Homeostasis imbalance process ontology: a study on COVID-19 infectious processes.

BACKGROUND: One significant challenge in addressing the coronavirus disease 2019 (COVID-19) pandemic is to grasp a comprehensive picture of its infectious mechanisms. We urgently need a consistent framework to capture the intricacies of its complicated viral infectious processes and diverse symptoms. RESULTS: We systematized COVID-19 infectious processes through an ontological approach and provided a unified description framework of causal relationships from the early infectious stage to severe clinical manifestations based on the homeostasis imbalance process ontology (HoIP). HoIP covers a broad range of processes in the body, ranging from normal to abnormal. Moreover, our imbalance model enabled us to distinguish viral functional demands from immune defense processes, thereby supporting the development of new drugs, and our research demonstrates how ontological reasoning contributes to the identification of patients at severe risk. CONCLUSIONS: The HoIP organises knowledge of COVID-19 infectious processes and related entities, such as molecules, drugs, and symptoms, with a consistent descriptive framework. HoIP is expected to harmonise the description of various heterogeneous processes and improve the interoperability of COVID-19 knowledge through the COVID-19 ontology harmonisation working group.

A community effort for COVID-19 Ontology Harmonization.

Ontologies have emerged to become critical to support data and knowledge representation, standardization, integration, and analysis. The SARS-CoV-2 pandemic led to the rapid proliferation of COVID-19 data, as well as the development of many COVID-19 ontologies. In the interest of supporting data interoperability, we initiated a community-based effort to harmonize COVID-19 ontologies. Our effort involves the collaborative discussion among developers of seven COVID-19 related ontologies, and the merging of four ontologies. This effort demonstrates the feasibility of harmonizing these ontologies in an interoperable framework to support integrative representation and analysis of COVID-19 related data and knowledge.

MoG+: a database of genomic variations across three mouse subspecies for biomedical research.

Laboratory mouse strains have mosaic genomes derived from at least three major subspecies that are distributed in Eurasia. Here, we describe genomic variations in ten inbred strains: Mus musculus musculus-derived BLG2/Ms, NJL/Ms, CHD/Ms, SWN/Ms, and KJR/Ms; M. m. domesticus-derived PGN2/Ms and BFM/Ms; M. m. castaneus-derived HMI/Ms; and JF1/Ms and MSM/Ms, which were derived from a hybrid between M. m. musculus and M. m. castaneus. These strains were established by Prof. Moriwaki in the 1980s and are collectively named the "Mishima Battery". These strains show large phenotypic variations in body size and in many physiological traits. We resequenced the genomes of the Mishima Battery strains and performed a comparative genomic analysis with dbSNP data. More than 81 million nucleotide coordinates were identified as variant sites due to the large genetic distances among the mouse subspecies; 8,062,070 new SNP sites were detected in this study, and these may underlie the large phenotypic diversity observed in the Mishima Battery. The new information was collected in a reconstructed genome database, termed MoG+ that includes new application software and viewers. MoG+ intuitively visualizes nucleotide variants in genes and intergenic regions, and amino acid substitutions across the three mouse subspecies. We report statistical data from the resequencing and comparative genomic analyses and newly collected phenotype data of the Mishima Battery, and provide a brief description of the functions of MoG+, which provides a searchable and unique data resource of the numerous genomic variations across the three mouse subspecies. The data in MoG+ will be invaluable for research into phenotype-genotype links in diverse mouse strains.

Establishment and application of information resource of mutant mice in RIKEN BioResource Research Center.

Online databases are crucial infrastructures to facilitate the wide effective and efficient use of mouse mutant resources in life sciences. The number and types of mouse resources have been rapidly growing due to the development of genetic modification technology with associated information of genomic sequence and phenotypes. Therefore, data integration technologies to improve the findability, accessibility, interoperability, and reusability of mouse strain data becomes essential for mouse strain repositories. In 2020, the RIKEN BioResource Research Center released an integrated database of bioresources including, experimental mouse strains, Arabidopsis thaliana as a laboratory plant, cell lines, microorganisms, and genetic materials using Resource Description Framework-related technologies. The integrated database shows multiple advanced features for the dissemination of bioresource information. The current version of our online catalog of mouse strains which functions as a part of the integrated database of bioresources is available from search bars on the page of the Center ( https://brc.riken.jp ) and the Experimental Animal Division ( https://mus.brc.riken.jp/ ) websites. The BioResource Research Center also released a genomic variation database of mouse strains established in Japan and Western Europe, MoG+ ( https://molossinus.brc.riken.jp/mogplus/ ), and a database for phenotype-phenotype associations across the mouse phenome using data from the International Mouse Phenotyping Platform. In this review, we describe features of current version of databases related to mouse strain resources in RIKEN BioResource Research Center and discuss future views.

Choosing preferable labels for the Japanese translation of the Human Phenotype Ontology.

The Human Phenotype Ontology (HPO) is the de facto standard ontology to describe human phenotypes in detail, and it is actively used, particularly in the field of rare disease diagnoses. For clinicians who are not fluent in English, the HPO has been translated into many languages, and there have been four initiatives to develop Japanese translations. At the Biomedical Linked Annotation Hackathon 6 (BLAH6), a rule-based approach was attempted to determine the preferable Japanese translation for each HPO term among the candidates developed by the four approaches. The relationship between the HPO and Mammalian Phenotype translations was also investigated, with the eventual goal of harmonizing the two translations to facilitate phenotype-based comparisons of species in Japanese through cross-species phenotype matching. In order to deal with the increase in the number of HPO terms and the need for manual curation, it would be useful to have a dictionary containing word-by-word correspondences and fixed translation phrases for English word order. These considerations seem applicable to HPO localization into other languages.

BioHackathon 2015: Semantics of data for life sciences and reproducible research.

We report on the activities of the 2015 edition of the BioHackathon, an annual event that brings together researchers and developers from around the world to develop tools and technologies that promote the reusability of biological data. We discuss issues surrounding the representation, publication, integration, mining and reuse of biological data and metadata across a wide range of biomedical data types of relevance for the life sciences, including chemistry, genotypes and phenotypes, orthology and phylogeny, proteomics, genomics, glycomics, and metabolomics. We describe our progress to address ongoing challenges to the reusability and reproducibility of research results, and identify outstanding issues that continue to impede the progress of bioinformatics research. We share our perspective on the state of the art, continued challenges, and goals for future research and development for the life sciences Semantic Web.

NBDC RDF portal: a comprehensive repository for semantic data in life sciences.

In the life sciences, researchers increasingly want to access multiple databases in an integrated way. However, different databases currently use different formats and vocabularies, hindering the proper integration of heterogeneous life science data. Adopting the Resource Description Framework (RDF) has the potential to address such issues by improving database interoperability, leading to advances in automatic data processing. Based on this idea, we have advised many Japanese database development groups to expose their databases in RDF. To further promote such activities, we have developed an RDF-based life science dataset repository called the National Bioscience Database Center (NBDC) RDF portal. All the datasets in this repository have been reviewed by the NBDC to ensure interoperability and queryability. As of July 2018, the service includes 21 RDF datasets, comprising over 45.5 billion triples. It provides SPARQL endpoints for all datasets, useful metadata and the ability to download RDF files. The NBDC RDF portal can be accessed at https://integbio.jp/rdf/.

Involvement of MAP3K8 and miR-17-5p in poor virologic response to interferon-based combination therapy for chronic hepatitis C.

Despite advances in chronic hepatitis C treatment, a proportion of patients respond poorly to treatment. This study aimed to explore hepatic mRNA and microRNA signatures involved in hepatitis C treatment resistance. Global hepatic mRNA and microRNA expression profiles were compared using microarray data between treatment responses. Quantitative real-time polymerase chain reaction validated the gene signatures from 130 patients who were infected with hepatitis C virus genotype 1b and treated with pegylated interferon-alpha and ribavirin combination therapy. The correlation between mRNA and microRNA was evaluated using in silico analysis and in vitro siRNA and microRNA inhibition/overexpression experiments. Multivariate regression analysis identified that the independent variables IL28B SNP rs8099917, hsa-miR-122-5p, hsa-miR-17-5p, and MAP3K8 were significantly associated with a poor virologic response. MAP3K8 and miR-17-5p expression were inversely correlated with treatment response. Furthermore, miR-17-5p repressed HCV production by targeting MAP3K8. Collectively, the data suggest that several molecules and the inverse correlation between mRNA and microRNA contributed to a host genetic refractory hepatitis C treatment response.

Enhancement of Dectin-2 gene expression by lignin-carbohydrate complex from Lentinus edodes mycelia extract (LEM) in a mouse macrophage-like cell line.

BACKGROUND: Lignin fractions of Lentinus edodes mycelia extract (LEM) have shown anti-HIV and immunopotentiating activity. However, the action point of lignin-carbohydrate complex has not been elucidated. In order to elucidate their action point, DNA microarray analysis was performed, using mouse macrophage-like J774.1 cells. MATERIALS AND METHODS: RNA was isolated with Qiagen RNeasy Plus Mini kit, hydridized with GeneChip MouseGene 1.0 ST arrays, and scanned with Affymetrix GeneChip Command Console software. RESULTS: One of the seven lignin-carbohydrate fractions isolated from LEM (Fr4) enhanced the expression of dectin-2 (4.2-fold) and toll-like receptor (TLR)-2 (2.5-fold) prominently, but only slightly modified the expression of dectin-1 (0.8-fold), complement receptor 3 (0.9-fold), TLR1, 3, 4, 9 and 13 (0.8- to 1.7-fold), spleen tyrosine kinase (Syk)b, zeta-chain (TCR) associated 70 kDa protein kinase (Zap70), Janus tyrosine kinase (Jak)2 (1.0- to 1.2-fold), nuclear factor (Nf)кb1, NFкb2, reticuloendotheliosis viral oncogene homolog (Rel)a, Relb (1.0- to 1.6-fold), Nfкbia, Nfкbib, Nfкbie, Nfкbil2 and Nfкbiz (0.8- to 2.3-fold). On the other hand, lipopolysaccharide did not affect the expression of dectin-2 or TLR-2. CONCLUSION: These data suggest the significant role of the activation of the dectin-2 signaling pathway in the action of lignin-carbohydrate complex on macrophages.

DNA microarray analysis of signaling pathway in macrophages stimulated by lignin-carbohydrate complex from lentinus edodes mycelia (LEM) extract.

In order to investigate the action point of lignin-carbohydrate complex (Fr4) from Lentinus edodes mycelia extract, DNA microarray analysis was performed, using mouse macrophage-like J774.1 cells. Among seven lignin-carbohydrate complex fractions, Fr4 showed the highest stimulatory activity of tumor necrosis factor production by mouse macrophage-like J774.1 cells, as well as its previously reported anti-HIV activity. Fr4 is composed of lignin precursors such as vanillic acid, syringic acid, p-coumaric acid and ferulic acid, with trace amounts of flavonoids and tannins, and negligible amount of lipopolysaccharides (LPS), confirming the authenticity of Fr4 as a lignin. DNA microarray analysis suggested that Fr4 may affect immune response-related gene expression; however, it may not affect the expression of as many genes as LPS does.

Distribution of lignin-carbohydrate complex in plant kingdom and its functionality as alternative medicine.

Lignin-carbohydrate complexes (LCCs) are major cell wall components formed by the dehydrogenation of three monolignols, p-coumaryl, coniferyl and sinapyl alcohols. Diverse pharmacological activities of LCCs distributed into various plants were summarized. LCCs showed one order higher anti-HIV activity than tannins and flavonoids. Mechanism of anti-HIV activity induction includes the inhibition of HIV adsorption to and penetration into the cells, and inhibition of reverse transcriptase and protease. Limited digestion experiments demonstrated that a phenylpropenoid polymer, but not a sugar moiety, is important for anti-HIV activity. Dehydrogenation polymers of phenylpropenoids without carbohydrate showed higher anti-HIV activity, whereas phenylpropenoid monomers were inactive, suggesting the importance of highly polymerized structure. LCCs inhibited the plaque formation and RNA polymerase activity of influenza virus, and reduced the lethality of virus infection in mice. LCCs inhibited the plaque formation of HSV-1, and oral intake of LCC-vitamin C tablet reduced the symptoms in HSV-1-infected patients. LCCs stimulated the iodination of myeloperoxidase-positive human monocytes, neutrophiles and promyelocytic leukemia that may be involved in the bacterial killing mechanism. LCCs stimulated splenocyte proliferation, and showed both pro- and anti-inflammatory activity in activated macrophage. Preliminary DNA array analysis demonstrated the activation of the signal pathway of chemokine expression via TLR2. The molecular weight, solubility, sterilization method and association with other components during extraction step may produce diverse biological activity of LCCs. Broad and potent anti-viral activity and synergism with vitamin C suggest functionality of LCC as alternative medicine.

A preliminary approach to creating an overview of lactoferrin multi-functionality utilizing a text mining method.

Lactoferrin is a multi-functional metal-binding glycoprotein that exhibits many biological functions of interest to many researchers from the fields of clinical medicine, dentistry, pharmacology, veterinary medicine, nutrition and milk science. To date, a number of academic reports concerning the biological activities of lactoferrin have been published and are easily accessible through public data repositories. However, as the literature is expanding daily, this presents challenges in understanding the larger picture of lactoferrin function and mechanisms. In order to overcome the "analysis paralysis" associated with lactoferrin information, we attempted to apply a text mining method to the accumulated lactoferrin literature. To this end, we used the information extraction system GENPAC (provided by Nalapro Technologies Inc., Tokyo). This information extraction system uses natural language processing and text mining technology. This system analyzes the sentences and titles from abstracts stored in the PubMed database, and can automatically extract binary relations that consist of interactions between genes/proteins, chemicals and diseases/functions. We expect that such information visualization analysis will be useful in determining novel relationships among a multitude of lactoferrin functions and mechanisms. We have demonstrated the utilization of this method to find pathways of lactoferrin participation in neovascularization, Helicobacter pylori attack on gastric mucosa, atopic dermatitis and lipid metabolism.

Event ontology: a pathway-centric ontology for biological processes.

Event ontology is a new biomedical ontology developed to annotate pathway components in a pathway database. It organizes the concepts and terms of sub-pathways, pathways, biological phenomena, experimental conditions, medications, and external stimuli appearing in biological pathways (e.g. signal transduction, disease-, metabolic-, molecular interaction-, genetic interaction pathways, etc.). Concepts in the Event ontology are extracted manually from scientific literature. Each term has links to external databases such as Gene Ontology, Reactome, KEGG, BioCyc, and PubMed.