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The Reactome Knowledgebase (https://reactome.org), an Elixir and GCBR core biological data resource, provides manually curated molecular details of a broad range of normal and disease-related biological processes. Processes are annotated as an ordered network of molecular transformations in a single consistent data model. Reactome thus functions both as a digital archive of manually curated human biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. Here we review progress towards annotation of the entire human proteome, targeted annotation of disease-causing genetic variants of proteins and of small-molecule drugs in a pathway context, and towards supporting explicit annotation of cell- and tissue-specific pathways. Finally, we briefly discuss issues involved in making Reactome more fully interoperable with other related resources such as the Gene Ontology and maintaining the resulting community resource network., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose: The theft of drugs from healthcare facilities, also known as drug diversion, occurs frequently but is often undetected. This paper describes a research study to develop and test novel drug diversion detection methods. Improved diversion detection and reduction in diversion improves patient safety, limits harm to the person diverting, reduces the public health impact of substance use disorder, and mitigates significant liability risk to pharmacists and their organizations., Methods: Ten acute care inpatient hospitals across 4 independent health systems extracted 2 datasets from various health information technology systems. Both datasets were consolidated, normalized, classified, and sampled to provide a harmonious dataset for analysis. Supervised machine learning methods were iteratively used on the initial sample dataset to train algorithms to classify medication movement transactions as involving a low or high risk of diversion. Thereafter, the resulting machine learning model classified the risk of diversion in a historical dataset capturing 8 to 24 months of history that included 27.9 million medication movement transactions by 19,037 nursing, 1,047 pharmacy, and 712 anesthesia clinicians and that included 22 known, blinded diversion cases to measure when the model would have detected the diversion compared to when the diversion was actually detected by existing methods., Results: The machine learning model had 96.3% accuracy, 95.9% specificity, and 96.6% sensitivity in detecting transactions involving a high risk of diversion using the initial sample dataset. In subsequent testing using the much larger historical dataset, the analytics detected known diversion cases (n = 22) in blinded data faster than existing detection methods (a mean of 160 days and a median of 74 days faster; range, 7-579 days faster)., Conclusion: The study showed that (1) consolidated datasets and (2) supervised machine learning can detect known diversion cases faster than existing detection methods. Users of the technology also noted improved investigation efficiency., (© American Society of Health-System Pharmacists 2022.)

The Reactome Knowledgebase (https://reactome.org), an Elixir core resource, provides manually curated molecular details across a broad range of physiological and pathological biological processes in humans, including both hereditary and acquired disease processes. The processes are annotated as an ordered network of molecular transformations in a single consistent data model. Reactome thus functions both as a digital archive of manually curated human biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. Recent curation work has expanded our annotations of normal and disease-associated signaling processes and of the drugs that target them, in particular infections caused by the SARS-CoV-1 and SARS-CoV-2 coronaviruses and the host response to infection. New tools support better simultaneous analysis of high-throughput data from multiple sources and the placement of understudied ('dark') proteins from analyzed datasets in the context of Reactome's manually curated pathways., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Reactome Knowledgebase (https://reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations in a single consistent data model, an extended version of a classic metabolic map. Reactome functions both as an archive of biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. To extend our ability to annotate human disease processes, we have implemented a new drug class and have used it initially to annotate drugs relevant to cardiovascular disease. Our annotation model depends on external domain experts to identify new areas for annotation and to review new content. New web pages facilitate recruitment of community experts and allow those who have contributed to Reactome to identify their contributions and link them to their ORCID records. To improve visualization of our content, we have implemented a new tool to automatically lay out the components of individual reactions with multiple options for downloading the reaction diagrams and associated data, and a new display of our event hierarchy that will facilitate visual interpretation of pathway analysis results., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The Reactome Knowledgebase (https://reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism, and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression profiles or somatic mutation catalogues from tumor cells. To support the continued brisk growth in the size and complexity of Reactome, we have implemented a graph database, improved performance of data analysis tools, and designed new data structures and strategies to boost diagram viewer performance. To make our website more accessible to human users, we have improved pathway display and navigation by implementing interactive Enhanced High Level Diagrams (EHLDs) with an associated icon library, and subpathway highlighting and zooming, in a simplified and reorganized web site with adaptive design. To encourage re-use of our content, we have enabled export of pathway diagrams as 'PowerPoint' files., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Motivation: Reactome is a free, open-source, open-data, curated and peer-reviewed knowledge base of biomolecular pathways. Pathways are arranged in a hierarchical structure that largely corresponds to the GO biological process hierarchy, allowing the user to navigate from high level concepts like immune system to detailed pathway diagrams showing biomolecular events like membrane transport or phosphorylation. Here, we present new developments in the Reactome visualization system that facilitate navigation through the pathway hierarchy and enable efficient reuse of Reactome visualizations for users' own research presentations and publications., Results: For the higher levels of the hierarchy, Reactome now provides scalable, interactive textbook-style diagrams in SVG format, which are also freely downloadable and editable. Repeated diagram elements like 'mitochondrion' or 'receptor' are available as a library of graphic elements. Detailed lower-level diagrams are now downloadable in editable PPTX format as sets of interconnected objects., Availability and Implementation: http://reactome.org., Contact: fabregat@ebi.ac.uk or hhe@ebi.ac.uk., (© The Author 2017. Published by Oxford University Press.)

The Reactome Knowledgebase (www.reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression pattern surveys or somatic mutation catalogues from tumour cells. Over the last two years we redeveloped major components of the Reactome web interface to improve usability, responsiveness and data visualization. A new pathway diagram viewer provides a faster, clearer interface and smooth zooming from the entire reaction network to the details of individual reactions. Tool performance for analysis of user datasets has been substantially improved, now generating detailed results for genome-wide expression datasets within seconds. The analysis module can now be accessed through a RESTFul interface, facilitating its inclusion in third party applications. A new overview module allows the visualization of analysis results on a genome-wide Reactome pathway hierarchy using a single screen page. The search interface now provides auto-completion as well as a faceted search to narrow result lists efficiently., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Reactome (http://www.reactome.org) is a manually curated open-source open-data resource of human pathways and reactions. The current version 46 describes 7088 human proteins (34% of the predicted human proteome), participating in 6744 reactions based on data extracted from 15 107 research publications with PubMed links. The Reactome Web site and analysis tool set have been completely redesigned to increase speed, flexibility and user friendliness. The data model has been extended to support annotation of disease processes due to infectious agents and to mutation.

Reactome (http://www.reactome.org) is a collaboration among groups at the Ontario Institute for Cancer Research, Cold Spring Harbor Laboratory, New York University School of Medicine and The European Bioinformatics Institute, to develop an open source curated bioinformatics database of human pathways and reactions. Recently, we developed a new web site with improved tools for pathway browsing and data analysis. The Pathway Browser is an Systems Biology Graphical Notation (SBGN)-based visualization system that supports zooming, scrolling and event highlighting. It exploits PSIQUIC web services to overlay our curated pathways with molecular interaction data from the Reactome Functional Interaction Network and external interaction databases such as IntAct, BioGRID, ChEMBL, iRefIndex, MINT and STRING. Our Pathway and Expression Analysis tools enable ID mapping, pathway assignment and overrepresentation analysis of user-supplied data sets. To support pathway annotation and analysis in other species, we continue to make orthology-based inferences of pathways in non-human species, applying Ensembl Compara to identify orthologs of curated human proteins in each of 20 other species. The resulting inferred pathway sets can be browsed and analyzed with our Species Comparison tool. Collaborations are also underway to create manually curated data sets on the Reactome framework for chicken, Drosophila and rice.

A dual-task method was employed to assess the effects of backpack carriage weight on 20 young adults' balance and rapid decision making. During two separate sessions, participants' balance was perturbed during 18, 60-second trials by altering visual and/or somatosensory conditions. Concurrent balance control and auditory choice-reaction task performance were assessed. Each participant wore an all-purpose, lightweight, individual, carrying equipment (ALICE) backpack containing a load equal to 30% of his/her body weight throughout one session. Within-subjects analyses revealed that carriage load disrupted balance control and degraded cognitive processes but only on trials that required executive, higher-level, mental processing. The magnitude of the effects of the backpack load on balance and cognitive performance was similar over 22 minutes of testing. Carriage load degrades both balance control and situational awareness of ROTC cadets.

Reactome (http://www.reactome.org) is an expert-authored, peer-reviewed knowledgebase of human reactions and pathways that functions as a data mining resource and electronic textbook. Its current release includes 2975 human proteins, 2907 reactions and 4455 literature citations. A new entity-level pathway viewer and improved search and data mining tools facilitate searching and visualizing pathway data and the analysis of user-supplied high-throughput data sets. Reactome has increased its utility to the model organism communities with improved orthology prediction methods allowing pathway inference for 22 species and through collaborations to create manually curated Reactome pathway datasets for species including Arabidopsis, Oryza sativa (rice), Drosophila and Gallus gallus (chicken). Reactome's data content and software can all be freely used and redistributed under open source terms.

Although corticosteroids are recommended as adjunctive therapy for tuberculous meningitis, the mechanism underlying their beneficial effect is poorly understood. In this study, human microglia and astrocytes were infected with Mycobacterium tuberculosis H37Rv, and cytokine and chemokine expression was examined with and without dexamethasone treatment. Microglia were the principal cells infected by tubercle bacilli, which elicited robust amounts of several cytokines and chemokines. Treatment with dexamethasone markedly suppressed production of these mediators. The results of this study support the concept that microglia play an important role in neuropathogenesis of tuberculosis and that dexamethasone could operate via modulation of the production of proinflammatory cytokines and chemokines by these brain macrophages.

To identify genes involved in Arabidopsis thaliana petal and stamen organogenesis, we used a gene trap approach to examine the patterns of reporter expression at each stage of flower development of 1765 gene trap lines. In 80 lines, the reporter gene showed petal- and/or stamen-specific expression or lack of expression, or expression in distinct patterns within the petals and/or the stamens, including distinct suborgan domains of expression, such as tissue-specific lines marking epidermis and vasculature, as well as lines demarcating the proximodistal or abaxial/adaxial axes of the organs. Interestingly, reporter gene expression was typically restricted along the proximodistal axis of petals and stamens, indicating the importance of this developmental axis in patterning of gene expression domains in these organs. We identified novel domains of gene expression along the axis marking the midregion of the petals and apical and basal parts of the anthers. Most of the genes tagged in these 80 lines were identified, and their possible functions in petal and/or stamen differentiation are discussed. We also scored the floral phenotypes of the 1765 gene trap lines and recovered two mutants affecting previously uncharacterized genes. In addition to revealing common domains of gene expression, the gene trap lines reported here provide both useful markers and valuable starting points for reverse genetic analyses of the differentiation pathways in petal and stamen development.

The argasid tick Ornithodoros coriaceus (Koch) is the only confirmed vector of epizootic bovine abortion (EBA) in the United States. The disease and its tick vector have historically been reported in the foothills of the Sierra Nevada Mountains and coast ranges of California. In the past two decades, the range of EBA has apparently expanded into southern Oregon and northern Nevada. Possible explanations for this expansion include 1) increased recognition and reporting of EBA in these regions; 2) widespread movement of tick-infested and EBA-infected hosts with subsequent colonization of these regions by infected ticks; and 3) widespread movement of the EBA agent, independent of tick movements, into extant tick populations in these new regions. The current study was performed to evaluate these hypotheses by examining patterns of variability in a 420-bp segment of the 16S mitochondrial rDNA gene sequence among 210 O. coriaceus individuals from 14 sites in California, Oregon, and Nevada. Sixty-three unique haplotypes were identified in the ticks tested, with 84% of the sequence variation attributable to among-population variation and 16% to within-population variation. A majority of the haplotypes were unique to their particular collection site, whereas only four collection sites shared haplotypes. Overall, very little evidence of gene flow among tick populations was detected, making it unlikely that widespread tick movement had introduced O. coriaceus and the EBA agent into new regions.

Microsatellites, which have rapidly become the preferred markers in population genetics, reliably assign individual chinook salmon to the winter, fall, late-fall, or spring chinook runs in the Sacramento River in California's Central Valley (Banks et al. 2000. Can. J. Fish. Aquat. Sci. 57:915-927). A substantial proportion of this discriminatory power comes from Ots-2, a simple CA repeat, which is expected to evolve rapidly under the stepwise mutation model. We have sequenced a 300-bp region around this locus and typed 668 microsatellite-flanking sequence haplotypes to explore further the basis of this microsatellite divergence. Three sites of nucleotide polymorphism in the Ots-2 flanking sequence define five haplotypes that are shared by the Californian and Canadian populations. The Ots-2 microsatellite alleles are nonrandomly distributed among these five haplotypes in a pattern of gametic disequilibrium that is also shared among populations. Divergence between the winter run and other Central Valley stocks appears to be caused by a combination of surprisingly static evolution at Ots-2 within a context of more rapidly changing haplotype frequencies.

Data from 1238 fishes from 19 sturgeon species and 1 paddlefish were used to analyze heteroplasmy in sturgeon. Lengths of central repeat units ranged from 74 to 83 bp among sturgeon species. No repeat sequence was found in the paddlefish, Polyodon spathula. A general feature of the repeat units was the presence of termination associated sequence (TAS) motifs. About 50% of 138 interspecific mutations observed among the D-loop sequences are located 10 bp down- and upstream from these TAS motifs. Interestingly, most homoplasmic species showed deletions upstream to the TAS motifs, whereas deletions downstream to the TAS motifs observed in two species do not seem to preclude heteroplasmy. Calculations of secondary structures and thermal stabilities of repeat units showed DeltaG values for all heteroplasmic species to be <-8 and for most homoplasmic species DeltaG value to be >-8. Most heteroplasmic fishes had two and/or three repeat units. No homoplasmic sturgeon with >2 repeat units were observed. Molecular phylogeny based on the entire cytochrome b showed that heteroplasmy probably resulted from a single evolutionary event. Our data demonstrate that heteroplasmy is present in most sturgeon species and suggest that the thermal stability of the secondary structure of the repeat unit in combination with mutations downstream of the TAS sequences influences heteroplasmy.

Two distinct GH-binding proteins (GHBP) are present in circulation in the human. The major GHBP (high affinity GHBP) is homologous to the extracellular portion of the GH receptor and the concentration of this protein in circulation may reflect the status of the GH receptor in the tissues. To gain information about the concentration of GHBPs in children with insulin-dependent diabetes mellitus (IDDM), we measured GHBP in the serum of 46 children with IDDM and compared it to that in 53 healthy control subjects matched for age and sexual maturity. The total GHBP concentration in the group of pubertal and postpubertal IDDM patients was lower than that measured in the control group (mean +/- SEM: 7.8 +/- 0.4 vs. 9.0 +/- 0.5%, P = 0.05). The diabetic children in stages II to IV of puberty had a lower GHBP level compared to their healthy controls (7.6 +/- 0.4 vs. 9.1 +/- 0.5%, P = 0.02), whereas the difference between the diabetic and control group of postpubertal children was not statistically different (8.3 +/- 0.7 vs. 9.7 +/- 0.7%, P = 0.1). In a randomly selected subset of eight patients and eight controls, the concentration of the individual GHBPs (i.e. high affinity and low affinity (GHBP) was estimated by gel chromatography. There was no difference in the low affinity GHBP between the two groups (9.9 +/- 0.6% vs. 9.9 +/- 0.4%), but the high affinity GHBP was less in the diabetic group than in the control group (10.5 +/- 0.9 vs. 15.6 +/- 1.0%, P less than 0.01). In the diabetic group, there was no correlation between the GHBP levels and age, duration of diabetes, hemoglobin A1, or insulin dose. We conclude that in IDDM there is less of the high affinity GHBP, suggesting a decrease in the number of GH receptors in these patients. This decrease may contribute to GH resistance manifesting as decreased insulin-like growth factor-I levels despite high GH levels in patients with IDDM.

Hymenoptera are characterized by a haplo-diploid mechanism of sex determination. Females are diploid and males are haploid. However, in many species diploid males may occur if individuals are homozygous at a sex determining locus. Diploid males were found in three out of four populations (nest aggregations) of the primitively eusocial, halictine bee Lasioglossum zephyrum for which samples of males were examined electrophoretically. The frequency of diploid males was greater in a small, geographically isolated population (the "Robinson" nest aggregation) than in a large population that had nearby neighboring populations (the "Salmon Creek A" nest aggregation). In addition, the proportion of polymorphic loci was lower in the Robinson nest aggregation suggesting that a bottleneck event or loss of alleles due to small population size occurred in the Robinson population that involved a loss in the number of alleles at the sex determining locus., (© 1990 The Society for the Study of Evolution.)

The results of more than 300 pairwise examinations of biochemical loci for joint segregation in brook trout (Salvelinus fontinalis) and in the hybridized genome of lake trout (S. namaycush) X brook trout are summarized. Nineteen loci have been assigned to tahe following eight linkage groupings on the basis of nonrandom assortment, including cases of both classical linkage and pseudolinkage: ODH with PMI with PGI-3, PGI-2 with SDH, ADA-1 with AGP-2, AAT-1(1,2) with AGP-1 with MDH-1, MDH-3 with MDH-4, LDH-3 with LDH-4, IDH-3 with ME-2 and GUS with CPK-1. Pseudolinkage (an excess of nonparental progeny types) was observed only for male testcross parents. The results suggest that this phenomenon involves homeologous chromosome arms as evidenced by the de novo association of presumed duplicate loci in each case. Classical linkage has not been found for the five pairs of duplicate loci examined in Salvelinus, suggesting that not all of the eight metacentrics in the haploid complement involve fusions of homeologous chromosomes. Females consistently showed a greater degree of recombination.

The recently evolved autotetraploid frog, Hyla versicolor , was examined electrophoretically for evidence of genomic restructuring leading to diploidization. Loci were tested against the progeny ratios expected if inheritance was disomic vs. tetrasomic. Two loci (Mpi and Sod-2) appeared to be inherited tetrasomically, one (Mdh-2) appeared to be inherited disomically, and one (Tpi) appeared to be inherited disomically in one family and tetrasomically in another family, when tested conventionally against 1:2:1 and 1:4:1 segregation ratios. The minimum number of progeny required for this type of analysis for codominant alleles is shown to be 92. Progeny resulting from double reduction were observed, and the occurrence of a null allele class at Mpi was noted. A reexamination of expected progeny ratios in tetraploid organisms reveals that tetrasomic inheritance patterns cannot be predicted without adequate knowledge of the amount of crossing-over, the proportion of tetravalents vs. random bivalents that are formed, and the ratio and types of centromere segregation (alternate and adjacent) that occur from tetravalents in the species being studied. However, disomic inheritance can be unambiguously confirmed only by the production of all heteroallelic gametes from homobivalent, symmetrically heterozygous individuals. In addition, a method is described for estimating genecentromere distances using the ratio of progeny genotypes in certain crosses in tetraploid species.

Fifteen classical linkage groups were identified in two salmonid species (Salmo trutta and Salmo gairdneri) and three fertile, interspecific hybrids (S. gairdneri X Salmo clarki, Salvelinus fontinalis X Salvelinus namaycush and S. fontinalis X Salvelinus alpinus) by backcrossing multiply heterozygous individuals. These linkage relationships of electrophoretically detected, protein coding loci were highly conserved among species. The loci encoding the enzymes appeared to be randomly distributed among the salmonid chromosomes. Recombination frequencies were generally greater in females than in males. In males, certain linkage groups were pseudolinked with other linkage groups, presumably because of facultative multivalent pairing and directed disjunction of chromosomes. Five such pseudolinkage groups were identified and they also appeared to be common among species and hybrids. Duplicate loci were never classically linked with each other, although some exhibited pseudolinkage and some showed evidence of exchanging alleles. Gene-centromere recombination frequencies estimated from genotypic distributions of gynogenetic offspring were consistent with map locations inferred from female intergenic recombination frequencies. These linkage relationships support the contention that all extant salmonids arose from a common tetraploid progenitor and that this progenitor may have been a segmental allotetraploid.