analysis and visualization, and (7) data integration solutions. Detailed descriptions of functions and requirements are provided to guide customized data analysis workflows.

Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches.

Introduction: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Methods: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors. Results: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19. Discussion: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.

Wikipedia on the CompTox Chemicals Dashboard: Connecting Resources to Enrich Public Chemical Data.

The online encyclopedia Wikipedia aggregates a large amount of data on chemistry, encompassing well over 20,000 individual Wikipedia pages and serves the general public as well as the chemistry community. Many other chemical databases and services utilize these data, and previous projects have focused on methods to index, search, and extract it for review and use. We present a comprehensive effort that combines bulk automated data extraction over tens of thousands of pages, semiautomated data extraction over hundreds of pages, and fine-grained manual extraction of individual lists and compounds of interest. We then correlate these data with the existing contents of the U.S. Environmental Protection Agency's (EPA) Distributed Structure-Searchable Toxicity (DSSTox) database. This was performed with a number of intentions including ensuring as complete a mapping as possible between the Dashboard and Wikipedia so that relevant snippets of the article are loaded for the user to review. Conflicts between Dashboard content and Wikipedia in terms of, for example, identifiers such as chemical registry numbers, names, and InChIs and structure-based collisions such as SMILES were identified and used as the basis of curation of both DSSTox and Wikipedia. This work also allowed us to evaluate available data for sets of chemicals of interest to the Agency, such as synthetic cannabinoids, and expand the content in DSSTox as appropriate. This work also led to improved bidirectional linkage of the detailed chemistry and usage information from Wikipedia with expert-curated structure and identifier data from DSSTox for a new list of nearly 20,000 chemicals. All of this work ultimately enhances the data mappings that allow for the display of the introduction of the Wikipedia article in the community-accessible web-based EPA Comptox Chemicals Dashboard, enhancing the user experience for the thousands of users per day accessing the resource.

Understanding signaling and metabolic paths using semantified and harmonized information about biological interactions.

To grasp the complexity of biological processes, the biological knowledge is often translated into schematic diagrams of, for example, signalling and metabolic pathways. These pathway diagrams describe relevant connections between biological entities and incorporate domain knowledge in a visual format making it easier for humans to interpret. Still, these diagrams can be represented in machine readable formats, as done in the KEGG, Reactome, and WikiPathways databases. However, while humans are good at interpreting the message of the creators of diagrams, algorithms struggle when the diversity in drawing approaches increases. WikiPathways supports multiple drawing styles which need harmonizing to offer semantically enriched access. Particularly challenging, here, are the interactions between the biological entities that underlie the biological causality. These interactions provide information about the biological process (metabolic conversion, inhibition, etc.), the direction, and the participating entities. Availability of the interactions in a semantic and harmonized format is essential for searching the full network of biological interactions. We here study how the graphically-modelled biological knowledge in diagrams can be semantified and harmonized, and exemplify how the resulting data is used to programmatically answer biological questions. We find that we can translate graphically modelled knowledge to a sufficient degree into a semantic model and discuss some of the current limitations. We then use this to show that reproducible notebooks can be used to explore up- and downstream targets of MECP2 and to analyse the sphingolipid metabolism. Our results demonstrate that most of the graphical biological knowledge from WikiPathways is modelled into the semantic layer with the semantic information intact and connectivity information preserved. Being able to evaluate how biological elements affect each other is useful and allows, for example, the identification of up or downstream targets that will have a similar effect when modified.

Providing Adverse Outcome Pathways from the AOP-Wiki in a Semantic Web Format to Increase Usability and Accessibility of the Content.

Introduction: The AOP-Wiki is the main platform for the development and storage of adverse outcome pathways (AOPs). These AOPs describe mechanistic information about toxicodynamic processes and can be used to develop effective risk assessment strategies. However, it is challenging to automatically and systematically parse, filter, and use its contents. We explored solutions to better structure the AOP-Wiki content, and to link it with chemical and biological resources. Together, this allows more detailed exploration, which can be automated. Materials and Methods: We converted the complete AOP-Wiki content into resource description framework (RDF) triples. We used >20 ontologies for the semantic annotation of property-object relations, including the Chemical Information Ontology, Dublin Core, and the AOP Ontology. Results: The resulting RDF contains >122,000 triples describing 158 unique properties of >15,000 unique subjects. Furthermore, >3500 link-outs were added to 12 chemical databases, and >7500 link-outs to 4 gene and protein databases. The AOP-Wiki RDF has been made available at https://aopwiki.rdf.bigcat-bioinformatics.org. Discussion: SPARQL queries can be used to answer biological and toxicological questions, such as listing measurement methods for all Key Events leading to an Adverse Outcome of interest. The full power that the use of this new resource provides becomes apparent when combining the content with external databases using federated queries. Conclusion: Overall, the AOP-Wiki RDF allows new ways to explore the rapidly growing AOP knowledge and makes the integration of this database in automated workflows possible, making the AOP-Wiki more FAIR.

The AOP-DB RDF: Applying FAIR Principles to the Semantic Integration of AOP Data Using the Research Description Framework.

Computational toxicology is central to the current transformation occurring in toxicology and chemical risk assessment. There is a need for more efficient use of existing data to characterize human toxicological response data for environmental chemicals in the US and Europe. The Adverse Outcome Pathway (AOP) framework helps to organize existing mechanistic information and contributes to what is currently being described as New Approach Methodologies (NAMs). AOP knowledge and data are currently submitted directly by users and stored in the AOP-Wiki (https://aopwiki.org/). Automatic and systematic parsing of AOP-Wiki data is challenging, so we have created the EPA Adverse Outcome Pathway Database. The AOP-DB, developed by the US EPA to assist in the biological and mechanistic characterization of AOP data, provides a broad, systems-level overview of the biological context of AOPs. Here we describe the recent semantic mapping efforts for the AOP-DB, and how this process facilitates the integration of AOP-DB data with other toxicologically relevant datasets through a use case example.

Research Techniques Made Simple: Lipidomic Analysis in Skin Research.

Although lipids are crucial molecules for cell structure, metabolism, and signaling in most organs, they have additional specific functions in the skin. Lipids are required for the maintenance and regulation of the epidermal barrier, physical properties of the skin, and defense against microbes. Analysis of the lipidome-the totality of lipids-is of similar complexity to those of proteomics or other omics, with lipid structures ranging from simple, linear, to highly complex structures. In addition, the ordering and chemical modifications of lipids have consequences on their biological function, especially in the skin. Recent advances in analytic capability (usually with mass spectrometry), bioinformatic processing, and integration with other dermatological big data have allowed researchers to increasingly understand the roles of specific lipid species in skin biology. In this paper, we review the techniques used to analyze skin lipidomics and epilipidomics.

Investigating the Molecular Processes behind the Cell-Specific Toxicity Response to Titanium Dioxide Nanobelts.

Some engineered nanomaterials incite toxicological effects, but the underlying molecular processes are understudied. The varied physicochemical properties cause different initial molecular interactions, complicating toxicological predictions. Gene expression data allow us to study the responses of genes and biological processes. Overrepresentation analysis identifies enriched biological processes using the experimental data but prompts broad results instead of detailed toxicological processes. We demonstrate a targeted filtering approach to compare public gene expression data for low and high exposure on three cell lines to titanium dioxide nanobelts. Our workflow finds cell and concentration-specific changes in affected pathways linked to four Gene Ontology terms (apoptosis, inflammation, DNA damage, and oxidative stress) to select pathways with a clear toxicity focus. We saw more differentially expressed genes at higher exposure, but our analysis identifies clear differences between the cell lines in affected processes. Colorectal adenocarcinoma cells showed resilience to both concentrations. Small airway epithelial cells displayed a cytotoxic response to the high concentration, but not as strongly as monocytic-like cells. The pathway-gene networks highlighted the gene overlap between altered toxicity-related pathways. The automated workflow is flexible and can focus on other biological processes by selecting other GO terms.

A resource to explore the discovery of rare diseases and their causative genes.

Here, we describe a dataset with information about monogenic, rare diseases with a known genetic background, supplemented with manually extracted provenance for the disease itself and the discovery of the underlying genetic cause. We assembled a collection of 4166 rare monogenic diseases and linked them to 3163 causative genes, annotated with OMIM and Ensembl identifiers and HGNC symbols. The PubMed identifiers of the scientific publications, which for the first time described the rare diseases, and the publications, which found the genes causing the diseases were added using information from OMIM, PubMed, Wikipedia, whonamedit.com, and Google Scholar. The data are available under CC0 license as spreadsheet and as RDF in a semantic model modified from DisGeNET, and was added to Wikidata. This dataset relies on publicly available data and publications with a PubMed identifier, but by our effort to make the data interoperable and linked, we can now analyse this data. Our analysis revealed the timeline of rare disease and causative gene discovery and links them to developments in methods.

A strategy towards the generation of testable adverse outcome pathways for nanomaterials.

Manufactured nanomaterials (NMs) are increasingly used in a wide range of industrial applications leading to a constant increase in the market size of nano-enabled products. The increased production and use of NMs are raising concerns among different stakeholder groups with regard to their effects on human and environmental health. Currently, nanosafety hazard assessment is still widely performed using in vivo (animal) models, however the development of robust and reg­ulatory relevant strategies is required to prioritize and/or reduce animal testing. An adverse outcome pathway (AOP) is a structured representation of biological events that start from a molecular initiating event (MIE) leading to an adverse outcome (AO) through a series of key events (KEs). The AOP framework offers great advancement to risk assessment and regulatory safety assessments. While AOPs for chemicals have been more frequently reported, the AOP collection for NMs is limited. By using existing AOPs, we aimed to generate simple and testable strategies to predict if a given NM has the potential to induce a MIE leading to an AO through a series of KEs. Firstly, we identified potential MIEs or initial KEs reported for NMs in the literature. Then, we searched the identified MIE or initial KEs as keywords in the AOP-Wiki to find associated AOPs. Finally, using two case studies, we demonstrate how in vitro strategies can be used to test the identified MIE/KEs.

A protocol for adding knowledge to Wikidata: aligning resources on human coronaviruses.

BACKGROUND: Pandemics, even more than other medical problems, require swift integration of knowledge. When caused by a new virus, understanding the underlying biology may help finding solutions. In a setting where there are a large number of loosely related projects and initiatives, we need common ground, also known as a "commons." Wikidata, a public knowledge graph aligned with Wikipedia, is such a commons and uses unique identifiers to link knowledge in other knowledge bases. However, Wikidata may not always have the right schema for the urgent questions. In this paper, we address this problem by showing how a data schema required for the integration can be modeled with entity schemas represented by Shape Expressions. RESULTS: As a telling example, we describe the process of aligning resources on the genomes and proteomes of the SARS-CoV-2 virus and related viruses as well as how Shape Expressions can be defined for Wikidata to model the knowledge, helping others studying the SARS-CoV-2 pandemic. How this model can be used to make data between various resources interoperable is demonstrated by integrating data from NCBI (National Center for Biotechnology Information) Taxonomy, NCBI Genes, UniProt, and WikiPathways. Based on that model, a set of automated applications or bots were written for regular updates of these sources in Wikidata and added to a platform for automatically running these updates. CONCLUSIONS: Although this workflow is developed and applied in the context of the COVID-19 pandemic, to demonstrate its broader applicability it was also applied to other human coronaviruses (MERS, SARS, human coronavirus NL63, human coronavirus 229E, human coronavirus HKU1, human coronavirus OC4).

A catalogue of 863 Rett-syndrome-causing MECP2 mutations and lessons learned from data integration.

Rett syndrome (RTT) is a rare neurological disorder mostly caused by a genetic variation in MECP2. Making new MECP2 variants and the related phenotypes available provides data for better understanding of disease mechanisms and faster identification of variants for diagnosis. This is, however, currently hampered by the lack of interoperability between genotype-phenotype databases. Here, we demonstrate on the example of MECP2 in RTT that by making the genotype-phenotype data more Findable, Accessible, Interoperable, and Reusable (FAIR), we can facilitate prioritization and analysis of variants. In total, 10,968 MECP2 variants were successfully integrated. Among these variants 863 unique confirmed RTT causing and 209 unique confirmed benign variants were found. This dataset was used for comparison of pathogenicity predicting tools, protein consequences, and identification of ambiguous variants. Prediction tools generally recognised the RTT causing and benign variants, however, there was a broad range of overlap Nineteen variants were identified that were annotated as both disease-causing and benign, suggesting that there are additional factors in these cases contributing to disease development.

WikiPathways: connecting communities.

WikiPathways (https://www.wikipathways.org) is a biological pathway database known for its collaborative nature and open science approaches. With the core idea of the scientific community developing and curating biological knowledge in pathway models, WikiPathways lowers all barriers for accessing and using its content. Increasingly more content creators, initiatives, projects and tools have started using WikiPathways. Central in this growth and increased use of WikiPathways are the various communities that focus on particular subsets of molecular pathways such as for rare diseases and lipid metabolism. Knowledge from published pathway figures helps prioritize pathway development, using optical character and named entity recognition. We show the growth of WikiPathways over the last three years, highlight the new communities and collaborations of pathway authors and curators, and describe various technologies to connect to external resources and initiatives. The road toward a sustainable, community-driven pathway database goes through integration with other resources such as Wikidata and allowing more use, curation and redistribution of WikiPathways content.