PathVisio 3: An Extendable Pathway Analysis Toolbox

PathVisio is a commonly used pathway editor, visualization and analysis software. Biological pathways have been used by biologists for many years to describe the detailed steps in biological processes. Those powerful, visual representations help researchers to better understand, share and discuss knowledge. Since the first publication of PathVisio in 2008, the original paper was cited more than 170 times and PathVisio was used in many different biological studies. As an online editor PathVisio is also integrated in the community curated pathway database WikiPathways.Here we present the third version of PathVisio with the newest additions and improvements of the application. The core features of PathVisio are pathway drawing, advanced data visualization and pathway statistics. Additionally, PathVisio 3 introduces a new powerful extension systems that allows other developers to contribute additional functionality in form of plugins without changing the core application.PathVisio can be downloaded from http://www.pathvisio.org and in 2014 PathVisio 3 has been downloaded over 5,500 times. There are already more than 15 plugins available in the central plugin repository. PathVisio is a freely available, open-source tool published under the Apache 2.0 license (http://www.apache.org/licenses/LICENSE-2.0). It is implemented in Java and thus runs on all major operating systems. The code repository is available at http://svn.bigcat.unimaas.nl/pathvisio. The support mailing list for users is available on https://groups.google.com/forum/#!forum/wikipathways-discuss and for developers on https://groups.google.com/forum/#!forum/wikipathways-devel.

This is a PLOS Computational Biology software article.

     

A Linnaeus NG TM interactive key to the Lithocolletinae of North-West Europe aimed at accelerating the accumulation of reliable biodiversity data (Lepidoptera,Gracillariidae)

We present an interactive key that is available online through any web browser without the need to install any additional software, making it an easily accessible tool for the larger public. The key can be found at http://identify.naturalis.nl/lithocolletinae. The key includes all 86 North-West European Lithocolletinae, a subfamily of smaller moths (“micro-moths”) that is commonly not treated in field guides. The user can input data on several external morphological character systems in addition to distribution, host plant and even characteristics of the larval feeding traces to reach an identification. We expect that this will enable more people to contribute with reliable observation data on this group of moths and alleviate the workload of taxonomic specialists, allowing them to focus on other new keys or taxonomic work.     

Genome sequence of the Lebeckia ambigua-nodulating “Burkholderia sprentiae” strain WSM5005T

“Burkholderia sprentiae” strain WSM5005^T is an aerobic, motile, Gram-negative, non-spore-forming rod that was isolated in Australia from an effective N₂-fixing root nodule of Lebeckia ambigua collected in Klawer, Western Cape of South Africa, in October 2007. Here we describe the features of “Burkholderia sprentiae” strain WSM5005^T, together with the genome sequence and its annotation. The 7,761,063 bp high-quality-draft genome is arranged in 8 scaffolds of 236 contigs, contains 7,147 protein-coding genes and 76 RNA-only encoding genes, and is one of 20 rhizobial genomes sequenced as part of the DOE Joint Genome Institute 2010 Community Sequencing Program.     

Epistasis Test in Meta-Analysis: A Multi-Parameter Markov Chain Monte Carlo Model for Consistency of Evidence

Conventional genome-wide association studies (GWAS) have been proven to be a successful strategy for identifying genetic variants associated with complex human traits. However, there is still a large heritability gap between GWAS and transitional family studies. The “missing heritability” has been suggested to be due to lack of studies focused on epistasis, also called gene–gene interactions, because individual trials have often had insufficient sample size. Meta-analysis is a common method for increasing statistical power. However, sufficient detailed information is difficult to obtain. A previous study employed a meta-regression-based method to detect epistasis, but it faced the challenge of inconsistent estimates. Here, we describe a Markov chain Monte Carlo-based method, called “Epistasis Test in Meta-Analysis” (ETMA), which uses genotype summary data to obtain consistent estimates of epistasis effects in meta-analysis. We defined a series of conditions to generate simulation data and tested the power and type I error rates in ETMA, individual data analysis and conventional meta-regression-based method. ETMA not only successfully facilitated consistency of evidence but also yielded acceptable type I error and higher power than conventional meta-regression. We applied ETMA to three real meta-analysis data sets. We found significant gene–gene interactions in the renin–angiotensin system and the polycyclic aromatic hydrocarbon metabolism pathway, with strong supporting evidence. In addition, glutathione S-transferase (GST) mu 1 and theta 1 were confirmed to exert independent effects on cancer. We concluded that the application of ETMA to real meta-analysis data was successful. Finally, we developed an R package, etma, for the detection of epistasis in meta-analysis [etma is available via the Comprehensive R Archive Network (CRAN) at https://cran.r-project.org/web/packages/etma/index.html].     

Automatic Assignment of Prokaryotic Genes to Functional Categories Using Literature Profiling

In the last years, there was an exponential increase in the number of publicly available genomes. Once finished, most genome projects lack financial support to review annotations. A few of these gene annotations are based on a combination of bioinformatics evidence, however, in most cases, annotations are based solely on sequence similarity to a previously known gene, which was most probably annotated in the same way. As a result, a large number of predicted genes remain unassigned to any functional category despite the fact that there is enough evidence in the literature to predict their function. We developed a classifier trained with term-frequency vectors automatically disclosed from text corpora of an ensemble of genes representative of each functional category of the J. Craig Venter Institute Comprehensive Microbial Resource (JCVI-CMR) ontology. The classifier achieved up to 84% precision with 68% recall (for confidence≥0.4), F-measure 0.76 (recall and precision equally weighted) in an independent set of 2,220 genes, from 13 bacterial species, previously classified by JCVI-CMR into unambiguous categories of its ontology. Finally, the classifier assigned (confidence≥0.7) to functional categories a total of 5,235 out of the ∼24 thousand genes previously in categories “Unknown function” or “Unclassified” for which there is literature in MEDLINE. Two biologists reviewed the literature of 100 of these genes, randomly picket, and assigned them to the same functional categories predicted by the automatic classifier. Our results confirmed the hypothesis that it is possible to confidently assign genes of a real world repository to functional categories, based exclusively on the automatic profiling of its associated literature. The LitProf - Gene Classifier web server is accessible at: www.cebio.org/litprofGC.     

"Just Another Tool for Online Studies” (JATOS): An Easy Solution for Setup and Management of Web Servers Supporting Online Studies

We present here “Just Another Tool for Online Studies” (JATOS): an open source, cross-platform web application with a graphical user interface (GUI) that greatly simplifies setting up and communicating with a web server to host online studies that are written in JavaScript. JATOS is easy to install in all three major platforms (Microsoft Windows, Mac OS X, and Linux), and seamlessly pairs with a database for secure data storage. It can be installed on a server or locally, allowing researchers to try the application and feasibility of their studies within a browser environment, before engaging in setting up a server. All communication with the JATOS server takes place via a GUI (with no need to use a command line interface), making JATOS an especially accessible tool for researchers without a strong IT background. We describe JATOS’ main features and implementation and provide a detailed tutorial along with example studies to help interested researchers to set up their online studies. JATOS can be found under the Internet address: www.jatos.org.     

Ensemble-Based Network Aggregation Improves the Accuracy of Gene Network Reconstruction

Reverse engineering approaches to constructing gene regulatory networks (GRNs) based on genome-wide mRNA expression data have led to significant biological findings, such as the discovery of novel drug targets. However, the reliability of the reconstructed GRNs needs to be improved. Here, we propose an ensemble-based network aggregation approach to improving the accuracy of network topologies constructed from mRNA expression data. To evaluate the performances of different approaches, we created dozens of simulated networks from combinations of gene-set sizes and sample sizes and also tested our methods on three Escherichia coli datasets. We demonstrate that the ensemble-based network aggregation approach can be used to effectively integrate GRNs constructed from different studies – producing more accurate networks. We also apply this approach to building a network from epithelial mesenchymal transition (EMT) signature microarray data and identify hub genes that might be potential drug targets. The R code used to perform all of the analyses is available in an R package entitled “ENA”, accessible on CRAN (http://cran.r-project.org/web/packages/ENA/).     

Tinnitus Suppression by Intracochlear Electrical Stimulation in Single Sided Deafness – A Prospective Clinical Trial: Follow-Up

IntroductionEarlier studies show that a Cochlear Implant (CI), capable of providing intracochlear electrical stimulation independent of environmental sounds, appears to suppress tinnitus at least for minutes. The current main objective is to compare the long-term suppressive effects of looped (i.e. repeated) electrical stimulation (without environmental sound perception) with the standard stimulation pattern of a CI (with environmental sound perception). This could open new possibilities for the development of a “Tinnitus Implant” (TI), an intracochlear pulse generator for the suppression of tinnitus.ResultsResults show that tinnitus can be suppressed with intracochlear electrical stimulation independent of environmental sounds, even long term. No significant difference in tinnitus suppression was found between the standard clinical CI and the TI.ConclusionIt can be concluded that coding of environmental sounds is no requirement for tinnitus suppression with intracochlear electrical stimulation. It is therefore plausible that tinnitus suppression by CI is not solely caused by an attention shift from the tinnitus to environmental sounds. Both the standard clinical CI and the experimental TI are potential treatment options for tinnitus. These findings offer perspectives for a successful clinical application of the TI, possibly even in patients with significant residual hearing.

Trial Registration

TrialRegister.nl NTR3374     

Complete genome sequence of the Radiation-Resistant bacterium Rubrobacter radiotolerans RSPS-4

Rubrobacter radiotolerans strain RSPS-4 is a slightly thermophilic member of the phylum “Actinobacteria” isolated from a hot spring in São Pedro do Sul, Portugal. This aerobic and halotolerant bacterium is also extremely resistant to gamma and UV radiation, which are the main reasons for the interest in sequencing its genome. Here, we present the complete genome sequence of strain RSPS-4 as well as its assembly and annotation. We also compare the gene sequence of this organism with that of the type strain of the species R. radiotolerans isolated from a hot spring in Japan. The genome of strain RSPS-4 comprises one circular chromosome of 2,875,491 bp with a G+C content of 66.91%, and 3 circular plasmids of 190,889 bp, 149,806 bp and 51,047 bp, harboring 3,214 predicted protein coding genes, 46 tRNA genes and a single rRNA operon.     

GeneComps and ChemComps: a new CTD metric to identify genes and chemicals with shared toxicogenomic profiles

The Comparative Toxicogenomics Database is a public resource that promotes understanding about the effects of environmental chemicals on human health. Currently, CTD describes over 184,000 molecular interactions for more than 5,100 chemicals and 16,300 genes/proteins. We have leveraged this dataset of chemical-gene relationships to compute similarity indices following the statistical method of the Jaccard index. These scores are used to produce lists of comparable genes (“GeneComps”) or chemicals (“ChemComps”) based on shared toxicogenomic profiles. GeneComps and ChemComps are now provided for every curated gene and chemical in CTD. ChemComps are particularly significant because they provide a way to group chemicals based upon their biological effects, instead of their physical or structural properties. These metrics provide a novel way to view and classify genes and chemicals and will help advance testable hypotheses about environmental chemical-genedisease networks.

Availability

CTD is freely available at http://ctd.mdibl.org/     

Non-contiguous finished genome sequence of plant-growth promoting Serratia proteamaculans S4

Serratia proteamaculans S4 (previously Serratia sp. S4), isolated from the rhizosphere of wild Equisetum sp., has the ability to stimulate plant growth and to suppress the growth of several soil-borne fungal pathogens of economically important crops. Here we present the non-contiguous, finished genome sequence of S. proteamaculans S4, which consists of a 5,324,944 bp circular chromosome and a 129,797 bp circular plasmid. The chromosome contains 5,008 predicted genes while the plasmid comprises 134 predicted genes. In total, 4,993 genes are assigned as protein-coding genes. The genome consists of 22 rRNA genes, 82 tRNA genes and 58 pseudogenes. This genome is a part of the project “Genomics of four rapeseed plant growth-promoting bacteria with antagonistic effect on plant pathogens” awarded through the 2010 DOE-JGI’s Community Sequencing Program.     

Vfold: A Web Server for RNA Structure and Folding Thermodynamics Prediction

Background

The ever increasing discovery of non-coding RNAs leads to unprecedented demand for the accurate modeling of RNA folding, including the predictions of two-dimensional (base pair) and three-dimensional all-atom structures and folding stabilities. Accurate modeling of RNA structure and stability has far-reaching impact on our understanding of RNA functions in human health and our ability to design RNA-based therapeutic strategies.

Results

The Vfold server offers a web interface to predict (a) RNA two-dimensional structure from the nucleotide sequence, (b) three-dimensional structure from the two-dimensional structure and the sequence, and (c) folding thermodynamics (heat capacity melting curve) from the sequence. To predict the two-dimensional structure (base pairs), the server generates an ensemble of structures, including loop structures with the different intra-loop mismatches, and evaluates the free energies using the experimental parameters for the base stacks and the loop entropy parameters given by a coarse-grained RNA folding model (the Vfold model) for the loops. To predict the three-dimensional structure, the server assembles the motif scaffolds using structure templates extracted from the known PDB structures and refines the structure using all-atom energy minimization.

Conclusions

The Vfold-based web server provides a user friendly tool for the prediction of RNA structure and stability. The web server and the source codes are freely accessible for public use at “http://rna.physics.missouri.edu”.     

ClassyFlu: Classification of Influenza A Viruses with Discriminatively Trained Profile-HMMs

Accurate and rapid characterization of influenza A virus (IAV) hemagglutinin (HA) and neuraminidase (NA) sequences with respect to subtype and clade is at the basis of extended diagnostic services and implicit to molecular epidemiologic studies. ClassyFlu is a new tool and web service for the classification of IAV sequences of the HA and NA gene into subtypes and phylogenetic clades using discriminatively trained profile hidden Markov models (HMMs), one for each subtype or clade. ClassyFlu merely requires as input unaligned, full-length or partial HA or NA DNA sequences. It enables rapid and highly accurate assignment of HA sequences to subtypes H1–H17 but particularly focusses on the finer grained assignment of sequences of highly pathogenic avian influenza viruses of subtype H5N1 according to the cladistics proposed by the H5N1 Evolution Working Group. NA sequences are classified into subtypes N1–N10. ClassyFlu was compared to semiautomatic classification approaches using BLAST and phylogenetics and additionally for H5 sequences to the new “Highly Pathogenic H5N1 Clade Classification Tool” (IRD-CT) proposed by the Influenza Research Database. Our results show that both web tools (ClassyFlu and IRD-CT), although based on different methods, are nearly equivalent in performance and both are more accurate and faster than semiautomatic classification. A retraining of ClassyFlu to altered cladistics as well as an extension of ClassyFlu to other IAV genome segments or fragments thereof is undemanding. This is exemplified by unambiguous assignment to a distinct cluster within subtype H7 of sequences of H7N9 viruses which emerged in China early in 2013 and caused more than 130 human infections. http://bioinf.uni-greifswald.de/ClassyFlu is a free web service. For local execution, the ClassyFlu source code in PERL is freely available.