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author:("Ohta, tomoto")
1.  A method for integrating and ranking the evidence for biochemical pathways by mining reactions from text 
Bioinformatics  2013;29(13):i44-i52.
Motivation: To create, verify and maintain pathway models, curators must discover and assess knowledge distributed over the vast body of biological literature. Methods supporting these tasks must understand both the pathway model representations and the natural language in the literature. These methods should identify and order documents by relevance to any given pathway reaction. No existing system has addressed all aspects of this challenge.
Method: We present novel methods for associating pathway model reactions with relevant publications. Our approach extracts the reactions directly from the models and then turns them into queries for three text mining-based MEDLINE literature search systems. These queries are executed, and the resulting documents are combined and ranked according to their relevance to the reactions of interest. We manually annotate document-reaction pairs with the relevance of the document to the reaction and use this annotation to study several ranking methods, using various heuristic and machine-learning approaches.
Results: Our evaluation shows that the annotated document-reaction pairs can be used to create a rule-based document ranking system, and that machine learning can be used to rank documents by their relevance to pathway reactions. We find that a Support Vector Machine-based system outperforms several baselines and matches the performance of the rule-based system. The success of the query extraction and ranking methods are used to update our existing pathway search system, PathText.
Availability: An online demonstration of PathText 2 and the annotated corpus are available for research purposes at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3694679  PMID: 23813008
2.  Wide coverage biomedical event extraction using multiple partially overlapping corpora 
BMC Bioinformatics  2013;14:175.
Biomedical events are key to understanding physiological processes and disease, and wide coverage extraction is required for comprehensive automatic analysis of statements describing biomedical systems in the literature. In turn, the training and evaluation of extraction methods requires manually annotated corpora. However, as manual annotation is time-consuming and expensive, any single event-annotated corpus can only cover a limited number of semantic types. Although combined use of several such corpora could potentially allow an extraction system to achieve broad semantic coverage, there has been little research into learning from multiple corpora with partially overlapping semantic annotation scopes.
We propose a method for learning from multiple corpora with partial semantic annotation overlap, and implement this method to improve our existing event extraction system, EventMine. An evaluation using seven event annotated corpora, including 65 event types in total, shows that learning from overlapping corpora can produce a single, corpus-independent, wide coverage extraction system that outperforms systems trained on single corpora and exceeds previously reported results on two established event extraction tasks from the BioNLP Shared Task 2011.
The proposed method allows the training of a wide-coverage, state-of-the-art event extraction system from multiple corpora with partial semantic annotation overlap. The resulting single model makes broad-coverage extraction straightforward in practice by removing the need to either select a subset of compatible corpora or semantic types, or to merge results from several models trained on different individual corpora. Multi-corpus learning also allows annotation efforts to focus on covering additional semantic types, rather than aiming for exhaustive coverage in any single annotation effort, or extending the coverage of semantic types annotated in existing corpora.
PMCID: PMC3680179  PMID: 23731785
3.  Characterization of Magnaporthe oryzae Chrysovirus 1 Structural Proteins and Their Expression in Saccharomyces cerevisiae 
Journal of Virology  2012;86(15):8287-8295.
Magnaporthe oryzae chrysovirus 1 (MoCV1), which is associated with an impaired growth phenotype of its host fungus, harbors four major proteins: P130 (130 kDa), P70 (70 kDa), P65 (65 kDa), and P58 (58 kDa). N-terminal sequence analysis of each protein revealed that P130 was encoded by double-stranded RNA1 (dsRNA1) (open reading frame 1 [ORF1] 1,127 amino acids [aa]), P70 by dsRNA4 (ORF4; 812 aa), and P58 by dsRNA3 (ORF3; 799 aa), although the molecular masses of P58 and P70 were significantly smaller than those deduced for ORF3 and ORF4, respectively. P65 was a degraded form of P70. Full-size proteins of ORF3 (84 kDa) and ORF4 (85 kDa) were produced in Escherichia coli. Antisera against these recombinant proteins detected full-size proteins encoded by ORF3 and ORF4 in mycelia cultured for 9, 15, and 28 days, and the antisera also detected smaller degraded proteins, namely, P58, P70, and P65, in mycelia cultured for 28 days. These full-size proteins and P58 and P70 were also components of viral particles, indicating that MoCV1 particles might have at least two forms during vegetative growth of the host fungus. Expression of the ORF4 protein in Saccharomyces cerevisiae resulted in cytological changes, with a large central vacuole associated with these growth defects. MoCV1 has five dsRNA segments, as do two Fusarium graminearum viruses (FgV-ch9 and FgV2), and forms a separate clade with FgV-ch9, FgV2, Aspergillus mycovirus 1816 (AsV1816), and Agaricus bisporus virus 1 (AbV1) in the Chrysoviridae family on the basis of their RdRp protein sequences.
PMCID: PMC3421670  PMID: 22623797
4.  BioCause: Annotating and analysing causality in the biomedical domain 
BMC Bioinformatics  2013;14:2.
Biomedical corpora annotated with event-level information represent an important resource for domain-specific information extraction (IE) systems. However, bio-event annotation alone cannot cater for all the needs of biologists. Unlike work on relation and event extraction, most of which focusses on specific events and named entities, we aim to build a comprehensive resource, covering all statements of causal association present in discourse. Causality lies at the heart of biomedical knowledge, such as diagnosis, pathology or systems biology, and, thus, automatic causality recognition can greatly reduce the human workload by suggesting possible causal connections and aiding in the curation of pathway models. A biomedical text corpus annotated with such relations is, hence, crucial for developing and evaluating biomedical text mining.
We have defined an annotation scheme for enriching biomedical domain corpora with causality relations. This schema has subsequently been used to annotate 851 causal relations to form BioCause, a collection of 19 open-access full-text biomedical journal articles belonging to the subdomain of infectious diseases. These documents have been pre-annotated with named entity and event information in the context of previous shared tasks. We report an inter-annotator agreement rate of over 60% for triggers and of over 80% for arguments using an exact match constraint. These increase significantly using a relaxed match setting. Moreover, we analyse and describe the causality relations in BioCause from various points of view. This information can then be leveraged for the training of automatic causality detection systems.
Augmenting named entity and event annotations with information about causal discourse relations could benefit the development of more sophisticated IE systems. These will further influence the development of multiple tasks, such as enabling textual inference to detect entailments, discovering new facts and providing new hypotheses for experimental work.
PMCID: PMC3621543  PMID: 23323613
5.  Event extraction across multiple levels of biological organization 
Bioinformatics  2012;28(18):i575-i581.
Motivation: Event extraction using expressive structured representations has been a significant focus of recent efforts in biomedical information extraction. However, event extraction resources and methods have so far focused almost exclusively on molecular-level entities and processes, limiting their applicability.
Results: We extend the event extraction approach to biomedical information extraction to encompass all levels of biological organization from the molecular to the whole organism. We present the ontological foundations, target types and guidelines for entity and event annotation and introduce the new multi-level event extraction (MLEE) corpus, manually annotated using a structured representation for event extraction. We further adapt and evaluate named entity and event extraction methods for the new task, demonstrating that both can be achieved with performance broadly comparable with that for established molecular entity and event extraction tasks.
Availability: The resources and methods introduced in this study are available from
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3436834  PMID: 22962484
6.  Overview of the ID, EPI and REL tasks of BioNLP Shared Task 2011 
BMC Bioinformatics  2012;13(Suppl 11):S2.
We present the preparation, resources, results and analysis of three tasks of the BioNLP Shared Task 2011: the main tasks on Infectious Diseases (ID) and Epigenetics and Post-translational Modifications (EPI), and the supporting task on Entity Relations (REL). The two main tasks represent extensions of the event extraction model introduced in the BioNLP Shared Task 2009 (ST'09) to two new areas of biomedical scientific literature, each motivated by the needs of specific biocuration tasks. The ID task concerns the molecular mechanisms of infection, virulence and resistance, focusing in particular on the functions of a class of signaling systems that are ubiquitous in bacteria. The EPI task is dedicated to the extraction of statements regarding chemical modifications of DNA and proteins, with particular emphasis on changes relating to the epigenetic control of gene expression. By contrast to these two application-oriented main tasks, the REL task seeks to support extraction in general by separating challenges relating to part-of relations into a subproblem that can be addressed by independent systems. Seven groups participated in each of the two main tasks and four groups in the supporting task. The participating systems indicated advances in the capability of event extraction methods and demonstrated generalization in many aspects: from abstracts to full texts, from previously considered subdomains to new ones, and from the ST'09 extraction targets to other entities and events. The highest performance achieved in the supporting task REL, 58% F-score, is broadly comparable with levels reported for other relation extraction tasks. For the ID task, the highest-performing system achieved 56% F-score, comparable to the state-of-the-art performance at the established ST'09 task. In the EPI task, the best result was 53% F-score for the full set of extraction targets and 69% F-score for a reduced set of core extraction targets, approaching a level of performance sufficient for user-facing applications. In this study, we extend on previously reported results and perform further analyses of the outputs of the participating systems. We place specific emphasis on aspects of system performance relating to real-world applicability, considering alternate evaluation metrics and performing additional manual analysis of system outputs. We further demonstrate that the strengths of extraction systems can be combined to improve on the performance achieved by any system in isolation. The manually annotated corpora, supporting resources, and evaluation tools for all tasks are available from and the tasks continue as open challenges for all interested parties.
PMCID: PMC3384257  PMID: 22759456
8.  Near-Neutrality, Robustness, and Epigenetics 
Genome Biology and Evolution  2011;3:1034-1038.
The nearly neutral theory emphasizes the interaction of drift and weak selection in evolution. With progress of genome biology, the applicability of the nearly neutral theory has expanded. The genome-wide analyses of synonymous and nonsynonymous substitutions at protein-coding regions show prevalence of very weak selection. Many patterns of evolution of gene regulation are also in agreement with the nearly neutral prediction. Our consideration on near-neutrality expands in relation to the progress on molecular understanding of robustness and epigenetics. Both are bridges to link genotypes with phenotypes and important for understanding how weak selection and drift interact in the evolution of complex systems.
PMCID: PMC3227401  PMID: 21979156
near-neutrality; robustness; epigenetics
9.  Ontology design patterns to disambiguate relations between genes and gene products in GENIA 
Journal of Biomedical Semantics  2011;2(Suppl 5):S1.
Annotated reference corpora play an important role in biomedical information extraction. A semantic annotation of the natural language texts in these reference corpora using formal ontologies is challenging due to the inherent ambiguity of natural language. The provision of formal definitions and axioms for semantic annotations offers the means for ensuring consistency as well as enables the development of verifiable annotation guidelines. Consistent semantic annotations facilitate the automatic discovery of new information through deductive inferences.
We provide a formal characterization of the relations used in the recent GENIA corpus annotations. For this purpose, we both select existing axiom systems based on the desired properties of the relations within the domain and develop new axioms for several relations. To apply this ontology of relations to the semantic annotation of text corpora, we implement two ontology design patterns. In addition, we provide a software application to convert annotated GENIA abstracts into OWL ontologies by combining both the ontology of relations and the design patterns. As a result, the GENIA abstracts become available as OWL ontologies and are amenable for automated verification, deductive inferences and other knowledge-based applications.
Documentation, implementation and examples are available from
PMCID: PMC3239299  PMID: 22166341
10.  Event extraction for DNA methylation 
Journal of Biomedical Semantics  2011;2(Suppl 5):S2.
We consider the task of automatically extracting DNA methylation events from the biomedical domain literature. DNA methylation is a key mechanism of epigenetic control of gene expression and implicated in many cancers, but there has been little study of automatic information extraction for DNA methylation.
We present an annotation scheme for DNA methylation following the representation of the BioNLP shared task on event extraction, select a set of 200 abstracts including a representative sample of all PubMed citations relevant to DNA methylation, and introduce manual annotation for this corpus marking nearly 3000 gene/protein mentions and 1500 DNA methylation and demethylation events. We retrain a state-of-the-art event extraction system on the corpus and find that automatic extraction of DNA methylation events, the methylated genes, and their methylation sites can be performed at 78% precision and 76% recall.
Our results demonstrate that reliable extraction methods for DNA methylation events can be created through corpus annotation and straightforward retraining of a general event extraction system. The introduced resources are freely available for use in research from the GENIA project homepage
PMCID: PMC3239302  PMID: 22166595
11.  An analysis of gene/protein associations at PubMed scale 
Journal of Biomedical Semantics  2011;2(Suppl 5):S5.
Event extraction following the GENIA Event corpus and BioNLP shared task models has been a considerable focus of recent work in biomedical information extraction. This work includes efforts applying event extraction methods to the entire PubMed literature database, far beyond the narrow subdomains of biomedicine for which annotated resources for extraction method development are available.
In the present study, our aim is to estimate the coverage of all statements of gene/protein associations in PubMed that existing resources for event extraction can provide. We base our analysis on a recently released corpus automatically annotated for gene/protein entities and syntactic analyses covering the entire PubMed, and use named entity co-occurrence, shortest dependency paths and an unlexicalized classifier to identify likely statements of gene/protein associations. A set of high-frequency/high-likelihood association statements are then manually analyzed with reference to the GENIA ontology.
We present a first estimate of the overall coverage of gene/protein associations provided by existing resources for event extraction. Our results suggest that for event-type associations this coverage may be over 90%. We also identify several biologically significant associations of genes and proteins that are not addressed by these resources, suggesting directions for further extension of extraction coverage.
PMCID: PMC3239305  PMID: 22166173
12.  Linguistic scope-based and biological event-based speculation and negation annotations in the BioScope and Genia Event corpora 
Journal of Biomedical Semantics  2011;2(Suppl 5):S8.
The treatment of negation and hedging in natural language processing has received much interest recently, especially in the biomedical domain. However, open access corpora annotated for negation and/or speculation are hardly available for training and testing applications, and even if they are, they sometimes follow different design principles. In this paper, the annotation principles of the two largest corpora containing annotation for negation and speculation – BioScope and Genia Event – are compared. BioScope marks linguistic cues and their scopes for negation and hedging while in Genia biological events are marked for uncertainty and/or negation.
Differences among the annotations of the two corpora are thematically categorized and the frequency of each category is estimated. We found that the largest amount of differences is due to the issue that scopes – which cover text spans – deal with the key events and each argument (including events within events) of these events is under the scope as well. In contrast, Genia deals with the modality of events within events independently.
The analysis of multiple layers of annotation (linguistic scopes and biological events) showed that the detection of negation/hedge keywords and their scopes can contribute to determining the modality of key events (denoted by the main predicate). On the other hand, for the detection of the negation and speculation status of events within events, additional syntax-based rules investigating the dependency path between the modality cue and the event cue have to be employed.
PMCID: PMC3239308  PMID: 22166355
13.  Gene Conversion and Evolution of Gene Families: An Overview  
Genes  2010;1(3):349-356.
The importance of gene conversion for the evolution of gene families is reviewed. Four problems concerning gene conversion, i.e., concerted evolution, generation of useful variation, deleterious effects, and relation to neofunctionalization, are discussed by surveying reported examples of evolving gene families. Emphasis is given toward understanding interactive effects of gene conversion and natural selection.
PMCID: PMC3966226  PMID: 24710091
interaction of gene conversion and selection; concerted evolution; generation of gene diversity
14.  Medie and Info-pubmed: 2010 update 
BMC Bioinformatics  2010;11(Suppl 5):P7.
PMCID: PMC2956400
15.  New challenges for text mining: mapping between text and manually curated pathways 
BMC Bioinformatics  2008;9(Suppl 3):S5.
Associating literature with pathways poses new challenges to the Text Mining (TM) community. There are three main challenges to this task: (1) the identification of the mapping position of a specific entity or reaction in a given pathway, (2) the recognition of the causal relationships among multiple reactions, and (3) the formulation and implementation of required inferences based on biological domain knowledge.
To address these challenges, we constructed new resources to link the text with a model pathway; they are: the GENIA pathway corpus with event annotation and NF-kB pathway. Through their detailed analysis, we address the untapped resource, ‘bio-inference,’ as well as the differences between text and pathway representation. Here, we show the precise comparisons of their representations and the nine classes of ‘bio-inference’ schemes observed in the pathway corpus.
We believe that the creation of such rich resources and their detailed analysis is the significant first step for accelerating the research of the automatic construction of pathway from text.
PMCID: PMC2352872  PMID: 18426550
16.  Corpus annotation for mining biomedical events from literature 
BMC Bioinformatics  2008;9:10.
Advanced Text Mining (TM) such as semantic enrichment of papers, event or relation extraction, and intelligent Question Answering have increasingly attracted attention in the bio-medical domain. For such attempts to succeed, text annotation from the biological point of view is indispensable. However, due to the complexity of the task, semantic annotation has never been tried on a large scale, apart from relatively simple term annotation.
We have completed a new type of semantic annotation, event annotation, which is an addition to the existing annotations in the GENIA corpus. The corpus has already been annotated with POS (Parts of Speech), syntactic trees, terms, etc. The new annotation was made on half of the GENIA corpus, consisting of 1,000 Medline abstracts. It contains 9,372 sentences in which 36,114 events are identified. The major challenges during event annotation were (1) to design a scheme of annotation which meets specific requirements of text annotation, (2) to achieve biology-oriented annotation which reflect biologists' interpretation of text, and (3) to ensure the homogeneity of annotation quality across annotators. To meet these challenges, we introduced new concepts such as Single-facet Annotation and Semantic Typing, which have collectively contributed to successful completion of a large scale annotation.
The resulting event-annotated corpus is the largest and one of the best in quality among similar annotation efforts. We expect it to become a valuable resource for NLP (Natural Language Processing)-based TM in the bio-medical domain.
PMCID: PMC2267702  PMID: 18182099
17.  rpoS Function Is Essential for bgl Silencing Caused by C-Terminally Truncated H-NS in Escherichia coli 
Journal of Bacteriology  1999;181(20):6278-6283.
From evolutionary and physiological viewpoints, the Escherichia coli bgl operon is intriguing because its expression is silent (Bgl− phenotype), at least under several laboratory conditions. H-NS, a nucleoid protein, is known as a DNA-binding protein involved in bgl silencing. However, we previously found that bgl expression is still silent in a certain subset of hns mutations, each of which results in a defect in its DNA-binding ability. Based on this fact, we proposed a model in which a postulated DNA-binding protein(s) has an adapter function by interacting with both the cis-acting element of the bgl promoter and the mutated H-NS. To identify such a presumed adapter molecule, we attempted to isolate mutants exhibiting the Bgl+ phenotype in the background of hns60, encoding the mutant H-NS protein lacking the DNA-binding domain by random insertion mutagenesis with the mini-Tn10cam transposon. These isolated mutations were mapped to five loci on the chromosome. Among these loci, three appeared to be leuO, hns, and bglJ, which were previously characterized, while the other two were novel. Genetic analysis revealed that the two insertions are within the rpoS gene and in front of the lrhA gene, respectively. The former encodes the stationary-phase-specific sigma factor, ςS, and the latter encodes a LysR-like DNA-binding protein. It was found that ςS is defective in both types of mutant cells. These results showed that the rpoS function is involved in the mechanism underlying bgl silencing, at least in the hns60 background used in this study. We also examined whether the H-NS homolog StpA has such an adapter function, as was previously proposed. Our results did not support the idea that StpA has an adapter function in the genetic background used.
PMCID: PMC103760  PMID: 10515915
18.  The leuO Gene Product Has a Latent Ability To Relieve bgl Silencing in Escherichia coli 
Journal of Bacteriology  1998;180(1):190-193.
The Escherichia coli bgl operon is of interest, since its expression is silent (phenotypically Bgl−), at least under standard laboratory conditions. Here we attempted to identify a trans-acting factor(s) that is presumably relevant to the regulation of bgl by a random insertion mutagenesis with mini-Tn10. These collected mutations, conferring the phenotype of Bgl+, were localized in three loci on the genetic map, two of which appeared to be hns and bglJ, which were previously implicated as the factors affecting the Bgl phenotype. The other locus at 1 to 2 min on the genetic map appeared to be a new one. In this case, the insertion mutation was found to be just in front of the leuO gene encoding a putative LysR-like DNA-binding protein. Genetic analyses revealed that overproduction of LeuO in the wild-type cells causes the phenotype of Bgl+. A leuO deletion mutant was also characterized in terms of expression of bgl. From these results, the possible function of LeuO in bgl expression will be discussed from an evolutionary and/or ecological point of view.
PMCID: PMC106870  PMID: 9422614

Results 1-18 (18)