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1.  BioC interoperability track overview 
BioC is a new simple XML format for sharing biomedical text and annotations and libraries to read and write that format. This promotes the development of interoperable tools for natural language processing (NLP) of biomedical text. The interoperability track at the BioCreative IV workshop featured contributions using or highlighting the BioC format. These contributions included additional implementations of BioC, many new corpora in the format, biomedical NLP tools consuming and producing the format and online services using the format. The ease of use, broad support and rapidly growing number of tools demonstrate the need for and value of the BioC format.
Database URL: http://bioc.sourceforge.net/
doi:10.1093/database/bau053
PMCID: PMC4074764  PMID: 24980129
3.  iSimp in BioC standard format: enhancing the interoperability of a sentence simplification system 
This article reports the use of the BioC standard format in our sentence simplification system, iSimp, and demonstrates its general utility. iSimp is designed to simplify complex sentences commonly found in the biomedical text, and has been shown to improve existing text mining applications that rely on the analysis of sentence structures. By adopting the BioC format, we aim to make iSimp readily interoperable with other applications in the biomedical domain. To examine the utility of iSimp in BioC, we implemented a rule-based relation extraction system that uses iSimp as a preprocessing module and BioC for data exchange. Evaluation on the training corpus of BioNLP-ST 2011 GENIA Event Extraction (GE) task showed that iSimp sentence simplification improved the recall by 3.2% without reducing precision. The iSimp simplification-annotated corpora, both our previously used corpus and the GE corpus in the current study, have been converted into the BioC format and made publicly available at the project’s Web site: http://research.bioinformatics.udel.edu/isimp/.
Database URL:http://research.bioinformatics.udel.edu/isimp/
doi:10.1093/database/bau038
PMCID: PMC4028706  PMID: 24850848
4.  Software for pre-processing Illumina next-generation sequencing short read sequences 
Background
When compared to Sanger sequencing technology, next-generation sequencing (NGS) technologies are hindered by shorter sequence read length, higher base-call error rate, non-uniform coverage, and platform-specific sequencing artifacts. These characteristics lower the quality of their downstream analyses, e.g. de novo and reference-based assembly, by introducing sequencing artifacts and errors that may contribute to incorrect interpretation of data. Although many tools have been developed for quality control and pre-processing of NGS data, none of them provide flexible and comprehensive trimming options in conjunction with parallel processing to expedite pre-processing of large NGS datasets.
Methods
We developed ngsShoRT (next-generation sequencing Short Reads Trimmer), a flexible and comprehensive open-source software package written in Perl that provides a set of algorithms commonly used for pre-processing NGS short read sequences. We compared the features and performance of ngsShoRT with existing tools: CutAdapt, NGS QC Toolkit and Trimmomatic. We also compared the effects of using pre-processed short read sequences generated by different algorithms on de novo and reference-based assembly for three different genomes: Caenorhabditis elegans, Saccharomyces cerevisiae S288c, and Escherichia coli O157 H7.
Results
Several combinations of ngsShoRT algorithms were tested on publicly available Illumina GA II, HiSeq 2000, and MiSeq eukaryotic and bacteria genomic short read sequences with the focus on removing sequencing artifacts and low-quality reads and/or bases. Our results show that across three organisms and three sequencing platforms, trimming improved the mean quality scores of trimmed sequences. Using trimmed sequences for de novo and reference-based assembly improved assembly quality as well as assembler performance. In general, ngsShoRT outperformed comparable trimming tools in terms of trimming speed and improvement of de novo and reference-based assembly as measured by assembly contiguity and correctness.
Conclusions
Trimming of short read sequences can improve the quality of de novo and reference-based assembly and assembler performance. The parallel processing capability of ngsShoRT reduces trimming time and improves the memory efficiency when dealing with large datasets. We recommend combining sequencing artifacts removal, and quality score based read filtering and base trimming as the most consistent method for improving sequence quality and downstream assemblies.
ngsShoRT source code, user guide and tutorial are available at http://research.bioinformatics.udel.edu/genomics/ngsShoRT/. ngsShoRT can be incorporated as a pre-processing step in genome and transcriptome assembly projects.
doi:10.1186/1751-0473-9-8
PMCID: PMC4064128  PMID: 24955109
Next-generation sequencing; Illumina; Trimming; De novo assembly; Reference-based assembly; Perl
5.  Prediction of contact matrix for protein–protein interaction 
Bioinformatics  2013;29(8):1018-1025.
Motivation: Prediction of protein–protein interaction has become an important part of systems biology in reverse engineering the biological networks for better understanding the molecular biology of the cell. Although significant progress has been made in terms of prediction accuracy, most computational methods only predict whether two proteins interact but not their interacting residues—the information that can be very valuable for understanding the interaction mechanisms and designing modulation of the interaction. In this work, we developed a computational method to predict the interacting residue pairs—contact matrix for interacting protein domains, whose rows and columns correspond to the residues in the two interacting domains respectively and whose values (1 or 0) indicate whether the corresponding residues (do or do not) interact.
Results: Our method is based on supervised learning using support vector machines. For each domain involved in a given domain–domain interaction (DDI), an interaction profile hidden Markov model (ipHMM) is first built for the domain family, and then each residue position for a member domain sequence is represented as a 20-dimension vector of Fisher scores, characterizing how similar it is as compared with the family profile at that position. Each element of the contact matrix for a sequence pair is now represented by a feature vector from concatenating the vectors of the two corresponding residues, and the task is to predict the element value (1 or 0) from the feature vector. A support vector machine is trained for a given DDI, using either a consensus contact matrix or contact matrices for individual sequence pairs, and is tested by leave-one-out cross validation. The performance averaged over a set of 115 DDIs collected from the 3 DID database shows significant improvement (sensitivity up to 85%, and specificity up to 85%), as compared with a multiple sequence alignment-based method (sensitivity 57%, and specificity 78%) previously reported in the literature.
Contact: lliao@cis.udel.edu or wuc@cis.udel.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt076
PMCID: PMC3624801  PMID: 23418186
6.  BioC: a minimalist approach to interoperability for biomedical text processing 
A vast amount of scientific information is encoded in natural language text, and the quantity of such text has become so great that it is no longer economically feasible to have a human as the first step in the search process. Natural language processing and text mining tools have become essential to facilitate the search for and extraction of information from text. This has led to vigorous research efforts to create useful tools and to create humanly labeled text corpora, which can be used to improve such tools. To encourage combining these efforts into larger, more powerful and more capable systems, a common interchange format to represent, store and exchange the data in a simple manner between different language processing systems and text mining tools is highly desirable. Here we propose a simple extensible mark-up language format to share text documents and annotations. The proposed annotation approach allows a large number of different annotations to be represented including sentences, tokens, parts of speech, named entities such as genes or diseases and relationships between named entities. In addition, we provide simple code to hold this data, read it from and write it back to extensible mark-up language files and perform some sample processing. We also describe completed as well as ongoing work to apply the approach in several directions. Code and data are available at http://bioc.sourceforge.net/.
Database URL: http://bioc.sourceforge.net/
doi:10.1093/database/bat064
PMCID: PMC3889917  PMID: 24048470
7.  PIRSF Family Classification System for Protein Functional and Evolutionary Analysis 
The PIRSF protein classification system (http://pir.georgetown.edu/pirsf/) reflects evolutionary relationships of full-length proteins and domains. The primary PIRSF classification unit is the homeomorphic family, whose members are both homologous (evolved from a common ancestor) and homeomorphic (sharing full-length sequence similarity and a common domain architecture). PIRSF families are curated systematically based on literature review and integrative sequence and functional analysis, including sequence and structure similarity, domain architecture, functional association, genome context, and phyletic pattern. The results of classification and expert annotation are summarized in PIRSF family reports with graphical viewers for taxonomic distribution, domain architecture, family hierarchy, and multiple alignment and phylogenetic tree. The PIRSF system provides a comprehensive resource for bioinformatics analysis and comparative studies of protein function and evolution. Domain or fold-based searches allow identification of evolutionarily related protein families sharing domains or structural folds. Functional convergence and functional divergence are revealed by the relationships between protein classification and curated family functions. The taxonomic distribution allows the identification of lineage-specific or broadly conserved protein families and can reveal horizontal gene transfer. Here we demonstrate, with illustrative examples, how to use the web-based PIRSF system as a tool for functional and evolutionary studies of protein families.
PMCID: PMC2674652  PMID: 19455212
Domain architecture; Functional convergence; Functional divergence; Genome context; Protein family classification; Taxonomic distribution
8.  Transcription factors and genetic circuits orchestrating the complex, multilayered response of Clostridium acetobutylicum to butanol and butyrate stress 
BMC Systems Biology  2013;7:120.
Background
Organisms of the genus Clostridium are Gram-positive endospore formers of great importance to the carbon cycle, human normo- and pathophysiology, but also in biofuel and biorefinery applications. Exposure of Clostridium organisms to chemical and in particular toxic metabolite stress is ubiquitous in both natural (such as in the human microbiome) and engineered environments, engaging both the general stress response as well as specialized programs. Yet, despite its fundamental and applied significance, it remains largely unexplored at the systems level.
Results
We generated a total of 96 individual sets of microarray data examining the transcriptional changes in C. acetobutylicum, a model Clostridium organism, in response to three levels of chemical stress from the native metabolites, butanol and butyrate. We identified 164 significantly differentially expressed transcriptional regulators and detailed the cellular programs associated with general and stressor-specific responses, many previously unexplored. Pattern-based, comparative genomic analyses enabled us, for the first time, to construct a detailed picture of the genetic circuitry underlying the stress response. Notably, a list of the regulons and DNA binding motifs of the stress-related transcription factors were identified: two heat-shock response regulators, HrcA and CtsR; the SOS response regulator LexA; the redox sensor Rex; and the peroxide sensor PerR. Moreover, several transcriptional regulators controlling stress-responsive amino acid and purine metabolism and their regulons were also identified, including ArgR (arginine biosynthesis and catabolism regulator), HisR (histidine biosynthesis regulator), CymR (cysteine metabolism repressor) and PurR (purine metabolism repressor).
Conclusions
Using an exceptionally large set of temporal transcriptional data and regulon analyses, we successfully built a STRING-based stress response network model integrating important players for the general and specialized metabolite stress response in C. acetobutylicum. Since the majority of the transcription factors and their target genes are highly conserved in other organisms of the Clostridium genus, this network would be largely applicable to other Clostridium organisms. The network informs the molecular basis of Clostridium responses to toxic metabolites in natural ecosystems and the microbiome, and will facilitate the construction of genome-scale models with added regulatory-network dimensions to guide the development of tolerant strains.
doi:10.1186/1752-0509-7-120
PMCID: PMC3828012  PMID: 24196194
Gene expression; Protein-protein interaction; Transcriptional regulatory network (TRN); Transcription factor (TF); TF binding site (TFBS); Transcriptional regulator (TR)
9.  Omics-Based Molecular Target and Biomarker Identification 
Genomic, proteomic, and other omic-based approaches are now broadly used in biomedical research to facilitate the understanding of disease mechanisms and identification of molecular targets and biomarkers for therapeutic and diagnostic development. While the Omics technologies and bioinformatics tools for analyzing Omics data are rapidly advancing, the functional analysis and interpretation of the data remain challenging due to the inherent nature of the generally long workflows of Omics experiments. We adopt a strategy that emphasizes the use of curated knowledge resources coupled with expert-guided examination and interpretation of Omics data for the selection of potential molecular targets. We describe a downstream workflow and procedures for functional analysis that focus on biological pathways, from which molecular targets can be derived and proposed for experimental validation.
doi:10.1007/978-1-61779-027-0_26
PMCID: PMC3742302  PMID: 21370102
Proteomics; Genomics; Bioinformatics; Biological pathways; Cell signaling; Databases; Molecular targets; Biomarkers
10.  Construction of protein phosphorylation networks by data mining, text mining and ontology integration: analysis of the spindle checkpoint 
Knowledge representation of the role of phosphorylation is essential for the meaningful understanding of many biological processes. However, such a representation is challenging because proteins can exist in numerous phosphorylated forms with each one having its own characteristic protein–protein interactions (PPIs), functions and subcellular localization. In this article, we evaluate the current state of phosphorylation event curation and then present a bioinformatics framework for the annotation and representation of phosphorylated proteins and construction of phosphorylation networks that addresses some of the gaps in current curation efforts. The integrated approach involves (i) text mining guided by RLIMS-P, a tool that identifies phosphorylation-related information in scientific literature; (ii) data mining from curated PPI databases; (iii) protein form and complex representation using the Protein Ontology (PRO); (iv) functional annotation using the Gene Ontology (GO); and (v) network visualization and analysis with Cytoscape. We use this framework to study the spindle checkpoint, the process that monitors the assembly of the mitotic spindle and blocks cell cycle progression at metaphase until all chromosomes have made bipolar spindle attachments. The phosphorylation networks we construct, centered on the human checkpoint kinase BUB1B (BubR1) and its yeast counterpart MAD3, offer a unique view of the spindle checkpoint that emphasizes biologically relevant phosphorylated forms, phosphorylation-state–specific PPIs and kinase–substrate relationships. Our approach for constructing protein phosphorylation networks can be applied to any biological process that is affected by phosphorylation.
Database URL: http://www.yeastgenome.org/
doi:10.1093/database/bat038
PMCID: PMC3675891  PMID: 23749465
11.  The eFIP system for text mining of protein interaction networks of phosphorylated proteins 
Protein phosphorylation is a central regulatory mechanism in signal transduction involved in most biological processes. Phosphorylation of a protein may lead to activation or repression of its activity, alternative subcellular location and interaction with different binding partners. Extracting this type of information from scientific literature is critical for connecting phosphorylated proteins with kinases and interaction partners, along with their functional outcomes, for knowledge discovery from phosphorylation protein networks. We have developed the Extracting Functional Impact of Phosphorylation (eFIP) text mining system, which combines several natural language processing techniques to find relevant abstracts mentioning phosphorylation of a given protein together with indications of protein–protein interactions (PPIs) and potential evidences for impact of phosphorylation on the PPIs. eFIP integrates our previously developed tools, Extracting Gene Related ABstracts (eGRAB) for document retrieval and name disambiguation, Rule-based LIterature Mining System (RLIMS-P) for Protein Phosphorylation for extraction of phosphorylation information, a PPI module to detect PPIs involving phosphorylated proteins and an impact module for relation extraction. The text mining system has been integrated into the curation workflow of the Protein Ontology (PRO) to capture knowledge about phosphorylated proteins. The eFIP web interface accepts gene/protein names or identifiers, or PubMed identifiers as input, and displays results as a ranked list of abstracts with sentence evidence and summary table, which can be exported in a spreadsheet upon result validation. As a participant in the BioCreative-2012 Interactive Text Mining track, the performance of eFIP was evaluated on document retrieval (F-measures of 78–100%), sentence-level information extraction (F-measures of 70–80%) and document ranking (normalized discounted cumulative gain measures of 93–100% and mean average precision of 0.86). The utility and usability of the eFIP web interface were also evaluated during the BioCreative Workshop. The use of the eFIP interface provided a significant speed-up (∼2.5-fold) for time to completion of the curation task. Additionally, eFIP significantly simplifies the task of finding relevant articles on PPI involving phosphorylated forms of a given protein.
Database URL: http://proteininformationresource.org/pirwww/iprolink/eFIP.shtml
doi:10.1093/database/bas044
PMCID: PMC3514748  PMID: 23221174
13.  Text mining for the biocuration workflow 
Molecular biology has become heavily dependent on biological knowledge encoded in expert curated biological databases. As the volume of biological literature increases, biocurators need help in keeping up with the literature; (semi-) automated aids for biocuration would seem to be an ideal application for natural language processing and text mining. However, to date, there have been few documented successes for improving biocuration throughput using text mining. Our initial investigations took place for the workshop on ‘Text Mining for the BioCuration Workflow’ at the third International Biocuration Conference (Berlin, 2009). We interviewed biocurators to obtain workflows from eight biological databases. This initial study revealed high-level commonalities, including (i) selection of documents for curation; (ii) indexing of documents with biologically relevant entities (e.g. genes); and (iii) detailed curation of specific relations (e.g. interactions); however, the detailed workflows also showed many variabilities. Following the workshop, we conducted a survey of biocurators. The survey identified biocurator priorities, including the handling of full text indexed with biological entities and support for the identification and prioritization of documents for curation. It also indicated that two-thirds of the biocuration teams had experimented with text mining and almost half were using text mining at that time. Analysis of our interviews and survey provide a set of requirements for the integration of text mining into the biocuration workflow. These can guide the identification of common needs across curated databases and encourage joint experimentation involving biocurators, text mining developers and the larger biomedical research community.
doi:10.1093/database/bas020
PMCID: PMC3328793  PMID: 22513129
14.  A comprehensive protein-centric ID mapping service for molecular data integration 
Bioinformatics  2011;27(8):1190-1191.
Motivation: Identifier (ID) mapping establishes links between various biological databases and is an essential first step for molecular data integration and functional annotation. ID mapping allows diverse molecular data on genes and proteins to be combined and mapped to functional pathways and ontologies. We have developed comprehensive protein-centric ID mapping services providing mappings for 90 IDs derived from databases on genes, proteins, pathways, diseases, structures, protein families, protein interaction, literature, ontologies, etc. The services are widely used and have been regularly updated since 2006.
Availability: www.uniprot.org/mappingandproteininformation-resource.org/pirwww/search/idmapping.shtml
Contact: huang@dbi.udel.edu
doi:10.1093/bioinformatics/btr101
PMCID: PMC3072559  PMID: 21478197
15.  Community annotation and bioinformatics workforce development in concert—Little Skate Genome Annotation Workshops and Jamborees 
Recent advances in high-throughput DNA sequencing technologies have equipped biologists with a powerful new set of tools for advancing research goals. The resulting flood of sequence data has made it critically important to train the next generation of scientists to handle the inherent bioinformatic challenges. The North East Bioinformatics Collaborative (NEBC) is undertaking the genome sequencing and annotation of the little skate (Leucoraja erinacea) to promote advancement of bioinformatics infrastructure in our region, with an emphasis on practical education to create a critical mass of informatically savvy life scientists. In support of the Little Skate Genome Project, the NEBC members have developed several annotation workshops and jamborees to provide training in genome sequencing, annotation and analysis. Acting as a nexus for both curation activities and dissemination of project data, a project web portal, SkateBase (http://skatebase.org) has been developed. As a case study to illustrate effective coupling of community annotation with workforce development, we report the results of the Mitochondrial Genome Annotation Jamborees organized to annotate the first completely assembled element of the Little Skate Genome Project, as a culminating experience for participants from our three prior annotation workshops. We are applying the physical/virtual infrastructure and lessons learned from these activities to enhance and streamline the genome annotation workflow, as we look toward our continuing efforts for larger-scale functional and structural community annotation of the L. erinacea genome.
doi:10.1093/database/bar064
PMCID: PMC3308154  PMID: 22434832
16.  Overview of the BioCreative III Workshop 
BMC Bioinformatics  2011;12(Suppl 8):S1.
Background
The overall goal of the BioCreative Workshops is to promote the development of text mining and text processing tools which are useful to the communities of researchers and database curators in the biological sciences. To this end BioCreative I was held in 2004, BioCreative II in 2007, and BioCreative II.5 in 2009. Each of these workshops involved humanly annotated test data for several basic tasks in text mining applied to the biomedical literature. Participants in the workshops were invited to compete in the tasks by constructing software systems to perform the tasks automatically and were given scores based on their performance. The results of these workshops have benefited the community in several ways. They have 1) provided evidence for the most effective methods currently available to solve specific problems; 2) revealed the current state of the art for performance on those problems; 3) and provided gold standard data and results on that data by which future advances can be gauged. This special issue contains overview papers for the three tasks of BioCreative III.
Results
The BioCreative III Workshop was held in September of 2010 and continued the tradition of a challenge evaluation on several tasks judged basic to effective text mining in biology, including a gene normalization (GN) task and two protein-protein interaction (PPI) tasks. In total the Workshop involved the work of twenty-three teams. Thirteen teams participated in the GN task which required the assignment of EntrezGene IDs to all named genes in full text papers without any species information being provided to a system. Ten teams participated in the PPI article classification task (ACT) requiring a system to classify and rank a PubMed® record as belonging to an article either having or not having “PPI relevant” information. Eight teams participated in the PPI interaction method task (IMT) where systems were given full text documents and were required to extract the experimental methods used to establish PPIs and a text segment supporting each such method. Gold standard data was compiled for each of these tasks and participants competed in developing systems to perform the tasks automatically.
BioCreative III also introduced a new interactive task (IAT), run as a demonstration task. The goal was to develop an interactive system to facilitate a user’s annotation of the unique database identifiers for all the genes appearing in an article. This task included ranking genes by importance (based preferably on the amount of described experimental information regarding genes). There was also an optional task to assist the user in finding the most relevant articles about a given gene. For BioCreative III, a user advisory group (UAG) was assembled and played an important role 1) in producing some of the gold standard annotations for the GN task, 2) in critiquing IAT systems, and 3) in providing guidance for a future more rigorous evaluation of IAT systems. Six teams participated in the IAT demonstration task and received feedback on their systems from the UAG group. Besides innovations in the GN and PPI tasks making them more realistic and practical and the introduction of the IAT task, discussions were begun on community data standards to promote interoperability and on user requirements and evaluation metrics to address utility and usability of systems.
Conclusions
In this paper we give a brief history of the BioCreative Workshops and how they relate to other text mining competitions in biology. This is followed by a synopsis of the three tasks GN, PPI, and IAT in BioCreative III with figures for best participant performance on the GN and PPI tasks. These results are discussed and compared with results from previous BioCreative Workshops and we conclude that the best performing systems for GN, PPI-ACT and PPI-IMT in realistic settings are not sufficient for fully automatic use. This provides evidence for the importance of interactive systems and we present our vision of how best to construct an interactive system for a GN or PPI like task in the remainder of the paper.
doi:10.1186/1471-2105-12-S8-S1
PMCID: PMC3269932  PMID: 22151647
17.  Representative Proteomes: A Stable, Scalable and Unbiased Proteome Set for Sequence Analysis and Functional Annotation 
PLoS ONE  2011;6(4):e18910.
The accelerating growth in the number of protein sequences taxes both the computational and manual resources needed to analyze them. One approach to dealing with this problem is to minimize the number of proteins subjected to such analysis in a way that minimizes loss of information. To this end we have developed a set of Representative Proteomes (RPs), each selected from a Representative Proteome Group (RPG) containing similar proteomes calculated based on co-membership in UniRef50 clusters. A Representative Proteome is the proteome that can best represent all the proteomes in its group in terms of the majority of the sequence space and information. RPs at 75%, 55%, 35% and 15% co-membership threshold (CMT) are provided to allow users to decrease or increase the granularity of the sequence space based on their requirements. We find that a CMT of 55% (RP55) most closely follows standard taxonomic classifications. Further analysis of this set reveals that sequence space is reduced by more than 80% relative to UniProtKB, while retaining both sequence diversity (over 95% of InterPro domains) and annotation information (93% of experimentally characterized proteins). All sets can be browsed and are available for sequence similarity searches and download at http://www.proteininformationresource.org/rps, while the set of 637 RPs determined using a 55% CMT are also available for text searches. Potential applications include sequence similarity searches, protein classification and targeted protein annotation and characterization.
doi:10.1371/journal.pone.0018910
PMCID: PMC3083393  PMID: 21556138
18.  The Protein Ontology: a structured representation of protein forms and complexes 
Nucleic Acids Research  2010;39(Database issue):D539-D545.
The Protein Ontology (PRO) provides a formal, logically-based classification of specific protein classes including structured representations of protein isoforms, variants and modified forms. Initially focused on proteins found in human, mouse and Escherichia coli, PRO now includes representations of protein complexes. The PRO Consortium works in concert with the developers of other biomedical ontologies and protein knowledge bases to provide the ability to formally organize and integrate representations of precise protein forms so as to enhance accessibility to results of protein research. PRO (http://pir.georgetown.edu/pro) is part of the Open Biomedical Ontology Foundry.
doi:10.1093/nar/gkq907
PMCID: PMC3013777  PMID: 20935045
19.  Phylogenomic Analysis of Marine Roseobacters 
PLoS ONE  2010;5(7):e11604.
Background
Members of the Roseobacter clade which play a key role in the biogeochemical cycles of the ocean are diverse and abundant, comprising 10–25% of the bacterioplankton in most marine surface waters. The rapid accumulation of whole-genome sequence data for the Roseobacter clade allows us to obtain a clearer picture of its evolution.
Methodology/Principal Findings
In this study about 1,200 likely orthologous protein families were identified from 17 Roseobacter bacteria genomes. Functional annotations for these genes are provided by iProClass. Phylogenetic trees were constructed for each gene using maximum likelihood (ML) and neighbor joining (NJ). Putative organismal phylogenetic trees were built with phylogenomic methods. These trees were compared and analyzed using principal coordinates analysis (PCoA), approximately unbiased (AU) and Shimodaira–Hasegawa (SH) tests. A core set of 694 genes with vertical descent signal that are resistant to horizontal gene transfer (HGT) is used to reconstruct a robust organismal phylogeny. In addition, we also discovered the most likely 109 HGT genes. The core set contains genes that encode ribosomal apparatus, ABC transporters and chaperones often found in the environmental metagenomic and metatranscriptomic data. These genes in the core set are spread out uniformly among the various functional classes and biological processes.
Conclusions/Significance
Here we report a new multigene-derived phylogenetic tree of the Roseobacter clade. Of particular interest is the HGT of eleven genes involved in vitamin B12 synthesis as well as key enzynmes for dimethylsulfoniopropionate (DMSP) degradation. These aquired genes are essential for the growth of Roseobacters and their eukaryotic partners.
doi:10.1371/journal.pone.0011604
PMCID: PMC2904699  PMID: 20657646
20.  Protein Bioinformatics Infrastructure for the Integration and Analysis of Multiple High-Throughput “omics” Data 
Advances in Bioinformatics  2010;2010:423589.
High-throughput “omics” technologies bring new opportunities for biological and biomedical researchers to ask complex questions and gain new scientific insights. However, the voluminous, complex, and context-dependent data being maintained in heterogeneous and distributed environments plus the lack of well-defined data standard and standardized nomenclature imposes a major challenge which requires advanced computational methods and bioinformatics infrastructures for integration, mining, visualization, and comparative analysis to facilitate data-driven hypothesis generation and biological knowledge discovery. In this paper, we present the challenges in high-throughput “omics” data integration and analysis, introduce a protein-centric approach for systems integration of large and heterogeneous high-throughput “omics” data including microarray, mass spectrometry, protein sequence, protein structure, and protein interaction data, and use scientific case study to illustrate how one can use varied “omics” data from different laboratories to make useful connections that could lead to new biological knowledge.
doi:10.1155/2010/423589
PMCID: PMC2847380  PMID: 20369061
21.  Community annotation in biology 
Biology Direct  2010;5:12.
Attempts to engage the scientific community to annotate biological data (such as protein/gene function) stored in databases have not been overly successful. There are several hypotheses on why this has not been successful but it is not clear which of these hypotheses are correct. In this study we have surveyed 50 biologists (who have recently published a paper characterizing a gene or protein) to better understand what would make them interested in providing input/contributions to biological databases. Based on our survey two things become clear: a) database managers need to proactively contact biologists to solicit contributions; and b) potential contributors need to be provided with an easy-to-use interface and clear instructions on what to annotate. Other factors such as 'reward' and 'employer/funding agency recognition' previously perceived as motivators was found to be less important. Based on this study we propose community annotation projects should devote resources to direct solicitation for input and streamlining of the processes or interfaces used to collect this input.
Reviewers
This article was reviewed by I. King Jordan, Daniel Haft and Yuriy Gusev
doi:10.1186/1745-6150-5-12
PMCID: PMC2834641  PMID: 20167071
22.  BioTagger-GM: A Gene/Protein Name Recognition System 
Objectives
Biomedical named entity recognition (BNER) is a critical component in automated systems that mine biomedical knowledge in free text. Among different types of entities in the domain, gene/protein would be the most studied one for BNER. Our goal is to develop a gene/protein name recognition system BioTagger-GM that exploits rich information in terminology sources using powerful machine learning frameworks and system combination.
Design
BioTagger-GM consists of four main components: (1) dictionary lookup—gene/protein names in BioThesaurus and biomedical terms in UMLS Metathesaurus are tagged in text, (2) machine learning—machine learning systems are trained using dictionary lookup results as one type of feature, (3) post-processing—heuristic rules are used to correct recognition errors, and (4) system combination—a voting scheme is used to combine recognition results from multiple systems.
Measurements
The BioCreAtIvE II Gene Mention (GM) corpus was used to evaluate the proposed method. To test its general applicability, the method was also evaluated on the JNLPBA corpus modified for gene/protein name recognition. The performance of the systems was evaluated through cross-validation tests and measured using precision, recall, and F-Measure.
Results
BioTagger-GM achieved an F-Measure of 0.8887 on the BioCreAtIvE II GM corpus, which is higher than that of the first-place system in the BioCreAtIvE II challenge. The applicability of the method was also confirmed on the modified JNLPBA corpus.
Conclusion
The results suggest that terminology sources, powerful machine learning frameworks, and system combination can be integrated to build an effective BNER system.
doi:10.1197/jamia.M2844
PMCID: PMC2649315  PMID: 19074302
23.  TGF-beta signaling proteins and the Protein Ontology 
BMC Bioinformatics  2009;10(Suppl 5):S3.
Background
The Protein Ontology (PRO) is designed as a formal and principled Open Biomedical Ontologies (OBO) Foundry ontology for proteins. The components of PRO extend from a classification of proteins on the basis of evolutionary relationships at the homeomorphic level to the representation of the multiple protein forms of a gene, including those resulting from alternative splicing, cleavage and/or post-translational modifications. Focusing specifically on the TGF-beta signaling proteins, we describe the building, curation, usage and dissemination of PRO.
Results
PRO is manually curated on the basis of PrePRO, an automatically generated file with content derived from standard protein data sources. Manual curation ensures that the treatment of the protein classes and the internal and external relationships conform to the PRO framework. The current release of PRO is based upon experimental data from mouse and human proteins wherein equivalent protein forms are represented by single terms. In addition to the PRO ontology, the annotation of PRO terms is released as a separate PRO association file, which contains, for each given PRO term, an annotation from the experimentally characterized sub-types as well as the corresponding database identifiers and sequence coordinates. The annotations are added in the form of relationship to other ontologies. Whenever possible, equivalent forms in other species are listed to facilitate cross-species comparison. Splice and allelic variants, gene fusion products and modified protein forms are all represented as entities in the ontology. Therefore, PRO provides for the representation of protein entities and a resource for describing the associated data. This makes PRO useful both for proteomics studies where isoforms and modified forms must be differentiated, and for studies of biological pathways, where representations need to take account of the different ways in which the cascade of events may depend on specific protein modifications.
Conclusion
PRO provides a framework for the formal representation of protein classes and protein forms in the OBO Foundry. It is designed to enable data retrieval and integration and machine reasoning at the molecular level of proteins, thereby facilitating cross-species comparisons, pathway analysis, disease modeling and the generation of new hypotheses.
doi:10.1186/1471-2105-10-S5-S3
PMCID: PMC2679403  PMID: 19426460
24.  Integrated Bioinformatics for Radiation-Induced Pathway Analysis from Proteomics and Microarray Data 
Functional analysis and interpretation of large-scale proteomics and gene expression data require effective use of bioinformatics tools and public knowledge resources coupled with expert-guided examination. An integrated bioinformatics approach was used to analyze cellular pathways in response to ionizing radiation. ATM, or ataxia-telangiectasia mutated , a serine-threonine protein kinase, plays critical roles in radiation responses, including cell cycle arrest and DNA repair. We analyzed radiation responsive pathways based on 2D-gel/MS proteomics and microarray gene expression data from fibroblasts expressing wild type or mutant ATM gene. The analysis showed that metabolism was significantly affected by radiation in an ATM dependent manner. In particular, purine metabolic pathways were differentially changed in the two cell lines. The expression of ribonucleoside-diphosphate reductase subunit M2 (RRM2) was increased in ATM-wild type cells at both mRNA and protein levels, but no changes were detected in ATM-mutated cells. Increased expression of p53 was observed 30min after irradiation of the ATM-wild type cells. These results suggest that RRM2 is a downstream target of the ATM-p53 pathway that mediates radiation-induced DNA repair. We demonstrated that the integrated bioinformatics approach facilitated pathway analysis, hypothesis generation and target gene/protein identification.
PMCID: PMC2603135  PMID: 19088860
bioinformatics; proteomics; radiation; purine metabolism; DNA repair; pathway and network
25.  A comparison study on algorithms of detecting long forms for short forms in biomedical text 
BMC Bioinformatics  2007;8(Suppl 9):S5.
Motivation
With more and more research dedicated to literature mining in the biomedical domain, more and more systems are available for people to choose from when building literature mining applications. In this study, we focus on one specific kind of literature mining task, i.e., detecting definitions of acronyms, abbreviations, and symbols in biomedical text. We denote acronyms, abbreviations, and symbols as short forms (SFs) and their corresponding definitions as long forms (LFs). The study was designed to answer the following questions; i) how well a system performs in detecting LFs from novel text, ii) what the coverage is for various terminological knowledge bases in including SFs as synonyms of their LFs, and iii) how to combine results from various SF knowledge bases.
Method
We evaluated the following three publicly available detection systems in detecting LFs for SFs: i) a handcrafted pattern/rule based system by Ao and Takagi, ALICE, ii) a machine learning system by Chang et al., and iii) a simple alignment-based program by Schwartz and Hearst. In addition, we investigated the conceptual coverage of two terminological knowledge bases: i) the UMLS (the Unified Medical Language System), and ii) the BioThesaurus (a thesaurus of names for all UniProt protein records). We also implemented a web interface that provides a virtual integration of various SF knowledge bases.
Results
We found that detection systems agree with each other on most cases, and the existing terminological knowledge bases have a good coverage of synonymous relationship for frequently defined LFs. The web interface allows people to detect SF definitions from text and to search several SF knowledge bases.
Availability
The web site is .
doi:10.1186/1471-2105-8-S9-S5
PMCID: PMC2217663  PMID: 18047706

Results 1-25 (43)