KEGG tools for classification and analysis of viral proteins.

The KEGG database and analysis tools (https://www.kegg.jp) have been developed mostly for understanding genes and genomes of cellular organisms. The KO (KEGG Orthology) dataset, which is a collection of functional orthologs, plays the role of linking genes in the genome to pathways and other molecular networks, enabling KEGG mapping to uncover hidden features in the genome. Although viruses were part of KEGG for some time, they were not fully integrated in the KEGG analysis tools, because the KO assignment rate is very low for virus genes. To supplement KOs a new dataset named virus ortholog clusters (VOCs) is computationally generated, covering 90% of viral proteins in KEGG. VOCs can be used, in place of KOs, for taxonomy mapping to uncover relationships of sequence similarity groups and taxonomic groups and for identifying conserved gene orders in virus genomes. Furthermore, selected VOCs are used to define tentative KOs for characterizing protein functions. Here an overview of KEGG tools is presented focusing on these extensions for viral protein analysis.

KEGG for taxonomy-based analysis of pathways and genomes.

KEGG (https://www.kegg.jp) is a manually curated database resource integrating various biological objects categorized into systems, genomic, chemical and health information. Each object (database entry) is identified by the KEGG identifier (kid), which generally takes the form of a prefix followed by a five-digit number, and can be retrieved by appending /entry/kid in the URL. The KEGG pathway map viewer, the Brite hierarchy viewer and the newly released KEGG genome browser can be launched by appending /pathway/kid, /brite/kid and /genome/kid, respectively, in the URL. Together with an improved annotation procedure for KO (KEGG Orthology) assignment, an increasing number of eukaryotic genomes have been included in KEGG for better representation of organisms in the taxonomic tree. Multiple taxonomy files are generated for classification of KEGG organisms and viruses, and the Brite hierarchy viewer is used for taxonomy mapping, a variant of Brite mapping in the new KEGG Mapper suite. The taxonomy mapping enables analysis of, for example, how functional links of genes in the pathway and physical links of genes on the chromosome are conserved among organism groups.

KEGG mapping tools for uncovering hidden features in biological data.

In contrast to artificial intelligence and machine learning approaches, KEGG (https://www.kegg.jp) has relied on human intelligence to develop "models" of biological systems, especially in the form of KEGG pathway maps that are manually created by capturing knowledge from published literature. The KEGG models can then be used in biological big data analysis, for example, for uncovering systemic functions of an organism hidden in its genome sequence through the simple procedure of KEGG mapping. Here we present an updated version of KEGG Mapper, a suite of KEGG mapping tools reported previously (Kanehisa and Sato, Protein Sci 2020; 29:28-35), together with the new versions of the KEGG pathway map viewer and the BRITE hierarchy viewer. Significant enhancements have been made for BRITE mapping, where the mapping result can be examined by manipulation of hierarchical trees, such as pruning and zooming. The tree manipulation feature has also been implemented in the taxonomy mapping tool for linking KO (KEGG Orthology) groups and modules to phenotypes.

KEGG as a reference resource for gene and protein annotation.

KEGG (http://www.kegg.jp/ or http://www.genome.jp/kegg/) is an integrated database resource for biological interpretation of genome sequences and other high-throughput data. Molecular functions of genes and proteins are associated with ortholog groups and stored in the KEGG Orthology (KO) database. The KEGG pathway maps, BRITE hierarchies and KEGG modules are developed as networks of KO nodes, representing high-level functions of the cell and the organism. Currently, more than 4000 complete genomes are annotated with KOs in the KEGG GENES database, which can be used as a reference data set for KO assignment and subsequent reconstruction of KEGG pathways and other molecular networks. As an annotation resource, the following improvements have been made. First, each KO record is re-examined and associated with protein sequence data used in experiments of functional characterization. Second, the GENES database now includes viruses, plasmids, and the addendum category for functionally characterized proteins that are not represented in complete genomes. Third, new automatic annotation servers, BlastKOALA and GhostKOALA, are made available utilizing the non-redundant pangenome data set generated from the GENES database. As a resource for translational bioinformatics, various data sets are created for antimicrobial resistance and drug interaction networks.

Data, information, knowledge and principle: back to metabolism in KEGG.

In the hierarchy of data, information and knowledge, computational methods play a major role in the initial processing of data to extract information, but they alone become less effective to compile knowledge from information. The Kyoto Encyclopedia of Genes and Genomes (KEGG) resource (http://www.kegg.jp/ or http://www.genome.jp/kegg/) has been developed as a reference knowledge base to assist this latter process. In particular, the KEGG pathway maps are widely used for biological interpretation of genome sequences and other high-throughput data. The link from genomes to pathways is made through the KEGG Orthology system, a collection of manually defined ortholog groups identified by K numbers. To better automate this interpretation process the KEGG modules defined by Boolean expressions of K numbers have been expanded and improved. Once genes in a genome are annotated with K numbers, the KEGG modules can be computationally evaluated revealing metabolic capacities and other phenotypic features. The reaction modules, which represent chemical units of reactions, have been used to analyze design principles of metabolic networks and also to improve the definition of K numbers and associated annotations. For translational bioinformatics, the KEGG MEDICUS resource has been developed by integrating drug labels (package inserts) used in society.

The effect of selective cyclooxygenase-2 inhibitor on human osteoclast precursors to influence osteoclastogenesis in vitro.

The inducible prostaglandin synthesis enzyme, cyclooxygenase-2 (COX-2), is involved in bone resorption and osteoclastogenesis, and acts indirectly through prostaglandin E2 (PG E2) produced by osteoblastic cells. This study was undertaken to investigate whether celecoxib (a selective COX-2 inhibitor) has a direct effect on human osteoclast precursors to influence osteoclastogenesis in vitro. Human peripheral blood mononuclear cells (PBMCs) were cultured on glass coverslips and dentine slices with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage colony stimulating factor (M-CSF). COX inhibitors including celecoxib were added to the cultures. Osteoclast formation was assessed as the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs), and the functional evidence of lacunar resorption pits on dentine slices was assessed. Celecoxib and indomethacin inhibited osteoclast formation and the extent of lacunar resorption in a dose-dependent manner, but the effect of indomethacin was less than that of celecoxib. Mofezolac affected neither the number of TRAP-positive MNCs nor the extent of lacunar resorption pits. These results indicate that celecoxib influences not only osteoclast formation through osteoblastic cells but also acts directly on circulating osteoclast precursors to influence human osteoclast differentiation. The effect of celecoxib on osteoclast precursors may be related to the COX-2 signal pathway.

[Bone disease with pain. Osteomyelitis in the long bone].

In the present time various antibiotics have been developed. But suppurative osteomyelitis has been very difficult to cure still up to now. If it fails to treat at the initial treatment, it recurs often. Many patients are annoyed by the recurrence. Moreover, increase of multiple resistance bacteria, opportunistic infection and traumatic osteomyelitis make them complex to treat. We have treated 256 osteomyelitis patients by debriding the infected area with closed irrigation before 1981. Then we have been treated 553 patients with Hyperbaric Oxygen Therapy (HBOT) . Include closed irrigation therapy, 95% of cases a good result occurred. The case that has fistula, sequestrum, foreign material or vast range of osteonecrosis is difficult to calm completely by only HBOT. In such cases, they should be taken curettage and closed irrigation.

A global representation of the carbohydrate structures: a tool for the analysis of glycan.

Glycan resources have been developed of late, such as carbohydrate databases, analysis tools, and algorithms for analysis of carbohydrate features. With this background, bioinformatics approaches to carbohydrate research have recently begun using a large amount of protein and carbohydrate data. This paper introduces one of these projects that elucidates the range of carbohydrate structures. In this study, the variety of carbohydrate structures have been enumerated in a global tree structure called variation trees, using the KEGG GLYCAN database, which is a public-domain glycan resource for bioinformatics analysis. Additionally, a glycosyltransferase mapping list of glycosyltransferases and their catalyzing glycosidic linkages was constructed. From this, we present the composite structure map (CSM), which is a structural variation map integrating its variation trees and glycosyltransferase map list. CSM is able to display, for example, expression data of glycosyltransferases in a compact manner, illustrating its versatility as a new bioinformatics resource and tool capable of analyzing carbohydrate structures on a global scale. These resources are available at http://www.genome.jp/kegg/glycan/.

Infliximab acts directly on human osteoclast precursors and enhances osteoclast formation induced by receptor activator of nuclear factor kappaB ligand in vitro.

Infliximab is known to protect against the development of joint destruction. In the present study, we sought to determine whether Infliximab acts directly on human osteoclast precursors and influences monocyte-osteoclast differentiation induced by receptor activator of nuclear factor kappaB ligand (RANKL) in vitro. Peripheral blood mononuclear cells (PBMCs) isolated from rheumatoid arthritis (RA) patients and normal controls were cultured in the presence of RANKL and macrophage colony stimulating factor. Infliximab, antihuman tumor necrosis factor alpha (TNFalpha), antihuman TNF soluble receptor p55 (TNFR p55), and antihuman TNF soluble receptor p75 (TNFR p75) antibodies were added. Osteoclast formation was determined by assessing the number of tartrate-resistant acid phosphatase (TRAP) staining cells and the extent of lacunar resorption. Addition of Infliximab resulted in a marked increase in the number of TRAP-positive multinucleated cells (TRAP(+) MNCs) and in the extent of lacunar resorption compared with the control cultures. Antihuman TNFalpha antibody showed the same effect; however, the addition of neither TNFR p55 nor TNFR p75 antibody affected the extent of TRAP(+) MNCs and lacunar resorption. Our results suggest that infliximab acts directly on early osteoclast precursors, and stimulates osteoclast formation and lacunar resorption induced by RANKL in vitro.