ALBERT

Description: Effects of benzoic acid (BA) on physicochemical properties and ecotoxicities of CuO nanoparticles (CuONPs) in model aqueous media were studied. The CuONPs had larger hydrodynamic sizes and higher surface zeta potentials during 96 h of settling in the presence of BA than when the BA were not present. BA interaction with CuONPs is shown to promote dissolved Cu release from CuONPs in a dose-dependent manner. The contribution of free Cu 2+ -ions to growth inhibition toxicity of the CuONP suspensions at a toxicologically relevant concentration for the green alga Scenedesmus obliquus was around 22 %, indicating that dissolved fraction was not the major source of toxicity of CuONPs. The toxicity of CuONPs increased as the BA concentration increased. BA significantly altered total antioxidant capacity of CuONPs-exposed algal cells. The mechanism of the BA effect on the CuONPs toxicity may be mainly associated with degree of agglomeration, dissolved Cu, and particle-induced oxidative stress.

Description: Mussel samples were collected monthly between October-2010 and October-2011 from four stations (Bosphorus, Bandırma, Gelibolu, Tekirdağ) in the Marmara Sea. Two consecutive months’ samples were homogenized and combined as a single group for analysis. Mussel samples were analyzed for Organochlorine pesticides (OCPs); (total-DDT, total-HCH, Endrin, α-Endosulfan, β-Endosulfan, Heptachlor) and Polychlorinated biphenyls (PCBs); (PCB 28, PCB 52, PCB 138, PCB 153, and PCB 180). All analyses were done according to Eurofins house method in ERGO Laboratory in Germany. Concentrations of α-endosulfan and heptachlor in mussel tissues were below method detection limits. The annual average OCPs concentrations among the stations ranged between 0.02 and 1.45 ng/g (wet weight), 1.9–99.75 ng/g (lipid weight) whereas the annual average PCBs concentrations among the stations ranged between 0.03 and 0.40 ng/g (wet weight), 1.71–26.48 ng/g (lipid weight), respectively. There was no relation between fat content of mussels and residues of the contaminants. PCB 138 and PCB 153 were the most predominant PCBs, while total-DDT and total-HCH were the most predominant OCPs in the mussels. Total-DDT concentrations were higher compared to total-HCH and PCBs isomers. Measured levels were below the national and international committees’ and institutions’ limits for human consumption and protection of aquatic biota.

Description: To monitor environmental pollutants in Faroese biota, samples from a top predator were analysed and put into a spatial and temporal context. Analysis of 20 Great Skua eggs sampled in 2012 from the Faroe Islands showed 〉70 % lower concentrations of legacy persistent organic pollutants (POPs) than in samples analysed in 1977. The 2012 Faroese eggs showed higher concentrations than for eggs in Shetland from about the same period (2008). Eggshells were analysed for sub-lethal effects but there were no detectable effects of legacy POP levels on eggshell colour or thickness. A temporal decline in legacy POPs would indicate a reduction in the general pollutant levels present in the environment as has been shown in other areas of the North Atlantic, but there are significant geographic differences in POPs levels likely due to differences in diet resulting in significantly different exposures on a relatively limited spatial scale.

Description: Motivation: Random sampling of the solution space has emerged as a popular tool to explore and infer properties of large metabolic networks. However, conventional sampling approaches commonly used do not eliminate thermodynamically unfeasible loops. Results: In order to overcome this limitation, we developed an efficient sampling algorithm called loopless Artificially Centered Hit-and-Run on a Box (ll-ACHRB). This algorithm is inspired by the Hit-and-Run on a Box algorithm for uniform sampling from general regions, but employs the directions of choice approach of Artificially Centered Hit-and-Run. A novel strategy for generating feasible warmup points improved both sampling efficiency and mixing. ll-ACHRB shows overall better performance than current strategies to generate feasible flux samples across several models. Furthermore, we demonstrate that a failure to eliminate unfeasible loops greatly affects sample statistics, in particular the correlation structure. Finally, we discuss recommendations for the interpretation of sampling results and possible algorithmic improvements. Availability and implementation: Source code for MATLAB and OCTAVE including examples are freely available for download at http://www.aibn.uq.edu.au/cssb-resources under Software. Optimization runs can use Gurobi Optimizer (by default if available) or GLPK (included with the algorithm). Contact: lars.nielsen@uq.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Effects of acute exposure to sublethal waterborne cadmium (Cd) on energy homeostasis in filter-feeding fishes have rarely been studied. The response patterns of energy substances were investigated in juvenile silver carp ( Hypophthalmichthys molitrix ) exposed to sublethal waterborne Cd for 96 h. The results showed the 96hLC 50 of Cd on juvenile silver carp was 1.723 mg/L. Sublethal acute exposure of Cd significantly affected the energy homeostasis of juvenile silver carp, including increase in plasma glucose and lactate, and decrease in plasma triglyceride, muscle glycogen and triglyceride and liver glycogen. The results indicated that glycogen and triglyceride prior to protein were mobilized to meet the increased demands for detoxication and repair mechanism to sublethal waterborne Cd exposure, and glycogen level depleted faster and restored slower in the liver than in the white muscle in juvenile silver carp.

Description: Nickel (Ni) and copper (Cu) are the most prevalent metals found in the soils in the Greater Sudbury Region (Canada) because of smelting emissions. The main objectives of the present study were to (1) determine the toxicity of nickel (Ni) and copper (Cu) at different doses in Betula papyrifera (white birch), (2) Characterize nickel resistance mechanism, and (3) assess segregating patterns for Ni and Cu resistance in B. papyrifera populations. This study revealed that B. papyrifera is resistant to Ni and Cu concentrations equivalent to the levels reported in metal-contaminated stands in the GSR. Resistant genotypes (RG) accumulate Ni in roots but not in leaves. Moderately susceptible (MSG) and susceptible genotypes (SG) show a high level of Ni translocation to leaves. Gene expression analysis showed differential regulation of genes in RG compared to MSG and SG. Analysis of segregation patterns suggests that resistance to Ni and Cu is controlled by single recessive genes.

Description: Nano-sized palladium (nano-Pd) is used in catalytic converters of automobiles, where it can be released into the environment by abrasion. Although these particles may subsequently be transported into surface water bodies, no data estimating their fate and toxicity in aquatic systems exists. This study characterized the particle size development of nano-Pd (advertised size ~12 nm; hydrodynamic size ~70 nm) in media with variable ionic strength (IS). Additionally, the particles’ acute toxicity for daphnids and chironomids was assessed. While nano-Pd agglomerated more quickly with increasing IS, it caused only marginal effects in both test species after 96 h of exposure. After 144 h of exposure, however, an EC 50 value of 1.23 mg nano-Pd/L for daphnids was determined indicating effects over the long run. When considering the relatively low environmental concentration of elemental Pd in surface waters (usually ng/L), though, this study suggests only a low aquatic risk in response to nano-Pd.

Description: Results: Here, we present a comprehensive analysis on the reproducibility of computational characterization of genomic variants using high throughput sequencing data. We reanalyzed the same datasets twice, using the same tools with the same parameters, where we only altered the order of reads in the input (i.e. FASTQ file). Reshuffling caused the reads from repetitive regions being mapped to different locations in the second alignment, and we observed similar results when we only applied a scatter/gather approach for read mapping—without prior shuffling. Our results show that, some of the most common variation discovery algorithms do not handle the ambiguous read mappings accurately when random locations are selected. In addition, we also observed that even when the exact same alignment is used, the GATK HaplotypeCaller generates slightly different call sets, which we pinpoint to the variant filtration step. We conclude that, algorithms at each step of genomic variation discovery and characterization need to treat ambiguous mappings in a deterministic fashion to ensure full replication of results. Availability and Implementation: Code, scripts and the generated VCF files are available at DOI:10.5281/zenodo.32611. Contact: calkan@cs.bilkent.edu.tr Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Animals from worms and insects to birds and mammals show distinct body plans; however, the embryonic development of diverse body plans with tissues and organs within is controlled by a surprisingly few signaling pathways. It is well recognized that combinatorial use of and dynamic interactions among signaling pathways follow specific logic to control complex and accurate developmental signaling and patterning, but it remains elusive what such logic is, or even, what it looks like. Results: We have developed a computational model for Drosophila eye development with innovated methods to reveal how interactions among multiple pathways control the dynamically generated hexagonal array of R8 cells. We obtained two novel findings. First, the coupling between the long-range inductive signals produced by the proneural Hh signaling and the short-range restrictive signals produced by the antineural Notch and EGFR signaling is essential for generating accurately spaced R8s. Second, the spatiotemporal orders of key signaling events reveal a robust pattern of lateral inhibition conducted by Ato-coordinated Notch and EGFR signaling to collectively determine R8 patterning. This pattern, stipulating the orders of signaling and comparable to the protocols of communication, may help decipher the well-appreciated but poorly defined logic of developmental signaling. Availability and implementation: The model is available upon request. Contact: hao.zhu@ymail.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: The growing amount of regulatory data from the ENCODE, Roadmap Epigenomics and other consortia provides a wealth of opportunities to investigate the functional impact of single nucleotide polymorphisms (SNPs). Yet, given the large number of regulatory datasets, researchers are posed with a challenge of how to efficiently utilize them to interpret the functional impact of SNP sets. Results: We developed the GenomeRunner web server to automate systematic statistical analysis of SNP sets within a regulatory context. Besides defining the functional impact of SNP sets, GenomeRunner implements novel regulatory similarity/differential analyses, and cell type-specific regulatory enrichment analysis. Validated against literature- and disease ontology-based approaches, analysis of 39 disease/trait-associated SNP sets demonstrated that the functional impact of SNP sets corresponds to known disease relationships. We identified a group of autoimmune diseases with SNPs distinctly enriched in the enhancers of T helper cell subpopulations, and demonstrated relevant cell type-specificity of the functional impact of other SNP sets. In summary, we show how systematic analysis of genomic data within a regulatory context can help interpreting the functional impact of SNP sets. Availability and Implementation: GenomeRunner web server is freely available at http://www.integrativegenomics.org/ . Contact: mikhail.dozmorov@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Adverse drug reactions (ADRs) are a central consideration during drug development. Here we present a machine learning classifier to prioritize ADRs for approved drugs and pre-clinical small-molecule compounds by combining chemical structure (CS) and gene expression (GE) features. The GE data is from the Library of Integrated Network-based Cellular Signatures (LINCS) L1000 dataset that measured changes in GE before and after treatment of human cells with over 20 000 small-molecule compounds including most of the FDA-approved drugs. Using various benchmarking methods, we show that the integration of GE data with the CS of the drugs can significantly improve the predictability of ADRs. Moreover, transforming GE features to enrichment vectors of biological terms further improves the predictive capability of the classifiers. The most predictive biological-term features can assist in understanding the drug mechanisms of action. Finally, we applied the classifier to all 〉20 000 small-molecules profiled, and developed a web portal for browsing and searching predictive small-molecule/ADR connections. Availability and Implementation: The interface for the adverse event predictions for the 〉20 000 LINCS compounds is available at http://maayanlab.net/SEP-L1000/ . Contact: avi.maayan@mssm.edu Supplementary information : Supplementary data are available at Bioinformatics online.

Description: Motivation: Environmental dissemination of antibiotic resistance genes (ARGs) has become an increasing concern for public health. Metagenomics approaches can effectively detect broad profiles of ARGs in environmental samples; however, the detection and subsequent classification of ARG-like sequences are time consuming and have been severe obstacles in employing metagenomic methods. We sought to accelerate quantification of ARGs in metagenomic data from environmental samples. Results: A Structured ARG reference database (SARG) was constructed by integrating ARDB and CARD, the two most commonly used databases. SARG was curated to remove redundant sequences and optimized to facilitate query sequence identification by similarity. A database with a hierarchical structure (type-subtype-reference sequence) was then constructed to facilitate classification (assigning ARG-like sequence to type, subtype and reference sequence) of sequences identified through similarity search. Utilizing SARG and a previously proposed hybrid functional gene annotation pipeline, we developed an online pipeline called ARGs-OAP for fast annotation and classification of ARG-like sequences from metagenomic data. We also evaluated and proposed a set of criteria important for efficiently conducting metagenomic analysis of ARGs using ARGs-OAP. Availability and Implementation: Perl script for ARGs-OAP can be downloaded from https://github.com/biofuture/Ublastx_stageone . ARGs-OAP can be accessed through http://smile.hku.hk/SARGs . Contact: zhangt@hku.hk or tiedjej@msu.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : Visualizing genomic data in chromosomal context can help detecting errors in data processing and may suggest new hypotheses to be tested. Here, we report a new tool for displaying large and diverse genomic data along chromosomes. The software is implemented in R so that visualization can be easily integrated with its numerous packages for processing genomic data. It supports simultaneous visualization of multiple tracks of data. Large genomic regions such as QTLs or synteny tracts may be shown along histograms of number of genes, genetic variants, or any other type of genomic element. Tracks can also contain values for continuous or categorical variables and the user can choose among points, connected lines, colored segments, or histograms for representing data. chromPlot takes data from tables in data.frame in GRanges formats. The information necessary to draw chromosomes for mouse and human is included with the package. For other organisms, chromPlot can read Gap and cytoBandIdeo tables from the UCSC Genome Browser. We present common use cases here, and a full tutorial is included as the package’s vignette. Availability and Implementation: chromPlot is distributed under a GLP2 licence at http://www.bioconductor.org . Contact: raverdugo@u.uchile.cl Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : The most important features of error correction tools for sequencing data are accuracy, memory efficiency and fast runtime. The previous version of BLESS was highly memory-efficient and accurate, but it was too slow to handle reads from large genomes. We have developed a new version of BLESS to improve runtime and accuracy while maintaining a small memory usage. The new version, called BLESS 2, has an error correction algorithm that is more accurate than BLESS, and the algorithm has been parallelized using hybrid MPI and OpenMP programming. BLESS 2 was compared with five top-performing tools, and it was found to be the fastest when it was executed on two computing nodes using MPI, with each node containing twelve cores. Also, BLESS 2 showed at least 11% higher gain while retaining the memory efficiency of the previous version for large genomes. Availability and implementation: Freely available at https://sourceforge.net/projects/bless-ec Contact: dchen@illinois.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Accurate segmentation of brain electron microscopy (EM) images is a critical step in dense circuit reconstruction. Although deep neural networks (DNNs) have been widely used in a number of applications in computer vision, most of these models that proved to be effective on image classification tasks cannot be applied directly to EM image segmentation, due to the different objectives of these tasks. As a result, it is desirable to develop an optimized architecture that uses the full power of DNNs and tailored specifically for EM image segmentation. Results: In this work, we proposed a novel design of DNNs for this task. We trained a pixel classifier that operates on raw pixel intensities with no preprocessing to generate probability values for each pixel being a membrane or not. Although the use of neural networks in image segmentation is not completely new, we developed novel insights and model architectures that allow us to achieve superior performance on EM image segmentation tasks. Our submission based on these insights to the 2D EM Image Segmentation Challenge achieved the best performance consistently across all the three evaluation metrics. This challenge is still ongoing and the results in this paper are as of June 5, 2015. Availability and Implementation : https://github.com/ahmed-fakhry/dive Contact : sji@eecs.wsu.edu

Description: : Hilbert curves enable high-resolution visualization of genomic data on a chromosome- or genome-wide scale. Here we present the HilbertCurve package that provides an easy-to-use interface for mapping genomic data to Hilbert curves. The package transforms the curve as a virtual axis, thereby hiding the details of the curve construction from the user. HilbertCurve supports multiple-layer overlay that makes it a powerful tool to correlate the spatial distribution of multiple feature types. Availability and implementation: The HilbertCurve package and documentation are freely available from the Bioconductor project: http://www.bioconductor.org/packages/devel/bioc/html/HilbertCurve.html Contact: m.schlesner@dkfz.de Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: The sequences among subgenomes in a polyploid species have high similarity, making it difficult to design genome-specific primers for sequence analysis. Results: We present GSP, a web-based platform to design genome-specific primers that distinguish subgenome sequences in a polyploid genome. GSP uses BLAST to extract homeologous sequences of the subgenomes in existing databases, performs a multiple sequence alignment, and design primers based on sequence variants in the alignment. An interactive primers diagram, a sequence alignment viewer and a virtual electrophoresis are displayed as parts of the primer design result. GSP also designs specific primers from multiple sequences uploaded by users. Availability and implementation: GSP is a user-friendly and efficient web platform freely accessible at http://probes.pw.usda.gov/GSP . Source code and command-line application are available at https://github.com/bioinfogenome/GSP . Contacts: yong.gu@ars.usda.gov or devin.coleman-derr@ars.usda.gov Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : The prediction of protein–protein complexes from the structures of unbound components is a challenging and powerful strategy to decipher the mechanism of many essential biological processes. We present a user-friendly protein–protein docking server based on an improved version of FRODOCK that includes a complementary knowledge-based potential. The web interface provides a very effective tool to explore and select protein–protein models and interactively screen them against experimental distance constraints. The competitive success rates and efficiency achieved allow the retrieval of reliable potential protein–protein binding conformations that can be further refined with more computationally demanding strategies. Availability and Implementation: The server is free and open to all users with no login requirement at http://frodock.chaconlab.org Contact: pablo@chaconlab.org Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : XIBD performs pairwise relatedness mapping on the X chromosome using dense single nucleotide polymorphism (SNP) data from either SNP chips or next generation sequencing data. It correctly accounts for the difference in chromosomal numbers between males and females and estimates global relatedness as well as regions of the genome that are identical by descent (IBD). XIBD also generates novel graphical summaries of all pairwise IBD tracts for a cohort making it very useful for disease locus mapping. Availability and implementation: XIBD is written in R/Rcpp and executed from shell scripts that are freely available from http://bioinf.wehi.edu.au/software/XIBD along with accompanying reference datasets. Contact: henden.l@wehi.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : Several approaches to the region-based association analysis of quantitative traits have recently been developed and successively applied. However, no software package has been developed that implements all of these approaches for either independent or structured samples. Here we introduce FREGAT (Family REGional Association Tests), an R package that can handle family and population samples and implements a wide range of region-based association methods including burden tests, functional linear models, and kernel machine-based regression. FREGAT can be used in genome/exome-wide region-based association studies of quantitative traits and candidate gene analysis. FREGAT offers many useful options to empower its users and increase the effectiveness and applicability of region-based association analysis. Availability and Implementation: https://cran.r-project.org/web/packages/FREGAT/index.html Supplementary Information: Supplementary data are available at Bioinformatics Online. Contact: belon@bionet.nsc.ru

Description: Motivation: There is a growing need in bioinformatics for easy-to-use software implementations of algorithms that are usable across platforms. At the same time, reproducibility of computational results is critical and often a challenge due to source code changes over time and dependencies. Results: The approach introduced in this paper addresses both of these needs with AlgoRun, a dedicated packaging system for implemented algorithms, using Docker technology. Implemented algorithms, packaged with AlgoRun, can be executed through a user-friendly interface directly from a web browser or via a standardized RESTful web API to allow easy integration into more complex workflows. The packaged algorithm includes the entire software execution environment, thereby eliminating the common problem of software dependencies and the irreproducibility of computations over time. AlgoRun-packaged algorithms can be published on http://algorun.org , a centralized searchable directory to find existing AlgoRun-packaged algorithms. Availability and implementation: AlgoRun is available at http://algorun.org and the source code under GPL license is available at https://github.com/algorun Contact: laubenbacher@uchc.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: This study continued our previous work (Sai et al. in Bull Environ Contam Toxicol 95:157–163, 2015a ) by analysing the effects of simazine on the liver histological structure and metamorphosis in the developing Xenopus laevis . Tadpoles (Nieuwkoop-Faber stage 46) were exposed to simazine at 0.1, 1.2, 11.0 and 100.9 μg/L for 100 days. When tadpoles were exposed to simazine at 11.0 and 100.9 µg/L, an increased mortality and damaged liver tissues were observed together with significant inhibition of percent of X . laevis completing metamorphosis on days 80 and 90 and prolonged time of completing metamorphosis. On the other hand, we found that simazine has no significant effects on liver weight and altered hepatosomatic index. Results of this study may be considered to inform risk assessment of the effects of simazine on the development of X . laevis .

Description: This study assessed the effects of road-related alteration of substrate, including increased salinity, on vegetation along a meridional gradient in Fennoscandia. Vegetation community composition were surveyed in 29 randomly selected 1-m 2 sized roadside plots. Number of plant species and plant cover (%) on the plots were positively interrelated ( p  〈 0.0001). Both variables also decreased towards the north and with increasing coarseness of the substrate. Canonical correspondence analysis (CCA) indicated that roadside vegetation diversity and composition were most related to the importance of the road (i.e. its size and traffic intensity) and substrate pH. Road importance affects plant dispersal, whereas substrate pH was found to be a factor limiting growth. CCA indicated also that vegetation composition was affected by the meridional gradient and by the substrate salinity; both substrate salinity pH and salinity were not related to meridional gradient. Our results indicate that roadside vegetation diversity and composition is driven by natural and anthropogenic factors.

Description: Motivation: Genome browsers that support fast navigation through vast datasets and provide interactive visual analytics functions can help scientists achieve deeper insight into biological systems. Toward this end, we developed Integrated Genome Browser (IGB), a highly configurable, interactive and fast open source desktop genome browser. Results: Here we describe multiple updates to IGB, including all-new capabilities to display and interact with data from high-throughput sequencing experiments. To demonstrate, we describe example visualizations and analyses of datasets from RNA-Seq, ChIP-Seq and bisulfite sequencing experiments. Understanding results from genome-scale experiments requires viewing the data in the context of reference genome annotations and other related datasets. To facilitate this, we enhanced IGB’s ability to consume data from diverse sources, including Galaxy, Distributed Annotation and IGB-specific Quickload servers. To support future visualization needs as new genome-scale assays enter wide use, we transformed the IGB codebase into a modular, extensible platform for developers to create and deploy all-new visualizations of genomic data. Availability and implementation: IGB is open source and is freely available from http://bioviz.org/igb . Contact: aloraine@uncc.edu

Description: Motivation: Single Molecule Real-Time (SMRT) sequencing technology and Oxford Nanopore technologies (ONT) produce reads over 10 kb in length, which have enabled high-quality genome assembly at an affordable cost. However, at present, long reads have an error rate as high as 10–15%. Complex and computationally intensive pipelines are required to assemble such reads. Results: We present a new mapper, minimap and a de novo assembler, miniasm, for efficiently mapping and assembling SMRT and ONT reads without an error correction stage. They can often assemble a sequencing run of bacterial data into a single contig in a few minutes, and assemble 45-fold Caenorhabditis elegans data in 9 min, orders of magnitude faster than the existing pipelines, though the consensus sequence error rate is as high as raw reads. We also introduce a pairwise read mapping format and a graphical fragment assembly format, and demonstrate the interoperability between ours and current tools. Availability and implementation: https://github.com/lh3/minimap and https://github.com/lh3/miniasm Contact: hengli@broadinstitute.org Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Alternative splicing represents a prime mechanism of post-transcriptional gene regulation whose misregulation is associated with a broad range of human diseases. Despite the vast availability of transcriptome data from different cell types and diseases, bioinformatics-based surveys of alternative splicing patterns remain a major challenge due to limited availability of analytical tools that combine high accuracy and rapidity. Results: We describe here a novel junction-centric method, jSplice, that enables de novo extraction of alternative splicing events from RNA-sequencing data with high accuracy, reliability and speed. Application to clear cell renal carcinoma (ccRCC) cell lines and 65 ccRCC patients revealed experimentally validatable alternative splicing changes and signatures able to prognosticate ccRCC outcome. In the aggregate, our results propose jSplice as a key analytic tool for the derivation of cell context-dependent alternative splicing patterns from large-scale RNA-sequencing datasets. Availability and implementation: jSplice is a standalone Python application freely available at http://www.mhs.biol.ethz.ch/research/krek/jsplice . Contact: wilhelm.krek@biol.ethz.ch Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Single-cell RNA-sequencing technology allows detection of gene expression at the single-cell level. One typical feature of the data is a bimodality in the cellular distribution even for highly expressed genes, primarily caused by a proportion of non-expressing cells. The standard and the over-dispersed gamma-Poisson models that are commonly used in bulk-cell RNA-sequencing are not able to capture this property. Results: We introduce a beta-Poisson mixture model that can capture the bimodality of the single-cell gene expression distribution. We further integrate the model into the generalized linear model framework in order to perform differential expression analyses. The whole analytical procedure is called BPSC. The results from several real single-cell RNA-seq datasets indicate that ~90% of the transcripts are well characterized by the beta-Poisson model; the model-fit from BPSC is better than the fit of the standard gamma-Poisson model in 〉 80% of the transcripts. Moreover, in differential expression analyses of simulated and real datasets, BPSC performs well against edgeR, a conventional method widely used in bulk-cell RNA-sequencing data, and against scde and MAST, two recent methods specifically designed for single-cell RNA-seq data. Availability and Implementation: An R package BPSC for model fitting and differential expression analyses of single-cell RNA-seq data is available under GPL-3 license at https://github.com/nghiavtr/BPSC . Contact: yudi.pawitan@ki.se or mattias.rantalainen@ki.se Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Biological network querying is a problem requiring a considerable computational effort to be solved. Given a target and a query network, it aims to find occurrences of the query in the target by considering topological and node similarities (i.e. mismatches between nodes, edges, or node labels). Querying tools that deal with similarities are crucial in biological network analysis because they provide meaningful results also in case of noisy data. In addition, as the size of available networks increases steadily, existing algorithms and tools are becoming unsuitable. This is rising new challenges for the design of more efficient and accurate solutions. Results: This paper presents APPAGATO , a stochastic and parallel algorithm to find approximate occurrences of a query network in biological networks. APPAGATO handles node, edge and node label mismatches. Thanks to its randomic and parallel nature, it applies to large networks and, compared with existing tools, it provides higher performance as well as statistically significant more accurate results. Tests have been performed on protein–protein interaction networks annotated with synthetic and real gene ontology terms. Case studies have been done by querying protein complexes among different species and tissues. Availability and implementation: APPAGATO has been developed on top of CUDA-C ++ Toolkit 7.0 framework. The software is available online http://profs.sci.univr.it/~bombieri/APPAGATO . Contact: rosalba.giugno@univr.it Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : We introduce SharpViSu, an interactive open-source software with a graphical user interface, which allows performing processing steps for localization data in an integrated manner. This includes common features and new tools such as correction of chromatic aberrations, drift correction based on iterative cross-correlation calculations, selection of localization events, reconstruction of 2D and 3D datasets in different representations, estimation of resolution by Fourier ring correlation, clustering analysis based on Voronoi diagrams and Ripley’s functions. SharpViSu is optimized to work with eventlist tables exported from most popular localization software. We show applications of these on single and double-labelled super-resolution data. Availability and implementation: SharpViSu is available as open source code and as compiled stand-alone application under https://github.com/andronovl/SharpViSu . Contact: klaholz@igbmc.fr Supplementary information: Supplementary data are available at Bioinformatics online.

Description: The antimicrobial activity of silver nanoparticles (AgNP) makes them useful in a wide range of products although their environmental impact is still uncertain. The main goal of this study was to evaluate short-term effects induced by AgNP on gills oxidative status and bacterial communities living at the skin mucus of zebrafish. Both the number of bacteria colony forming units and bacteria growth obtained from skin mucus were lower in all concentrations tested (25, 50 and 100 µg nAg/L). Besides, AgNP exposure caused a significant decrease in bacteria growth in zebrafish exposed to 100 µg nAg/L. AgNP accumulated in zebrafish gills at both highest concentrations tested, but this accumulation did not appear to result in oxidative stress. Overall the results indicated toxicological effects of AgNP on bacteria communities living at the zebrafish mucus surface. Although silver accumulation was verified in gills, no evidence of toxicity in terms of oxidative stress was found.

Description: Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant. Although multiple adverse effects of PFOS have been demonstrated, whether PFOS can accelerate aging and affect animal longevity remains unknown. In Caenorhabditis elegans , we found that a 50 h exposure to 0.2–200 µM PFOS reduced lifespan in a concentration dependent manner. In transgenic nematodes, lifespans are affected by mutations of daf - 16 , daf - 2 or age - 1 genes, which are related to the Insulin/IGF-1 Signaling pathway (IIS). PFOS exposure caused an additional reduction in average lifespan in daf - 2 ( e1370 ) and daf - 16b ( KO ) nematodes. In contrast, daf - 16 ( mu86 ) nematodes showed no additional reduction with PFOS exposure and age - 1 ( hx546 ) mutants did not exhibit a reduction in lifespan with PFOS exposure, compared with wildtype nematodes. Overall, our findings demonstrate that PFOS exposure accelerates aging and shortens longevity of animals. The PFOS-induced effect may involve genes of the IIS pathway, particularly daf - 16 and age - 1 .

Description: Two-stage in situ wetlands (two vertical flow constructed wetlands in parallel and a horizontal flow constructed wetland) were constructed for studying domestic wastewater purification and the correlations between contaminant removal and plant and soil enzyme activities. Results indicated the removal efficiency of NH 4 + and NO 3 − were significantly correlated with both urease and protease activity, and the removal of total phosphorus was significantly correlated with phosphatase activity. Chemical oxygen demand removal was not correlated with enzyme activity in constructed wetlands. Plant root enzyme (urease, phosphatase, protease and cellulose) activity correlation was apparent with all contaminant removal in the two vertical flow constructed wetlands. However, the correlation between the plant root enzyme activity and contaminant removal was poor in horizontal flow constructed wetlands. Results indicated that plant roots clearly played a role in the removal of contaminants.

Description: The objectives of this study were to determine the suitability of total serum lipid (TSL) concentrations, which were calculated by three different formulae, for pregnant women and to optimize the improved matrix solid-phase dispersion (MSPD) method. The results showed that the TSL predicted by the three formulae were significantly correlated to our measured values (sums of the total cholesterol, triglycerides and phospholipids contents). In particular, one of formulae was the most statistically suitable for pregnant women. Meanwhile, an improved MSPD method was developed to extract 22 POPs. The developed MSPD method was compared with SPE and EPA (8081 & 8082) to evaluate the performance of each extract method. The method validation showed that the results obtained using the improved MSPD method were closest to the actual concentration (adjusted by lipids), and the dispersion of the data was minimal.

Description: Cave ecosystems remain largely unstudied and risk being severely degraded as a result of anthropogenic activities. The Wonderfontein Cave, situated in the extensive gold mining region of the Witwatersrand Basin, is one such system that hosts a population of Clarias gariepinus , which is exposed to the influx of polluted mine water from the Wonderfontein Spruit River. The aim of this study was to investigate the bioaccumulation of metals, as well as relevant biomarkers, in C. gariepinus specimens sampled from the Wonderfontein Cave during high (April 2013) and low (September 2013) flow surveys. Results were also compared to a surface population associated with the Wonderfontein Spruit River. There were temporal differences in metal bioaccumulation patterns and this was attributed to the lack of dilution during the low flow period. Metals associated with acid mine drainage, i.e. Co, Mn and Zn were significantly higher in the Wonderfontein Cave population and were reflected in an increase in oxidative stress biomarkers (catalase, protein carbonyls and superoxide dismutase) and the induction of metallothionein, a biomarker of metal exposure. The surface population was exposed to metals associated with geological weathering processes, i.e. Fe and Al.

Description: Non-steroid anti-inflammatory drugs (NSAIDs) have been frequently detected in aquatic ecosystem and posed a huge risk to non-target organisms. The aim of this study was to evaluate the toxic effects of three typical NSAIDs, diclofenac (DFC), acetaminophen (APAP) and ibuprofen (IBP), toward the water flea Daphnia magna . All three NSAIDs showed remarkable time-dependent and concentration-dependent effects on D. magna , with DFC the highest and APAP the lowest toxic. Survival, growth and reproduction data of D. magna from all bioassays were used to determine the LC10 and LC50 (10 % lethal and median lethal concentrations) values of NSAIDs, as well as the EC10 and EC50 (10 % effect and median effect concentrations) values. Concentrations for the lethal and sublethal toxicity endpoints were mainly in the low ppm-range, of which reproduction was the most sensitive one, indicating that non-target organisms might be adversely affected by relevant ambient low-level concentrations of NSAIDs after long-time exposures.

Description: Avoidance of copper (Cu) by rainbow trout ( Oncorhynchus mykiss ) was evaluated using a Y-maze exposure system, with data collected over a 1-h exposure period using a digital camcorder. In exposures to five measured concentrations of dissolved copper (〈0.3, 1.2, 9.8, 48.3, and 98.6 µg Cu/L), plus control, significant avoidance behavior ( p  〈 0.05) relative to the control was observed at ≥9.8 µg Cu/L, but not at 1.2 µg Cu/L. The chronic value (i.e., geometric mean of these concentrations) was 3.43 µg Cu/L. Estimates of EC 50 values for avoidance of Cu ranged from 4.81 to 9.15 µg Cu/L over four 15-min time intervals of exposure to the metal. Based on water quality characterization of the control/diluent water, the U.S. Environmental Protection Agency (USEPA) water hardness- and biotic ligand model (BLM)-based chronic criteria for dissolved Cu were 8.03 and 2.26 µg Cu/L, respectively. This study suggested that enforcement of the BLM-based criterion would provide a higher level of protection of trout for this sensitive response than the hardness-based criterion.

Description: : A gene tree-species tree reconciliation explains the evolution of a gene tree within the species tree given a model of gene-family evolution. We describe ecceTERA, a program that implements a generic parsimony reconciliation algorithm, which accounts for gene duplication, loss and transfer (DTL) as well as speciation, involving sampled and unsampled lineages, within undated, fully dated or partially dated species trees. The ecceTERA reconciliation model and algorithm generalize or improve upon most published DTL parsimony algorithms for binary species trees and binary gene trees. Moreover, ecceTERA can estimate accurate species-tree aware gene trees using amalgamation. Availability and implementation : ecceTERA is freely available under http://mbb.univ-montp2.fr/MBB/download_sources/16__ecceTERA and can be run online at http://mbb.univ-montp2.fr/MBB/subsection/softExec.php?soft=eccetera . Contact: celine.scornavacca@umontpellier.fr Supplementary information: Supplementary data are available at Bioinformatics online.

Description: The aquatic environment is becoming increasingly contaminated with pharmaceuticals. Salicylic acid (SA), which can be used individually or appear as a degradation product of the widely used acetylsalicylic acid was chosen for testing. Juvenile zebrafish Danio rerio were subjected to OECD test No. 215 (fish, juvenile growth test) with salicylic acid concentrations of 0.004; 0.04; 0.4; 4 and 40 mg/L. Specific growth rate (SGR), histological changes, and parameters of oxidative stress were evaluated. SA had no effects on histological changes, SGR, glutathione reductase, and lipid peroxidation. Increased catalytic activity of GPx was found at 0.04 mg/L compared to control, increased catalytic activity of catalase was found at 0.04 and 4 mg/L compared to control, and increased catalytic activity of glutathione- S -transferase was found at 0.004 and 0.04 mg/L compared to control ( P  〈 0.05). Juvenile zebrafish turned out to be relatively insensitive to both environmentally relevant (0.004 mg/L) and higher concentrations of salicylic acid.

Description: : The popularity of using NMR spectroscopy in metabolomics and natural products has driven the development of an array of NMR spectral analysis tools and databases. Particularly, web applications are well used recently because they are platform-independent and easy to extend through reusable web components. Currently available web applications provide the analysis of NMR spectra. However, they still lack the necessary processing and interactive visualization functionalities. To overcome these limitations, we present NMRPro, a web component that can be easily incorporated into current web applications, enabling easy-to-use online interactive processing and visualization. NMRPro integrates server-side processing with client-side interactive visualization through three parts: a python package to efficiently process large NMR datasets on the server-side, a Django App managing server-client interaction, and SpecdrawJS for client-side interactive visualization. Availability and implementation: Demo and installation instructions are available at http://mamitsukalab.org/tools/nmrpro/ Contact: mohamed@kuicr.kyoto-u.ac.jp Supplementary information: Supplementary data are available at Bioinformatics online.

Description: In this study, seven kinds of synthetic musks were characterized in sediment samples of Yellow River Delta wetland, including celestolide, phantolide, traseolide, galaxolide, tonalide, musk xylene, and musk ketone. They were analyzed using gas chromatography–mass spectrometry (GC–MS), with recoveries of 91.85 %–105.35 % and the relative standard deviation (% RSD) were 3.30 %–8.11 % for all analytes. Galaxolide and tonalide were the main musk contaminants which were detected in sediment samples. The total concentrations of galaxolide ranged from 1.42 to 8.60 ng/g (mean 2.92 ng/g) (dry weight, dw); the total concentrations of tonalide ranged from the detection limit (LOD) to 3.63 ng/g (mean 1.69 ng/g, dw). The one reason of the higher level of SM pollutants was the domestic wastewater dumped by the local residents in some sites. And there was no significant correlation between SMs and TOC in sediment samples of Yellow River Delta wetland ( p  〉 0.05).

Description: Part of a 20–60 kb staphylococcal chromosome cassette called mec A encodes low-affinity penicillin-binding protein PBP2a and causes methicillin resistance. Among all methicillin-resistant bacteria, methicillin-resistant Staphylococcus aureus is a major pathogen and main concern worldwide. Although the origin of the mec A is not very well-defined, mec A homologues are also ubiquitous in methicillin-resistant non-staphylococcal bacteria. Due to the dissemination of methicillin resistance through the transmission of mec A gene among staphylococcal and non-staphylococcal bacteria inhabiting surface waters, there is a need to monitor mec A gene in these waters for public health safety. Therefore, this study aimed at monitoring mec A harboring bacteria inhabiting surface waters by using fluorescently labelled mec A-targeted oligonucleotide probes. Under the hybridization conditions of 55 % formamide and 0.020 M NaCl at 46°C, the oligonucleotide probe used in the study showed high hybridization stringency to the mec A gene targeted. The strong linear relationships observed between the signal intensity and the target gene were used to assess the population dynamics of mec A harboring isolates over a 2-year-period. The results indicated that mec A-targeted oligonucleotide probes can be effectively used for in situ monitoring of methicillin resistant isolates inhabiting surface waters.

Description: A simple, selective and highly sensitive spectrophotometric method has been developed for mercury determination utilizing its catalytic effect on the isoniazid-hexacyanoferrate (II) reaction. The paper presents for the first time (1) the catalytic effect of Hg (I) on the cited ligand substitution reactions and (2) the activating effect of thiourea on the behavior of mercury. The reaction was monitored spectrophotometrically at 423 nm using the initial rate method. The optimized reaction conditions were 5.0 mmol L −1 hexacyanoferrate (II), 0.5 mmol L −1 isoniazid, 150 mmol L −1 citrate buffer (pH 3.30 ± 0.05), and 0.2 mmol L −1 thiourea, at 50°C. Linear calibration graphs were obtained for 1–100 and 1–55 µg L −1 with detection limits, based on the 3S b -criterion, of 1.2 and 1.8 µg L −1 of Hg (II) and Hg (I), respectively. The method was conveniently applied to samples of wastewaters, inactivated vaccines, and frozen Bass fish fillet, without any prior separation or preconcentration.

Description: Yuma Proving Grounds (YPG) in western Arizona is a testing range where Depleted uranium (DU) penetrators have been historically fired. A portion of the fired DU penetrators are being managed under controlled conditions by leaving them in place. The widespread use of DU in armor-penetrating weapons has raised environmental and human health concerns. The present study is focused on the onsite management approach and on the potential interactions with plants local to YPG. A 30 day study was conducted to assess the toxicity of DU corrosion products (e.g., schoepite and meta-schoepite) in two grass species that are native to YPG, Bermuda ( Cynodon dactylon ) and Purple Threeawn ( Aristida purpurea ). In addition, the ability for plants to uptake DU was studied. The results of this study show a much lower threshold for biomass toxicity and higher plant concentrations, particularly in the roots than shoots, compared to previous studies.

Description: Zebrafish models for mild, moderate, and severe acute organophosphorus poisoning were previously developed by exposing zebrafish larvae to chlopyrifos-oxon. The phenotype of these models was characterized at several levels of biological organization. Oxidative stress and mitochondrial dysfunction were found to be involved in the development of the more severe phenotype. Here we used targeted gene expression to understand the dose-responsiveness of those two pathways and their involvement on generating the different zebrafish models. As the severe phenotype is irreversible after only 3 h of exposure, we also analyzed the response of the oxidative stress pathway at 3 and 24 h. Some of the genes related to oxidative stress were already differentially expressed at 3 h. There was an increase in differentially expressed genes related to both oxidative stress and mitochondrial function from the more mild to the more severe phenotype, suggesting the involvement of these mechanisms in increasing phenotype severity. Temporal data suggest that peroxynitrite leading to lipid peroxidation might be involved in phenotype transition and irreversibility.

Description: Characterizing wastewaters only on a chemical basis may be insufficient owing to their complex nature. The purpose of this study was to assess toxicity of textile dyeing wastewater based on analytical techniques and short term toxicity based bioassays. In this study, screening of the fractionated wastewater through GC–MS showed the presence of phenols, phthalic acid derivatives and chlorpyrifos. Metal analysis revealed that chromium, arsenic and mercury were present in amounts higher than the wastewater discharge limits. Textile dyeing wastewater was found to be highly mutagenic in the Ames test. DNA damage in sheep lymphocytes decreased linearly with an increase in the dilution of wastewater. MTT assay showed that 8.3 percent v/v wastewater decreased cell survival percentage to 50 %. It can be concluded from this study that short term toxicity tests such as Ames test, in vitro comet assay, and cytotoxicity assays may serve as useful indicators of wastewater pollution along with their organic and inorganic chemical characterizations.

Description: Although sewage sludge is a rich source of nutrients for arable farming and soil improvement, it can also be a source of pollutants. The effects of the land application of sludge on the PCB and nutrient content of leachate were investigated using cylindrical 650 mm length columns filled with poor quality soil. Treatments included no fertilization (control), fertilization using a 62.5 t/ha dose (O50) of sewage sludge from the largest Polish Wastewater Treatment Plant, in Lodz, and a 62.5 t/ha dose of sewage sludge mixed with CaO (O50Ca). The leaching of sludge-borne PCBs and nutrients was simulated by the application of distilled water in a quantity reflecting the annual rainfall of 562.5 mm. The obtained results demonstrate that application of sewage sludge and water simulated leaching of the most mobile chemical compounds, nitrate for example, whereas the addition of CaO decreased the average PCB and phosphorus concentrations in comparison to the control and O50 samples.

Description: Arsenic in drinking water is a serious problem for human health. Since the toxicity of arsenic species As(III) and As(V) is different, it is important to determine the concentrations separately. Therefore, it is necessary to develop an accurate and sensitive method for the speciation of arsenic. It was intended with this work to determine the concentrations of arsenic species in water samples collected from Izmir, Manisa and nearby areas. A batch type hydride generation atomic absorption spectrometer was used. As(V) gave no signal under the optimal measurement conditions of As(III). A certified reference drinking water was analyzed by the method and the results showed excellent agreement with the reported values. The procedure was applied to 34 water samples. Eleven tap water, two spring water, 19 artesian well water and two thermal water samples were analyzed under the optimal conditions.

Description: The sorption of radium 226 ( 226 Ra) on different clay materials (bentonite, illite and a mixture of bentonite–illite) was studied. Clay materials are used in the construction of disposal pits for technically enhanced naturally occurring radioactive materials (TENORM) wastes (i.e., contaminated soil and sludge) generated by the oil and gas industry operations. Experimental conditions (pH, clay materials quantity, and activity concentrations of 226 Ra) were changed in order to determine the optimal state for adsorption of 226 Ra. The results showed that the concentration of adsorbed 226 Ra on clay materials increased with time to reach an equilibrium state after approximately 5 h. More than 95 % of the radium was adsorbed. The mixture of bentonite–illite (1/9) exhibited the greatest adsorption of radium under all experimental conditions.

Description: Motivation: DNA methylation is an important epigenetic modification related to a variety of diseases including cancers. We focus on the methylation data from Illumina’s Infinium HumanMethylation450 BeadChip. One of the key issues of methylation analysis is to detect the differential methylation sites between case and control groups. Previous approaches describe data with simple summary statistics or kernel function, and then use statistical tests to determine the difference. However, a summary statistics-based approach cannot capture complicated underlying structure, and a kernel function-based approach lacks interpretability of results. Results: We propose a novel method D 3 M, for detection of differential distribution of methylation, based on distribution-valued data. Our method can detect the differences in high-order moments, such as shapes of underlying distributions in methylation profiles, based on the Wasserstein metric. We test the significance of the difference between case and control groups and provide an interpretable summary of the results. The simulation results show that the proposed method achieves promising accuracy and shows favorable results compared with previous methods. Glioblastoma multiforme and lower grade glioma data from The Cancer Genome Atlas show that our method supports recent biological advances and suggests new insights. Availability and Implementation: R implemented code is freely available from https://github.com/ymatts/D3M/ . Contact: ymatsui@med.nagoya-u.ac.jp or shimamura@med.nagoya-u.ac.jp Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Similarity-based methods have been widely used in order to infer the properties of genes and gene products containing little or no experimental annotation. New approaches that overcome the limitations of methods that rely solely upon sequence similarity are attracting increased attention. One of these novel approaches is to use the organization of the structural domains in proteins. Results: We propose a method for the automatic annotation of protein sequences in the UniProt Knowledgebase (UniProtKB) by comparing their domain architectures, classifying proteins based on the similarities and propagating functional annotation. The performance of this method was measured through a cross-validation analysis using the Gene Ontology (GO) annotation of a sub-set of UniProtKB/Swiss-Prot. The results demonstrate the effectiveness of this approach in detecting functional similarity with an average F-score: 0.85. We applied the method on nearly 55.3 million uncharacterized proteins in UniProtKB/TrEMBL resulted in 44 818 178 GO term predictions for 12 172 114 proteins. 22% of these predictions were for 2 812 016 previously non-annotated protein entries indicating the significance of the value added by this approach. Availability and implementation: The results of the method are available at: ftp://ftp.ebi.ac.uk/pub/contrib/martin/DAAC/ . Contact: tdogan@ebi.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Species identification and quantification are common tasks in metagenomics and pathogen detection studies. The most recent techniques are built on mapping the sequenced reads against a reference database (e.g. whole genomes, marker genes, proteins) followed by application-dependent analysis steps. Although these methods have been proven to be useful in many scenarios, there is still room for improvement in species and strain level detection, mainly for low abundant organisms. Results: We propose a new method: DUDes, a reference-based taxonomic profiler that introduces a novel top-down approach to analyze metagenomic Next-generation sequencing (NGS) samples. Rather than predicting an organism presence in the sample based only on relative abundances, DUDes first identifies possible candidates by comparing the strength of the read mapping in each node of the taxonomic tree in an iterative manner. Instead of using the lowest common ancestor we propose a new approach: the deepest uncommon descendent. We showed in experiments that DUDes works for single and multiple organisms and can identify low abundant taxonomic groups with high precision. Availability and Implementation: DUDes is open source and it is available at http://sf.net/p/dudes Supplementary information: Supplementary data are available at Bioinformatics online. Contact: renardB@rki.de

Description: Motivation: Moonlighting proteins (MPs) show multiple cellular functions within a single polypeptide chain. To understand the overall landscape of their functional diversity, it is important to establish a computational method that can identify MPs on a genome scale. Previously, we have systematically characterized MPs using functional and omics-scale information. In this work, we develop a computational prediction model for automatic identification of MPs using a diverse range of protein association information. Results: We incorporated a diverse range of protein association information to extract characteristic features of MPs, which range from gene ontology (GO), protein–protein interactions, gene expression, phylogenetic profiles, genetic interactions and network-based graph properties to protein structural properties, i.e. intrinsically disordered regions in the protein chain. Then, we used machine learning classifiers using the broad feature space for predicting MPs. Because many known MPs lack some proteomic features, we developed an imputation technique to fill such missing features. Results on the control dataset show that MPs can be predicted with over 98% accuracy when GO terms are available. Furthermore, using only the omics-based features the method can still identify MPs with over 75% accuracy. Last, we applied the method on three genomes: Saccharomyces cerevisiae , Caenorhabditis elegans and Homo sapiens , and found that about 2–10% of proteins in the genomes are potential MPs. Availability and Implementation: Code available at http://kiharalab.org/MPprediction Contact: dkihara@purdue.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Design of protein–protein interaction (PPI) inhibitors is a major challenge in Structural Bioinformatics. Peptides, especially short ones (5–15 amino acid long), are natural candidates for inhibition of protein–protein complexes due to several attractive features such as high structural compatibility with the protein binding site (mimicking the surface of one of the proteins), small size and the ability to form strong hotspot binding connections with the protein surface. Efficient rational peptide design is still a major challenge in computer aided drug design, due to the huge space of possible sequences, which is exponential in the length of the peptide, and the high flexibility of peptide conformations. Results: In this article we present PinaColada, a novel computational method for the design of peptide inhibitors for protein–protein interactions. We employ a version of the ant colony optimization heuristic, which is used to explore the exponential space ( 20n ) of length n peptide sequences, in combination with our fast robotics motivated PepCrawler algorithm, which explores the conformational space for each candidate sequence. PinaColada is being run in parallel, on a DELL PowerEdge 2.8 GHZ computer with 20 cores and 256 GB memory, and takes up to 24 h to design a peptide of 5-15 amino acids length. Availability and implementation: An online server available at: http://bioinfo3d.cs.tau.ac.il/PinaColada/. Contact: danielza@post.tau.ac.il ; wolfson@tau.ac.il

Description: Motivation: Whole-genome low-coverage sequencing has been combined with linkage-disequilibrium (LD)-based genotype refinement to accurately and cost-effectively infer genotypes in large cohorts of individuals. Most genotype refinement methods are based on hidden Markov models, which are accurate but computationally expensive. We introduce an algorithm that models LD using a simple multivariate Gaussian distribution. The key feature of our algorithm is its speed. Results: Our method is hundreds of times faster than other methods on the same data set and its scaling behaviour is linear in the number of samples. We demonstrate the performance of the method on both low- and high-coverage samples. Availability and implementation: The source code is available at https://github.com/illumina/marvin Contact: rarthur@illumina.com Supplementary information: Supplementary data are available at Bioinformatics online .

Description: Motivation : T-cell epitopes serve as molecular keys to initiate adaptive immune responses. Identification of T-cell epitopes is also a key step in rational vaccine design. Most available methods are driven by informatics and are critically dependent on experimentally obtained training data. Analysis of a training set from Immune Epitope Database (IEDB) for several alleles indicates that the sampling of the peptide space is extremely sparse covering a tiny fraction of the possible nonamer space, and also heavily skewed, thus restricting the range of epitope prediction. Results : We present a new epitope prediction method that has four distinct computational modules: (i) structural modelling, estimating statistical pair-potentials and constraint derivation, (ii) implicit modelling and interaction profiling, (iii) feature representation and binding affinity prediction and (iv) use of graphical models to extract peptide sequence signatures to predict epitopes for HLA class I alleles. Conclusions : HLaffy is a novel and efficient epitope prediction method that predicts epitopes for any Class-1 HLA allele, by estimating the binding strengths of peptide-HLA complexes which is achieved through learning pair-potentials important for peptide binding. It relies on the strength of the mechanistic understanding of peptide-HLA recognition and provides an estimate of the total ligand space for each allele. The performance of HLaffy is seen to be superior to the currently available methods. Availability and implementation : The method is made accessible through a webserver http://proline.biochem.iisc.ernet.in/HLaffy . Contact : nchandra@biochem.iisc.ernet.in Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: In vitro and in vivo cell proliferation is often studied using the dye carboxyfluorescein succinimidyl ester (CFSE). The CFSE time-series data provide information about the proliferation history of populations of cells. While the experimental procedures are well established and widely used, the analysis of CFSE time-series data is still challenging. Many available analysis tools do not account for cell age and employ optimization methods that are inefficient (or even unreliable). Results: We present a new model-based analysis method for CFSE time-series data. This method uses a flexible description of proliferating cell populations, namely, a division-, age- and label-structured population model. Efficient maximum likelihood and Bayesian estimation algorithms are introduced to infer the model parameters and their uncertainties. These methods exploit the forward sensitivity equations of the underlying partial differential equation model for efficient and accurate gradient calculation, thereby improving computational efficiency and reliability compared with alternative approaches and accelerating uncertainty analysis. The performance of the method is assessed by studying a dataset for immune cell proliferation. This revealed the importance of different factors on the proliferation rates of individual cells. Among others, the predominate effect of cell age on the division rate is found, which was not revealed by available computational methods. Availability and implementation: The MATLAB source code implementing the models and algorithms is available from http://janhasenauer.github.io/ShAPE-DALSP/ . Contact: jan.hasenauer@helmholtz-muenchen.de Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: The challenges of successfully applying causal inference methods include: (i) satisfying underlying assumptions, (ii) limitations in data/models accommodated by the software and (iii) low power of common multiple testing approaches. Results: The causal inference test (CIT) is based on hypothesis testing rather than estimation, allowing the testable assumptions to be evaluated in the determination of statistical significance. A user-friendly software package provides P -values and optionally permutation-based FDR estimates ( q -values) for potential mediators. It can handle single and multiple binary and continuous instrumental variables, binary or continuous outcome variables and adjustment covariates. Also, the permutation-based FDR option provides a non-parametric implementation. Conclusion: Simulation studies demonstrate the validity of the cit package and show a substantial advantage of permutation-based FDR over other common multiple testing strategies. Availability and implementation: The cit open-source R package is freely available from the CRAN website ( https://cran.r-project.org/web/packages/cit/index.html ) with embedded C ++ code that utilizes the GNU Scientific Library, also freely available ( http://www.gnu.org/software/gsl/ ). Contact: joshua.millstein@usc.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: The vast majority of the many thousands of disease-associated single nucleotide polymorphisms (SNPs) lie in the non-coding part of the genome. They are likely to affect regulatory elements, such as enhancers and promoters, rather than the function of a protein. To understand the molecular mechanisms underlying genetic diseases, it is therefore increasingly important to study the effect of a SNP on nearby molecular traits such as chromatin or transcription factor binding. Results: We developed SNPhood , a user-friendly Bioconductor R package to investigate, quantify and visualise the local epigenetic neighbourhood of a set of SNPs in terms of chromatin marks or TF binding sites using data from NGS experiments. Availability and implementation: SNPhood is publicly available and maintained as an R Bioconductor package at http://bioconductor.org/packages/SNPhood/ . Contact: judith.zaugg@embl.de Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Versatile and efficient variant calling tools are needed to analyze large scale sequencing datasets. In particular, identification of copy number changes remains a challenging task due to their complexity, susceptibility to sequencing biases, variation in coverage data and dependence on genome-wide sample properties, such as tumor polyploidy or polyclonality in cancer samples. Results: We have developed a new tool, Canvas, for identification of copy number changes from diverse sequencing experiments including whole-genome matched tumor-normal and single-sample normal re-sequencing, as well as whole-exome matched and unmatched tumor-normal studies. In addition to variant calling, Canvas infers genome-wide parameters such as cancer ploidy, purity and heterogeneity. It provides fast and easy-to-run workflows that can scale to thousands of samples and can be easily incorporated into variant calling pipelines. Availability and Implementation: Canvas is distributed under an open source license and can be downloaded from https://github.com/Illumina/canvas . Contact: eroller@illumina.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: p ileup.js is a new browser-based genome viewer. It is designed to facilitate the investigation of evidence for genomic variants within larger web applications. It takes advantage of recent developments in the JavaScript ecosystem to provide a modular, reliable and easily embedded library. Availability and implementation: The code and documentation for pileup.js is publicly available at https://github.com/hammerlab/pileup.js under the Apache 2.0 license. Contact : correspondence@hammerlab.org

Description: Motivation: We present an update to the pathway enrichment analysis tool ‘Pathway Analysis by Randomization Incorporating Structure (PARIS)’ that determines aggregated association signals generated from genome-wide association study results. Pathway-based analyses highlight biological pathways associated with phenotypes. PARIS uses a unique permutation strategy to evaluate the genomic structure of interrogated pathways, through permutation testing of genomic features, thus eliminating many of the over-testing concerns arising with other pathway analysis approaches. Results: We have updated PARIS to incorporate expanded pathway definitions through the incorporation of new expert knowledge from multiple database sources, through customized user provided pathways, and other improvements in user flexibility and functionality. Availability and implementation: PARIS is freely available to all users at https://ritchielab.psu.edu/software/paris-download . Contact: jnc43@case.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : Nucleotide Similarity Scanner (NSimScan) is specialized for searching massive DNA databases for distant similarities. Its targeted applications include phylogenomics, comparative and functional studies of non-coding sequences, contamination detection, etc. NSimScan outperforms industry standard tools in combined sensitivity, accuracy and speed, operating at sensitivity similar to BLAST, accuracy of ssearch and speed of MegaBLAST. Availability and implementation: NSimScan is available at https://github.com/abadona/qsimscan as a part of QSimScan package. It is implemented in C ++, distributed under MIT license and supported on Linux, OS X and Windows (with cygwin). Contact: dkaznadzey@yahoo.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : We present TreeDom, a web tool for graphically analysing the evolutionary history of domains in multi-domain proteins. Individual domains on the same protein chain may have distinct evolutionary histories, which is important to grasp in order to understand protein function. For instance, it may be important to know whether a domain was duplicated recently or long ago, to know the origin of inserted domains, or to know the pattern of domain loss within a protein family. TreeDom uses the Pfam database as the source of domain annotations, and displays these on a sequence tree. An advantage of TreeDom is that the user can limit the analysis to N sequences that are most similar to a query, or provide a list of sequence IDs to include. Using the Pfam alignment of the selected sequences, a tree is built and displayed together with the domain architecture of each sequence. Availablility and implementation: http://TreeDom.sbc.su.se Contact: Erik.Sonnhammer@scilifelab.se

Description: : The NCI-60 human tumor cell line panel is an invaluable resource for cancer researchers, providing drug sensitivity, molecular and phenotypic data for a range of cancer types. CellMiner is a web resource that provides tools for the acquisition and analysis of quality-controlled NCI-60 data. CellMiner supports queries of up to 150 drugs or genes, but the output is an Excel file for each drug or gene. This output format makes it difficult for researchers to explore the data from large queries. CellMiner Companion is a web application that facilitates the exploration and visualization of output from CellMiner, further increasing the accessibility of NCI-60 data. Availability and Implementation: The web application is freely accessible at https://pul-bioinformatics.shinyapps.io/CellMinerCompanion . The R source code can be downloaded at https://github.com/pepascuzzi/CellMinerCompanion.git . Contact: ppascuzz@purdue.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : SMeagol is a software tool to simulate highly realistic microscopy data based on spatial systems biology models, in order to facilitate development, validation and optimization of advanced analysis methods for live cell single molecule microscopy data. Availability and implementation: SMeagol runs on Matlab R2014 and later, and uses compiled binaries in C for reaction–diffusion simulations. Documentation, source code and binaries for Mac OS, Windows and Ubuntu Linux can be downloaded from http://smeagol.sourceforge.net . Contact: johan.elf@icm.uu.se Supplementary information : Supplementary data are available at Bioinformatics online.

Description: Motivation : Photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation (PAR-CLIP) is an experimental method based on next-generation sequencing for identifying the RNA interaction sites of a given protein. The method deliberately inserts T-to-C substitutions at the RNA-protein interaction sites, which provides a second layer of evidence compared with other CLIP methods. However, the experiment includes several sources of noise which cause both low-frequency errors and spurious high-frequency alterations. Therefore, rigorous statistical analysis is required in order to separate true T-to-C base changes, following cross-linking, from noise. So far, most of the existing PAR-CLIP data analysis methods focus on discarding the low-frequency errors and rely on high-frequency substitutions to report binding sites, not taking into account the possibility of high-frequency false positive substitutions. Results : Here, we introduce BMix , a new probabilistic method which explicitly accounts for the sources of noise in PAR-CLIP data and distinguishes cross-link induced T-to-C substitutions from low and high-frequency erroneous alterations. We demonstrate the superior speed and accuracy of our method compared with existing approaches on both simulated and real, publicly available human datasets. Availability and implementation : The model is freely accessible within the BMix toolbox at www.cbg.bsse.ethz.ch/software/BMix , available for Matlab and R. Supplementary information: Supplementary data is available at Bioinformatics online. Contact : niko.beerenwinkel@bsse.ethz.ch

Description: Motivation: Gene networks have become a central tool in the analysis of genomic data but are widely regarded as hard to interpret. This has motivated a great deal of comparative evaluation and research into best practices. We explore the possibility that this may lead to overfitting in the field as a whole. Results: We construct a model of ‘research communities’ sampling from real gene network data and machine learning methods to characterize performance trends. Our analysis reveals an important principle limiting the value of replication, namely that targeting it directly causes ‘easy’ or uninformative replication to dominate analyses. We find that when sampling across network data and algorithms with similar variability, the relationship between replicability and accuracy is positive (Spearman’s correlation, r s ~0.33) but where no such constraint is imposed, the relationship becomes negative for a given gene function ( r s ~ –0.13). We predict factors driving replicability in some prior analyses of gene networks and show that they are unconnected with the correctness of the original result, instead reflecting replicable biases. Without these biases, the original results also vanish replicably. We show these effects can occur quite far upstream in network data and that there is a strong tendency within protein–protein interaction data for highly replicable interactions to be associated with poor quality control. Availability and implementation: Algorithms, network data and a guide to the code available at: https://github.com/wimverleyen/AggregateGeneFunctionPrediction . Contact: jgillis@cshl.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Recent advances in single molecule real-time (SMRT) and nanopore sequencing technologies have enabled high-quality assemblies from long and inaccurate reads. However, these approaches require high coverage by long reads and remain expensive. On the other hand, the inexpensive short reads technologies produce accurate but fragmented assemblies. Thus, a hybrid approach that assembles long reads (with low coverage) and short reads has a potential to generate high-quality assemblies at reduced cost. Results: We describe hybrid SPA des algorithm for assembling short and long reads and benchmark it on a variety of bacterial assembly projects. Our results demonstrate that hybrid SPA des generates accurate assemblies (even in projects with relatively low coverage by long reads) thus reducing the overall cost of genome sequencing. We further present the first complete assembly of a genome from single cells using SMRT reads. Availability and implementation: hybrid SPA des is implemented in C++ as a part of SPAdes genome assembler and is publicly available at http://bioinf.spbau.ru/en/spades Contact: d.antipov@spbu.ru Supplementary information: supplementary data are available at Bioinformatics online.

Description: Motivation: There are numerous examples of RNA–RNA complexes, including microRNA–mRNA and small RNA–mRNA duplexes for regulation of translation, guide RNA interactions with target RNA for post-transcriptional modification and small nuclear RNA duplexes for splicing. Predicting the base pairs formed between two interacting sequences remains difficult, at least in part because of the competition between unimolecular and bimolecular structure. Results: Two algorithms were developed for improved prediction of bimolecular RNA structure that consider the competition between self-structure and bimolecular structure. These algorithms utilize two novel approaches to evaluate accessibility: free energy density minimization and pseudo-energy minimization. Free energy density minimization minimizes the folding free energy change per nucleotide involved in an intermolecular secondary structure. Pseudo-energy minimization (called AccessFold) minimizes the sum of free energy change and a pseudo-free energy penalty for bimolecular pairing of nucleotides that are unlikely to be accessible for bimolecular structure. The pseudo-free energy, derived from unimolecular pairing probabilities, is applied per nucleotide in bimolecular pairs, and this approach is able to predict binding sites that are split by unimolecular structures. A benchmark set of 17 bimolecular RNA structures was assembled to assess structure prediction. Pseudo-energy minimization provides a statistically significant improvement in sensitivity over the method that was found in a benchmark to be the most accurate previously available method, with an improvement from 36.8% to 57.8% in mean sensitivity for base pair prediction. Availability and implementation: Pseudo-energy minimization is available for download as AccessFold, under an open-source license and as part of the RNAstructure package, at: http://rna.urmc.rochester.edu/RNAstructure.html . Contact: david_mathews@urmc.rochester.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Simulating complex evolution scenarios of multiple populations is an important task for answering many basic questions relating to population genomics. Apart from the population samples, the underlying Ancestral Recombinations Graph (ARG) is an additional important means in hypothesis checking and reconstruction studies. Furthermore, complex simulations require a plethora of interdependent parameters making even the scenario-specification highly non-trivial. Results: We present an algorithm SimRA that simulates generic multiple population evolution model with admixture. It is based on random graphs that improve dramatically in time and space requirements of the classical algorithm of single populations. Using the underlying random graphs model, we also derive closed forms of expected values of the ARG characteristics i.e., height of the graph, number of recombinations, number of mutations and population diversity in terms of its defining parameters. This is crucial in aiding the user to specify meaningful parameters for the complex scenario simulations, not through trial-and-error based on raw compute power but intelligent parameter estimation. To the best of our knowledge this is the first time closed form expressions have been computed for the ARG properties. We show that the expected values closely match the empirical values through simulations. Finally, we demonstrate that SimRA produces the ARG in compact forms without compromising any accuracy. We demonstrate the compactness and accuracy through extensive experiments. Availability and implementation : SimRA ( Sim ulation based on R andom graph A lgorithms) source, executable, user manual and sample input-output sets are available for downloading at: https://github.com/ComputationalGenomics/SimRA Contact : parida@us.ibm.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation : The Optical Mapping System discovers structural variants and potentiates sequence assembly of genomes via scaffolding and comparisons that globally validate or correct sequence assemblies. Despite its utility, there are few publicly available tools for aligning optical mapping datasets. Results : Here we present software, named ‘Maligner’, for the alignment of both single molecule restriction maps (Rmaps) and in silico restriction maps of sequence contigs to a reference. Maligner provides two modes of alignment: an efficient, sensitive dynamic programming implementation that scales to large eukaryotic genomes, and a faster indexed based implementation for finding alignments with unmatched sites in the reference but not the query. We compare our software to other publicly available tools on Rmap datasets and show that Maligner finds more correct alignments in comparable runtime. Lastly, we introduce the M-Score statistic for normalizing alignment scores across restriction maps and demonstrate its utility for selecting high quality alignments. Availability and implementation : The Maligner software is written in C ++ and is available at https://github.com/LeeMendelowitz/maligner under the GNU General Public License. Contact : mpop@umiacs.umd.edu

Description: Motivation: The detection of genomic structural variation (SV) has advanced tremendously in recent years due to progress in high-throughput sequencing technologies. Novel sequence insertions, insertions without similarity to a human reference genome, have received less attention than other types of SVs due to the computational challenges in their detection from short read sequencing data, which inherently involves de novo assembly. De novo assembly is not only computationally challenging, but also requires high-quality data. Although the reads from a single individual may not always meet this requirement, using reads from multiple individuals can increase power to detect novel insertions. Results: We have developed the program PopIns , which can discover and characterize non-reference insertions of 100 bp or longer on a population scale. In this article, we describe the approach we implemented in PopIns. It takes as input a reads-to-reference alignment, assembles unaligned reads using a standard assembly tool, merges the contigs of different individuals into high-confidence sequences, anchors the merged sequences into the reference genome, and finally genotypes all individuals for the discovered insertions. Our tests on simulated data indicate that the merging step greatly improves the quality and reliability of predicted insertions and that PopIns shows significantly better recall and precision than the recent tool MindTheGap. Preliminary results on a dataset of 305 Icelanders demonstrate the practicality of the new approach. Availability and implementation: The source code of PopIns is available from http://github.com/bkehr/popins . Contact: birte.kehr@decode.is Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: High-throughput sequencing technologies provide access to an increasing number of bacterial genomes. Today, many analyses involve the comparison of biological properties among many strains of a given species, or among species of a particular genus. Tools that can help the microbiologist with these tasks become increasingly important. Results: Insyght is a comparative visualization tool whose core features combine a synchronized navigation across genomic data of multiple organisms with a versatile interoperability between complementary views. In this work, we have greatly increased the scope of the Insyght public dataset by including 2688 complete bacterial genomes available in Ensembl thus vastly improving its phylogenetic coverage. We also report the development of a virtual machine that allows users to easily set up and customize their own local Insyght server. Availability and implementation: http://genome.jouy.inra.fr/Insyght Contact: Thomas.Lacroix@jouy.inra.fr

Description: : Breast cancer is one of the most frequent cancers among women. Extensive studies into the molecular heterogeneity of breast cancer have produced a plethora of molecular subtype classification and prognosis prediction algorithms, as well as numerous gene expression signatures. However, reimplementation of these algorithms is a tedious but important task to enable comparison of existing signatures and classification models between each other and with new models. Here, we present the genefu R/Bioconductor package, a multi-tiered compendium of bioinformatics algorithms and gene signatures for molecular subtyping and prognostication in breast cancer. Availability and implementation: The genefu package is available from Bioconductor. http://www.bioconductor.org/packages/devel/bioc/html/genefu.html . Source code is also available on Github https://github.com/bhklab/genefu . Contact: bhaibeka@uhnresearch.ca Supplementary information: Supplementary data are available at Bioinformatics online.

Description: The potential use of acanthocephalans as bioindicators of Lead (Pb) pollution in Sampaloc Lake, Laguna, Philippines was investigated. Nile tilapias ( Oreochromis niloticus ) were collected and Pb concentrations were determined in fish tissues and in their acanthocephalan parasites, Acanthogyrus sp. Significantly higher levels of Pb were detected in the parasites relative to the fish host tissues ( p  = 0.001). Bioaccumulation capacity of the parasites against fish tissues were 102, 119, and 147 times higher than the fish intestine, liver, and muscles, respectively. Pb sensitivity of the parasites was quantified by exact logistic analysis showing higher odds of Pb detection ranging from 18 to 45 folds ( p  = 0.001–0.009). Interestingly, infected fish showed significantly lower Pb concentration in their tissues compared to uninfected fish ( p  = 0.001), suggesting parasites were able to sequester Pb and served as active biosinks. The Pb levels in the parasites were also hundred folds higher (988 times) relative to the ambient waters, indicating a potential role of fish parasites as metal biosinks in aquatic ecosystems.

Description: : Precise regulatory control of genes, particularly in eukaryotes, frequently requires the joint action of multiple sequence-specific transcription factors. A cis -regulatory module (CRM) is a genomic locus that is responsible for gene regulation and that contains multiple transcription factor binding sites in close proximity. Given a collection of known transcription factor binding motifs, many bioinformatics methods have been proposed over the past 15 years for identifying within a genomic sequence candidate CRMs consisting of clusters of those motifs. Results: The MCAST algorithm uses a hidden Markov model with a P -value-based scoring scheme to identify candidate CRMs. Here, we introduce a new version of MCAST that offers improved graphical output, a dynamic background model, statistical confidence estimates based on false discovery rate estimation and, most significantly, the ability to predict CRMs while taking into account epigenomic data such as DNase I sensitivity or histone modification data. We demonstrate the validity of MCAST’s statistical confidence estimates and the utility of epigenomic priors in identifying CRMs. Availability and implementation: MCAST is part of the MEME Suite software toolkit. A web server and source code are available at http://meme-suite.org and http://alternate.meme-suite.org . Contact: t.bailey@imb.uq.edu.au or william-noble@uw.edu Supplementary information : Supplementary data are available at Bioinformatics online.

Description: : Pharmacogenomics holds great promise for the development of biomarkers of drug response and the design of new therapeutic options, which are key challenges in precision medicine. However, such data are scattered and lack standards for efficient access and analysis, consequently preventing the realization of the full potential of pharmacogenomics. To address these issues, we implemented PharmacoGx , an easy-to-use, open source package for integrative analysis of multiple pharmacogenomic datasets. We demonstrate the utility of our package in comparing large drug sensitivity datasets, such as the Genomics of Drug Sensitivity in Cancer and the Cancer Cell Line Encyclopedia. Moreover, we show how to use our package to easily perform Connectivity Map analysis. With increasing availability of drug-related data, our package will open new avenues of research for meta-analysis of pharmacogenomic data. Availability and implementation : PharmacoGx is implemented in R and can be easily installed on any system. The package is available from CRAN and its source code is available from GitHub. Contact : bhaibeka@uhnresearch.ca or benjamin.haibe.kains@utoronto.ca Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : In population genetics and phylogeography, haplotype genealogy graphs are important tools for the visualization of population structure based on sequence data. In this type of graph, node sizes are often drawn in proportion to haplotype frequencies and edge lengths represent the minimum number of mutations separating adjacent nodes. I here present Fitchi, a new program that produces publication-ready haplotype genealogy graphs based on the Fitch algorithm. Availability and implementation: http://www.evoinformatics.eu/fitchi.htm Contact : michaelmatschiner@mac.com Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : Genome-wide association studies (GWASs) have successfully identified many sequence variants that are significantly associated with common diseases and traits. Tens of thousands of such trait-associated SNPs have already been cataloged, which we believe form a great resource for genomic research. Recent studies have demonstrated that the collection of trait-associated SNPs can be exploited to indicate whether a given genomic interval or intervals are likely to be functionally connected with certain phenotypes or diseases. Despite this importance, currently, there is no ready-to-use computational tool able to connect genomic intervals to phenotypes. Here, we present traseR , an easy-to-use R Bioconductor package that performs enrichment analyses of trait-associated SNPs in arbitrary genomic intervals with flexible options, including testing method, type of background and inclusion of SNPs in LD. Availability and implementation: The traseR R package preloaded with up-to-date collection of trait-associated SNPs are freely available in Bioconductor Contact: zhaohui.qin@emory.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : Data-dependent acquisition (DDA) is the most common method used to control the acquisition process of shotgun proteomics experiments. While novel DDA approaches have been proposed, their evaluation is made difficult by the need of programmatic control of a mass spectrometer. An alternative is in silico analysis, for which suitable software has been unavailable. To meet this need, we have developed MSAcquisitionSimulator—a collection of C ++ programs for simulating ground truth LC-MS data and the subsequent application of custom DDA algorithms. It provides an opportunity for researchers to test, refine and evaluate novel DDA algorithms prior to implementation on a mass spectrometer. Availability and implementation: The software is freely available from its Github repository http://www.github.com/DennisGoldfarb/MSAcquisitionSimulator/ which contains further documentation and usage instructions. Contact: weiwang@cs.ucla.edu or ben_major@med.unc.edu Supplementary information : Supplementary data are available at Bioinformatics online.

Description: : Coarse grain (CG) models allow long-scale simulations with a much lower computational cost than that of all-atom simulations. However, the absence of atomistic detail impedes the analysis of specific atomic interactions that are determinant in most interesting biomolecular processes. In order to study these phenomena, it is necessary to reconstruct the atomistic structure from the CG representation. This structure can be analyzed by itself or be used as an onset for atomistic molecular dynamics simulations. In this work, we present a computer program that accurately reconstructs the atomistic structure from a CG model for proteins, using a simple geometrical algorithm. Availability and implementation: The software is free and available online at http://www.ic.fcen.uba.ar/cg2aa/cg2aa.py Supplementary information: Supplementary data are available at Bioinformatics online. Contact: lula@qi.fcen.uba.ar

Description: : The Sun Grid Engine (SGE) high-performance computing batch queueing system is commonly used in bioinformatics analysis. Creating re-usable scripts for the SGE is a common challenge. The qsubsec template language and interpreter described here allow researchers to easily create generic template definitions that encapsulate a particular computational job, effectively separating the process logic from the specific run details. At submission time, the generic template is filled in with specific values. This system provides an intermediate level between simple scripting and complete workflow management tools. Availability and implementation: Qsubsec is open-source and is available at https://github.com/alastair-droop/qsubsec . Contact: a.p.droop@leeds.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : The lack of visualization frameworks to guide interpretation and facilitate discovery is a potential bottleneck for precision medicine, systems genetics and other studies. To address this we have developed an interactive, reproducible, web-based prioritization approach that builds on our earlier work. HitWalker2 is highly flexible and can utilize many data types and prioritization methods based upon available data and desired questions, allowing it to be utilized in a diverse range of studies such as cancer, infectious disease and psychiatric disorders. Availability and implementation: Source code is freely available at https://github.com/biodev/HitWalker2 and implemented using Python/Django, Neo4j and Javascript (D3.js and jQuery). We support major open source browsers (e.g. Firefox and Chromium/Chrome). Contact: wilmotb@ohsu.edu Supplementary information: Supplementary data are available at Bioinformatics online. Additional information/instructions are available at https://github.com/biodev/HitWalker2/wiki

Description: Motivation: Whole genome sequencing (WGS) of parent-offspring trios is a powerful approach for identifying disease-associated genes via detecting copy number variations (CNVs). Existing approaches, which detect CNVs for each individual in a trio independently, usually yield low-detection accuracy. Joint modeling approaches leveraging Mendelian transmission within the parent-offspring trio can be an efficient strategy to improve CNV detection accuracy. Results: In this study, we developed TrioCNV, a novel approach for jointly detecting CNVs in parent-offspring trios from WGS data. Using negative binomial regression, we modeled the read depth signal while considering both GC content bias and mappability bias. Moreover, we incorporated the family relationship and used a hidden Markov model to jointly infer CNVs for three samples of a parent-offspring trio. Through application to both simulated data and a trio from 1000 Genomes Project, we showed that TrioCNV achieved superior performance than existing approaches. Availability and implementation: The software TrioCNV implemented using a combination of Java and R is freely available from the website at https://github.com/yongzhuang/TrioCNV . Contact: ydwang@hit.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Recent advancements in molecular methods have made it possible to capture physical contacts between multiple chromatin fragments. The resulting association matrices provide a noisy estimate for average spatial proximity that can be used to gain insights into the genome organization inside the nucleus. However, extracting topological information from these data is challenging and their integration across resolutions is still poorly addressed. Recent findings suggest that a hierarchical approach could be advantageous for addressing these challenges. Results: We present an algorithmic framework, which is based on hierarchical block matrices (HBMs), for topological analysis and integration of chromosome conformation capture (3C) data. We first describe chromoHBM, an algorithm that compresses high-throughput 3C (HiT-3C) data into topological features that are efficiently summarized with an HBM representation. We suggest that instead of directly combining HiT-3C datasets across resolutions, which is a difficult task, we can integrate their HBM representations, and describe chromoHBM-3C, an algorithm which merges HBMs. Since three-dimensional (3D) reconstruction can also benefit from topological information, we further present chromoHBM-3D, an algorithm which exploits the HBM representation in order to gradually introduce topological constraints to the reconstruction process. We evaluate our approach in light of previous image microscopy findings and epigenetic data, and show that it can relate multiple spatial scales and provide a more complete view of the 3D genome architecture. Availability and implementation: The presented algorithms are available from: https://github.com/yolish/hbm . Contact: ys388@cam.ac.uk or pl219@cam.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: There are various reasons for rerunning bioinformatics tools and pipelines on sequencing data, including reproducing a past result, validation of a new tool or workflow using a known dataset, or tracking the impact of database changes. For identical results to be achieved, regularly updated reference sequence databases must be versioned and archived. Database administrators have tried to fill the requirements by supplying users with one-off versions of databases, but these are time consuming to set up and are inconsistent across resources. Disk storage and data backup performance has also discouraged maintaining multiple versions of databases since databases such as NCBI nr can consume 50 Gb or more disk space per version, with growth rates that parallel Moore's law. Results: Our end-to-end solution combines our own Kipper software package—a simple key-value large file versioning system—with BioMAJ (software for downloading sequence databases), and Galaxy (a web-based bioinformatics data processing platform). Available versions of databases can be recalled and used by command-line and Galaxy users. The Kipper data store format makes publishing curated FASTA databases convenient since in most cases it can store a range of versions into a file marginally larger than the size of the latest version. Availability and implementation: Kipper v1.0.0 and the Galaxy Versioned Data tool are written in Python and released as free and open source software available at https://github.com/Public-Health-Bioinformatics/kipper and https://github.com/Public-Health-Bioinformatics/versioned_data , respectively; detailed setup instructions can be found at https://github.com/Public-Health-Bioinformatics/versioned_data/blob/master/doc/setup.md Contact : Damion.Dooley@Bccdc.Ca or William.Hsiao@Bccdc.Ca Supplementary information: Supplementary data are available at Bioinformatics online.

Description: The aim of the present 1-year study was to investigate the effect of heavy metals in synthetic fertilizers on water and sediment quality in the Seyfe Lake, where agricultural activity was the only anthropogenic source. Metal concentrations of five different types of synthetic fertilizers used in agricultural fields within the Seyfe Lake closed basin were as follows: Zn 〉 Pb 〉 Cu 〉 Cr 〉 Cd 〉 As 〉 Ni 〉 Co. The annual average of heavy metal concentrations in the sediment samples were as follows: Zn 〉 Pb 〉 As 〉 Cr 〉 Ni 〉 Cu 〉 Cd 〉 Co. Seyfe Lake sediment was classified as anthropogenically “highly polluted” in terms of the As and Zn concentrations at each sample station based on the sediment quality guidelines. Furthermore, the sediment could be classified as “moderately to highly polluted” in terms of the As concentration, based on the geo-accumulation index.

Description: Dibenz[ a , h ]anthracene (D b A) is a polycyclic aromatic hydrocarbon that is released into the environment through incomplete combustion of gasoline, cigarettes, and coal tar. The effects of short-term (10 days) exposure of common carp ( Cyprinus carpio ) to D b A (0–50 µg L −1 ) were evaluated using the following four biomarkers: DNA damage, 7-ethoxyresorufin- O -deethylase (EROD) activity, acetylcholinesterase (AChE) activity, and vitellogenin (VTG) levels. An integrated biomarker response (IBR) was calculated for exposure to D b A, and the results were compared with those in our previous study of two other PAHs, benzo[ k ]fluoranthene (B k F) and benzo[ a ]pyrene (B a P). D b A exposure resulted in a significant ( p  〈 0.05) increase in DNA damage, EROD activity, and VTG levels relative to the control. By contrast, Db A did not affect AChE activity. The IBR increased as the concentration of D b A increased. Based on the IBR values, the order of toxicity for the PAHs was B k F 〉 B a P 〉 D b A. Our results suggest that the IBR can be used as a quantitative tool for evaluating the responses of multiple biomarkers to PAH exposure.

Description: Wild birds are exposed to insecticides in a variety of ways, at different dose levels and via multiple routes, including ingestion of contaminated food items, and dermal, inhalation, preening, and embryonic exposure. Most poisoning by insecticides occurs as a result of misuse or accidental exposure, but intentional killing of unwanted animals also occurs. In this study, we investigated insecticides in the gastric contents of dead wild birds that were suspected to have died from insecticide poisoning based on necropsy. The wild birds were found dead in various regions and locations such as in mountains, and agricultural and urban areas. A total of 182 dead wild birds of 27 species were analyzed in this study, and insecticide residue levels were determined in 60.4 % of the total samples analyzed. Monocrotophos and phosphamidon were the most common insecticides identified at rates of 50.0 % and 30.7 % of the insecticide-positive samples, respectively. Other insecticides identified in dead wild birds included organophosphorous, organochlorine and carbamate insecticides. However, there was limited evidence to conclusively establish the cause of death related to insecticides in this study. Nevertheless, considering the level of insecticide exposure, it is speculated that the exposure was mainly a result of accidental or intentional killing, and not from environmental residue.

Description: To examine how nanoparticles influence biogeochemical cycles in streams, we studied the acute impact of nanosilver (nAg) and nanoparticulate zero-valent iron (nZVI) exposure on nutrient and oxygen exchange across the sediment–water interface of two streams (agricultural canal and wetland) that differed in their water quality and sediment characteristics. At the agricultural site, nAg increased oxygen consumption and decreased N 2 flux rates from that observed in control incubations. nZVI caused sediment–water systems from both streams to go hypoxic within 1.5 h of exposure. N 2 flux rates were at least an order of magnitude higher in nZVI treatments as compared to control. Water column nitrate and nitrite concentrations were not impacted by nZVI exposure but total dissolved phosphorus concentrations were higher in cores treated with nZVI. nAg and nZVI exposure to surface water ecosystems can disrupt ecological function across the sediment–water interface.

Description: In this study, aquatic stability and toxic effects of TiO 2 and AgTiO 2 nanoparticles (NPs) were investigated on Artemia salina nauplii. AgTiO 2 was found to be more toxic to nauplii compared to TiO 2 . The mortality rate in nauplii increased significantly with increasing concentrations and duration of exposure. TiO 2 eliminations ranged between 27.8 % and 96.5 % at 50 and 1 mg/L TiO 2 exposed to nauplii, respectively. Accumulation and elimination of Ag in AgTiO 2 exposed nauplii were similar except at 1 mg/L AgTiO 2 . When NPs were mixed with water, the hydrodynamic dimensions of NPs significantly increased because of aggregation in saltwater but NP size decreased over time. NPs-exposed nauplii showed changes in eye formation, enlargement of the intestine, malformations in the outer shell and antennae loss were also observed. Since accumulation and toxicity of AgTiO 2 NPs was higher than TiO 2 alone, inevitably release of AgTiO 2 into aqueous environments can cause ecological risks.

Description: Concentrations of seven metals (As, Cd, Cr, Cu, Pb, Ni, and Zn) were analyzed in 33 bone tissue samples of Antillean manatees ( Trichechus manatus manatus ) found dead in lagoons and rivers of Tabasco and Campeche in the Gulf of Mexico and Chetumal Bay in the Caribbean region. The concentrations of Cr, Cu, Pb, and Zn were significantly different between regions, with greater levels found in the Gulf of Mexico group than in the Mexican Caribbean group ( p  〈 0.05). Pb concentrations differed significantly between adults and calves. No differences were observed between sexes. Metal concentrations detected in the manatee bones were higher than most of those reported for bones in other marine mammals around the world. Future studies are necessary to establish whether the metal concentrations represent a risk to the health of the species.

Description: Motivation: Rapid advances in genotyping and genome-wide association studies have enabled the discovery of many new genotype–phenotype associations at the resolution of individual markers. However, these associations explain only a small proportion of theoretically estimated heritability of most diseases. In this work, we propose an integrative mixture model called JBASE: joint Bayesian analysis of subphenotypes and epistasis. JBASE explores two major reasons of missing heritability: interactions between genetic variants, a phenomenon known as epistasis and phenotypic heterogeneity, addressed via subphenotyping. Results: Our extensive simulations in a wide range of scenarios repeatedly demonstrate that JBASE can identify true underlying subphenotypes, including their associated variants and their interactions, with high precision. In the presence of phenotypic heterogeneity, JBASE has higher Power and lower Type 1 Error than five state-of-the-art approaches. We applied our method to a sample of individuals from Mexico with Type 2 diabetes and discovered two novel epistatic modules, including two loci each, that define two subphenotypes characterized by differences in body mass index and waist-to-hip ratio. We successfully replicated these subphenotypes and epistatic modules in an independent dataset from Mexico genotyped with a different platform. Availability and implementation: JBASE is implemented in C++, supported on Linux and is available at http://www.cs.toronto.edu/~goldenberg/JBASE/jbase.tar.gz . The genotype data underlying this study are available upon approval by the ethics review board of the Medical Centre Siglo XXI. Please contact Dr Miguel Cruz at mcruzl@yahoo.com for assistance with the application. Contact: anna.goldenberg@utoronto.ca Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Protein phosphorylation is a post-translational modification that underlines various aspects of cellular signaling. A key step to reconstructing signaling networks involves identification of the set of all kinases and their substrates. Experimental characterization of kinase substrates is both expensive and time-consuming. To expedite the discovery of novel substrates, computational approaches based on kinase recognition sequence (motifs) from known substrates, protein structure, interaction and co-localization have been proposed. However, rarely do these methods take into account the dynamic responses of signaling cascades measured from in vivo cellular systems. Given that recent advances in mass spectrometry-based technologies make it possible to quantify phosphorylation on a proteome-wide scale, computational approaches that can integrate static features with dynamic phosphoproteome data would greatly facilitate the prediction of biologically relevant kinase-specific substrates. Results: Here, we propose a positive-unlabeled ensemble learning approach that integrates dynamic phosphoproteomics data with static kinase recognition motifs to predict novel substrates for kinases of interest. We extended a positive-unlabeled learning technique for an ensemble model, which significantly improves prediction sensitivity on novel substrates of kinases while retaining high specificity. We evaluated the performance of the proposed model using simulation studies and subsequently applied it to predict novel substrates of key kinases relevant to insulin signaling. Our analyses show that static sequence motifs and dynamic phosphoproteomics data are complementary and that the proposed integrated model performs better than methods relying only on static information for accurate prediction of kinase-specific substrates. Availability and implementation: Executable GUI tool, source code and documentation are freely available at https://github.com/PengyiYang/KSP-PUEL . Contact: pengyi.yang@nih.gov or jothi@mail.nih.gov Supplementary information: Supplementary data are available at Bioinformatics online.

Description: Motivation: Statistically assessing the relation between a set of genomic regions and other genomic features is a common challenging task in genomic and epigenomic analyses. Randomization based approaches implicitly take into account the complexity of the genome without the need of assuming an underlying statistical model. Summary: regioneR is an R package that implements a permutation test framework specifically designed to work with genomic regions. In addition to the predefined randomization and evaluation strategies, regioneR is fully customizable allowing the use of custom strategies to adapt it to specific questions. Finally, it also implements a novel function to evaluate the local specificity of the detected association. Availability and implementation: regioneR is an R package released under Artistic-2.0 License. The source code and documents are freely available through Bioconductor ( http://www.bioconductor.org/packages/regioneR ). Contact: rmalinverni@carrerasresearch.org

Description: : We present a method to identify approximately independent blocks of linkage disequilibrium in the human genome. These blocks enable automated analysis of multiple genome-wide association studies. Availability and implementation: code: http://bitbucket.org/nygcresearch/ldetect ; data: http://bitbucket.org/nygcresearch/ldetect-data . Contact: tberisa@nygenome.org Supplementary information: Supplementary data are available at Bioinformatics online.

Description: : DNA methylation is one of the most commonly studied epigenetic modifications due to its role in both disease and development. The Illumina HumanMethylation450 BeadChip is a cost-effective way to profile 〉450 000 CpGs across the human genome, making it a popular platform for profiling DNA methylation. Here we introduce missMethyl, an R package with a suite of tools for performing normalization, removal of unwanted variation in differential methylation analysis, differential variability testing and gene set analysis for the 450K array. Availability and implementation: missMethyl is an R package available from the Bioconductor project at www.bioconductor.org. Contact: alicia.oshlack@mcri.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.