ALBERT

Description: This study proposes a quantitative measurement of split of the second heart sound (S2) based on nonstationary signal decomposition to deal with overlaps and energy modeling of the subcomponents of S2. The second heart sound includes aortic (A2) and pulmonic (P2) closure sounds. However, the split detection is obscured due to A2-P2 overlap and low energy of P2. To identify such split, HVD method is used to decompose the S2 into a number of components while preserving the phase information. Further, A2s and P2s are localized using smoothed pseudo Wigner-Ville distribution followed by reassignment method. Finally, the split iscalculated by taking the differences between the means of time indices of A2s and P2s. Experiments on total 33 clips of S2 signals are performed for evaluation of the method. The mean ± standard deviation of the split is 34.7 ± 4.6 ms. The method measures the splitefficiently, even when A2-P2 overlap is ≤ 20 ms and the normalized peak temporal ratio of P2 to A2 is low (≥ 0.22). This proposed method thus, demonstrates its robustness by defining split detectability (SDT), the split detection aptness through detecting P2s, by measuring upto 96 percent. Such findings reveal the effectiveness of the method as competent against the other baselines, especially for A2-P2 overlaps and low energy P2.

Description: Post-acquisition denoising of magnetic resonance (MR) images is an important step to improve any quantitative measurement of the acquired data. In this paper, assuming a Rician noise model, a new filtering method based on the linear minimum mean square error (LMMSE) estimation is introduced, which employs the self-similarity property of the MR data to restore the noise-less signal. This method takes into account the structural characteristics of images and the Bayesian mean square error (Bmse) of the estimator to address the denoising problem. In general, a twofold data processing approach is developed; first, the noisy MR data is processed using a patch-based L 2 -norm similarity measure to provide the primary set of samples required for the estimation process. Afterwards, the Bmse of the estimator is derived as the optimization function to analyze the pre-selected samples and minimize the error between the estimated and the underlying signal. Compared to the LMMSE method and also its recently proposed SNR-adapted realization (SNLMMSE), the optimized way of choosing the samples together with the automatic adjustment of the filtering parameters lead to a more robust estimation performance with our approach. Experimental results show the competitive performance of the proposed method in comparison with related state-of-the-art methods.

Description: Large-scale ad hoc analytics of genomic data is popular using the R-programming language supported by over 700 software packages provided by Bioconductor. More recently, analytical jobs are benefitting from on-demand computing and storage, their scalability and their low maintenance cost, all of which are offered by the cloud. While biologists and bioinformaticists can take an analytical job and execute it on their personal workstations, it remains challenging to seamlessly execute the job on the cloud infrastructure without extensive knowledge of the cloud dashboard. How analytical jobs can not only with minimum effort be executed on the cloud, but also how both the resources and data required by the job can be managed is explored in this paper. An open-source light-weight framework for executing R-scripts using Bioconductor packages, referred to as ‘RBioCloud’, is designed and developed. RBioCloud offers a set of simple command-line tools for managing the cloud resources, the data and the execution of the job. Three biological test cases validate the feasibility of RBioCloud. The framework is available from http://www.rbiocloud.com .

Description: Of major interest to translational genomics is the intervention in gene regulatory networks (GRNs) to affect cell behavior; in particular, to alter pathological phenotypes. Owing to the complexity of GRNs, accurate network inference is practically challenging and GRN models often contain considerable amounts of uncertainty. Considering the cost and time required for conducting biological experiments, it is desirable to have a systematic method for prioritizing potential experiments so that an experiment can be chosen to optimally reduce network uncertainty. Moreover, from a translational perspective it is crucial that GRN uncertainty be quantified and reduced in a manner that pertains to the operational cost that it induces, such as the cost of network intervention. In this work, we utilize the concept of mean objective cost of uncertainty (MOCU) to propose a novel framework for optimal experimental design. In the proposed framework, potential experiments are prioritized based on the MOCU expected to remain after conducting the experiment. Based on this prioritization, one can select an optimal experiment with the largest potential to reduce the pertinent uncertainty present in the current network model. We demonstrate the effectiveness of the proposed method via extensive simulations based on synthetic and real gene regulatory networks.

Description: A novel approach to Contact Map Overlap (CMO) problem is proposed using the two dimensional clusters present in the contact maps. Each protein is represented as a set of the non-trivial clusters of contacts extracted from its contact map. The approach involves finding matching regions between the two contact maps using approximate 2D-pattern matching algorithm and dynamic programming technique. These matched pairs of small contact maps are submitted in parallel to a fast heuristic CMO algorithm. The approach facilitates parallelization at this level since all the pairs of contact maps can be submitted to the algorithm in parallel. Then, a merge algorithm is used in order to obtain the overall alignment. As a proof of concept, MSVNS, a heuristic CMO algorithm is used for global as well as local alignment. The divide and conquer approach is evaluated for two benchmark data sets that of Skolnick and Ding et al. It is interesting to note that along with achieving saving of time, better overlap is also obtained for certain protein folds.

Description: Canalizing genes possess broad regulatory power over a wide swath of regulatory processes. On the other hand, it has been hypothesized that the phenomenon of intrinsically multivariate prediction (IMP) is associated with canalization. However, applications have relied on user-selectable thresholds on the IMP score to decide on the presence of IMP. A methodology is developed here that avoids arbitrary thresholds, by providing a statistical test for the IMP score. In addition, the proposed procedure allows the incorporation of prior knowledge if available, which can alleviate the problem of loss of power due to small sample sizes. The issue of multiplicity of tests is addressed by family-wise error rate (FWER) and false discovery rate (FDR) controlling approaches. The proposed methodology is demonstrated by experiments using synthetic and real gene-expression data from studies on melanoma and ionizing radiation (IR) responsive genes. The results with the real data identified DUSP1 and p53, two well-known canalizing genes associated with melanoma and IR response, respectively, as the genes with a clear majority of IMP predictor pairs. This validates the potential of the proposed methodology as a tool for discovery of canalizing genes from binary gene-expression data. The procedure is made available through an R package.

Description: The Regression Network plugin for Cytoscape ( RegNetC ) implements the RegNet algorithm for the inference of transcriptional association network from gene expression profiles. This algorithm is a model tree-based method to detect the relationship between each gene and the remaining genes simultaneously instead of analyzing individually each pair of genes as correlation-based methods do. Model trees are a very useful technique to estimate the gene expression value by regression models and favours localized similarities over more global similarity, which is one of the major drawbacks of correlation-based methods. Here, we present an integrated software suite, named RegNetC , as a Cytoscape plugin that can operate on its own as well. RegNetC facilitates, according to user-defined parameters, the resulted transcriptional gene association network in .sif format for visualization, analysis and interoperates with other Cytoscape plugins, which can be exported for publication figures. In addition to the network, the RegNetC plugin also provides the quantitative relationships between genes expression values of those genes involved in the inferred network, i.e., those defined by the regression models.

Description: We introduce a new method for normalization of data acquired by liquid chromatography coupled with mass spectrometry (LC-MS) in label-free differential expression analysis. Normalization of LC-MS data is desired prior to subsequent statistical analysis to adjust variabilities in ion intensities that are not caused by biological differences but experimental bias. There are different sources of bias including variabilities during sample collection and sample storage, poor experimental design, noise, etc. In addition, instrument variability in experiments involving a large number of LC-MS runs leads to a significant drift in intensity measurements. Although various methods have been proposed for normalization of LC-MS data, there is no universally applicable approach. In this paper, we propose a Bayesian normalization model (BNM) that utilizes scan-level information from LC-MS data. Specifically, the proposed method uses peak shapes to model the scan-level data acquired from extracted ion chromatograms (EIC) with parameters considered as a linear mixed effects model. We extended the model into BNM with drift (BNMD) to compensate for the variability in intensity measurements due to long LC-MS runs. We evaluated the performance of our method using synthetic and experimental data. In comparison with several existing methods, the proposed BNM and BNMD yielded significant improvement.

Description: Performing clustering analysis is one of the important research topics in cancer discovery using gene expression profiles, which is crucial in facilitating the successful diagnosis and treatment of cancer. While there are quite a number of research works which perform tumor clustering, few of them considers how to incorporate fuzzy theory together with an optimization process into a consensus clustering framework to improve the performance of clustering analysis. In this paper, we first propose a random double clustering based cluster ensemble framework (RDCCE) to perform tumor clustering based on gene expression data. Specifically, RDCCE generates a set of representative features using a randomly selected clustering algorithm in the ensemble, and then assigns samples to their corresponding clusters based on the grouping results. In addition, we also introduce the random double clustering based fuzzy cluster ensemble framework (RDCFCE), which is designed to improve the performance of RDCCE by integrating the newly proposed fuzzy extension model into the ensemble framework. RDCFCE adopts the normalized cut algorithm as the consensus function to summarize the fuzzy matrices generated by the fuzzy extension models, partition the consensus matrix, and obtain the final result. Finally, adaptive RDCFCE (A-RDCFCE) is proposed to optimize RDCFCE and improve the performance of RDCFCE further by adopting a self-evolutionary process (SEPP) for the parameter set. Experiments on real cancer gene expression profiles indicate that RDCFCE and A-RDCFCE works well on these data sets, and outperform most of the state-of-the-art tumor clustering algorithms.

Description: Named-entity recognition (NER) plays an important role in the development of biomedical databases. However, the existing NER tools produce multifarious named-entities which may result in both curatable and non-curatable markers. To facilitate biocuration with a straightforward approach, classifying curatable named-entities is helpful with regard to accelerating the biocuration workflow. Co-occurrence Interaction Nexus with Named-entity Recognition (CoINNER) is a web-based tool that allows users to identify genes, chemicals, diseases, and action term mentions in the Comparative Toxicogenomic Database (CTD). To further discover interactions, CoINNER uses multiple advanced algorithms to recognize the mentions in the BioCreative IV CTD Track. CoINNER is developed based on a prototype system that annotated gene, chemical, and disease mentions in PubMed abstracts at BioCreative 2012 Track I (literature triage). We extended our previous system in developing CoINNER. The pre-tagging results of CoINNER were developed based on the state-of-the-art named entity recognition tools in BioCreative III. Next, a method based on conditional random fields (CRFs) is proposed to predict chemical and disease mentions in the articles. Finally, action term mentions were collected by latent Dirichlet allocation (LDA). At the BioCreative IV CTD Track, the best F-measures reached for gene/protein, chemical/drug and disease NER were 54 percent while CoINNER achieved a 61.5 percent F-measure. System URL: http://ikmbio.csie.ncku.edu.tw/coinner/introduction.htm.

Description: Next-generation short-read sequencing is widely utilized in genomic studies. Biological applications require an alignment step to map sequencing reads to the reference genome, before acquiring expected genomic information. This requirement makes alignment accuracy a key factor for effective biological interpretation. Normally, when accounting for measurement errors and single nucleotide polymorphisms, short read mappings with a few mismatches are generally considered acceptable. However, to further improve the efficiency of short-read sequencing alignment, we propose a method to retrieve additional reliably aligned reads (reads with more than a pre-defined number of mismatches), using a Bayesian-based approach. In this method, we first retrieve the sequence context around the mismatched nucleotides within the already aligned reads; these loci contain the genomic features where sequencing errors occur. Then, using the derived pattern, we evaluate the remaining (typically discarded) reads with more than the allowed number of mismatches, and calculate a score that represents the probability that a specific alignment is correct. This strategy allows the extraction of more reliably aligned reads, therefore improving alignment sensitivity. Implementation: The source code of our tool, ResSeq, can be downloaded from: https://github.com/hrbeubiocenter/Resseq.

Description: In genome assembly graphs, motifs such as tips, bubbles, and cross links are studied in order to find sequencing errors and to understand the nature of the genome. Superbubble, a complex generalization of bubbles, was recently proposed as an important subgraph class for analyzing assembly graphs. At present, a quadratic time algorithm is known. This paper gives an -time algorithm to solve this problem for a graph with $m$ edges.

Description: The papers in this special section focus on software and databases that are central in bioinformatics and computational biology.. These programs are playing more and more important roles in biology and medical research. These papers cover a broad range of topics, including computational genomics and transcriptomics, analysis of biological networks and interactions, drug design, biomedical signal/image analysis, biomedical text mining and ontologies, biological data mining, visualization and integration, and high performance computing application in bioinformatics.

Description: In the computational biology community, machine learning algorithms are key instruments for many applications, including the prediction of gene-functions based upon the available biomolecular annotations. Additionally, they may also be employed to compute similarity between genes or proteins. Here, we describe and discuss a software suite we developed to implement and make publicly available some of such prediction methods and a computational technique based upon Latent Semantic Indexing (LSI), which leverages both inferred and available annotations to search for semantically similar genes. The suite consists of three components. BioAnnotationPredictor is a computational software module to predict new gene-functions based upon Singular Value Decomposition of available annotations. SimilBio is a Web module that leverages annotations available or predicted by BioAnnotationPredictor to discover similarities between genes via LSI. The suite includes also SemSim , a new Web service built upon these modules to allow accessing them programmatically. We integrated SemSim in the Bio Search Computing framework (http://www.bioinformatics.deib.polimi.it/bio-seco/seco/), where users can exploit the Search Computing technology to run multi-topic complex queries on multiple integrated Web services. Accordingly, researchers may obtain ranked answers involving the computation of the functional similarity between genes in support of biomedical knowledge discovery.

Description: Identification of cancer subtypes plays an important role in revealing useful insights into disease pathogenesis and advancing personalized therapy. The recent development of high-throughput sequencing technologies has enabled the rapid collection of multi-platform genomic data (e.g., gene expression, miRNA expression, and DNA methylation) for the same set of tumor samples. Although numerous integrative clustering approaches have been developed to analyze cancer data, few of them are particularly designed to exploit both deep intrinsic statistical properties of each input modality and complex cross-modality correlations among multi-platform input data. In this paper, we propose a new machine learning model, called multimodal deep belief network (DBN), to cluster cancer patients from multi-platform observation data. In our integrative clustering framework, relationships among inherent features of each single modality are first encoded into multiple layers of hidden variables, and then a joint latent model is employed to fuse common features derived from multiple input modalities. A practical learning algorithm, called contrastive divergence (CD), is applied to infer the parameters of our multimodal DBN model in an unsupervised manner. Tests on two available cancer datasets show that our integrative data analysis approach can effectively extract a unified representation of latent features to capture both intra- and cross-modality correlations, and identify meaningful disease subtypes from multi-platform cancer data. In addition, our approach can identify key genes and miRNAs that may play distinct roles in the pathogenesis of different cancer subtypes. Among those key miRNAs, we found that the expression level of miR-29a is highly correlated with survival time in ovarian cancer patients. These results indicate that our multimodal DBN based data analysis approach may have practical applications in cancer pathogenesis studies and provide useful guidelines for personali- ed cancer therapy.

Description: The papers in this special issue contain extended versions of works that were originally presented at the Brazilian Symposium on Bioinformatics 2013 (BSB 2013), held in Recife, Brazil, November 3-6, 2013.

Description: Computational methods for predicting protein-protein interactions are important tools that can complement high-throughput technologies and guide biologists in designing new laboratory experiments. The proteins and the interactions between them can be described by a network which is characterized by several topological properties. Information about proteins and interactions between them, in combination with knowledge about topological properties of the network, can be used for developing computational methods that can accurately predict unknown protein-protein interactions. This paper presents a supervised learning framework based on Bayesian inference for combining two types of information: i) network topology information, and ii) information related to proteins and the interactions between them. The motivation of our model is that by combining these two types of information one can achieve a better accuracy in predicting protein-protein interactions, than by using models constructed from these two types of information independently.

Description: We develop a theory of algebraic operations over linear and context-free grammars that makes it possible to combine simple “atomic” grammars operating on single sequences into complex, multi-dimensional grammars. We demonstrate the utility of this framework by constructing the search spaces of complex alignment problems on multiple input sequences explicitly as algebraic expressions of very simple one-dimensional grammars. In particular, we provide a fully worked frameshift-aware, semiglobal DNA-protein alignment algorithm whose grammar is composed of products of small, atomic grammars. The compiler accompanying our theory makes it easy to experiment with the combination of multiple grammars and different operations. Composite grammars can be written out in $ {rm L}^AT_{E}X$ for documentation and as a guide to implementation of dynamic programming algorithms. An embedding in Haskell as a domain-specific language makes the theory directly accessible to writing and using grammar products without the detour of an external compiler. Software and supplemental files available here: http://www.bioinf.uni-leipzig.de/Software/gramprod/

Description: Recent advancements in genomics and proteomics provide a solid foundation for understanding the pathogenesis of diabetes. Proteomics of diabetes associated pathways help to identify the most potent target for the management of diabetes. The relevant datasets are scattered in various prominent sources which takes much time to select the therapeutic target for the clinical management of diabetes. However, additional information about target proteins is needed for validation. This lacuna may be resolved by linking diabetes associated genes, pathways and proteins and it will provide a strong base for the treatment and planning management strategies of diabetes. Thus, a web source “Diabetes Associated Proteins Database (DAPD)” has been developed to link the diabetes associated genes, pathways and proteins using PHP, MySQL. The current version of DAPD has been built with proteins associated with different types of diabetes. In addition, DAPD has been linked to external sources to gain the access to more participatory proteins and their pathway network. DAPD will reduce the time and it is expected to pave the way for the discovery of novel anti-diabetic leads using computational drug designing for diabetes management. DAPD is open accessed via following url www.mkarthikeyan.bioinfoau.org/dapd.

Description: Determining the glycan topology automatically from mass spectra represents a great challenge. Existing methods fall into approximate and exact ones. The former including greedy and heuristic ones can reduce the computational complexity, but suffer from information lost in the procedure of glycan interpretation. The latter including dynamic programming and exhaustive enumeration are much slower than the former. In the past years, nearly all emerging methods adopted a tree structure to represent a glycan. They share such problems as repetitive peak counting in reconstructing a candidate structure. Besides, tree-based glycan representation methods often have to give different computational formulas for binary and ternary glycans. We propose a new directed acyclic graph structure for glycan representation. Based on it, this work develops a de novo algorithm to accurately reconstruct the tree structure iteratively from mass spectra with logical constraints and some known biosynthesis rules, by a single computational formula. The experiments on multiple complex glycans extracted from human serum show that the proposed algorithm can achieve higher accuracy to determine a glycan topology than prior methods without increasing computational burden.

Description: A crucial step in understanding the architecture of cells and tissues from microscopy images, and consequently explain important biological events such as wound healing and cancer metastases, is the complete extraction and enumeration of individual filaments from the cellular cytoskeletal network. Current efforts at quantitative estimation of filament length distribution, architecture and orientation from microscopy images are predominantly limited to visual estimation and indirect experimental inference. Here we demonstrate the application of a new algorithm to reliably estimate centerlines of biological filament bundles and extract individual filaments from the centerlines by systematically disambiguating filament intersections. We utilize a filament enhancement step followed by reverse diffusion based filament localization and an integer programming based set combination to systematically extract accurate filaments automatically from microscopy images. Experiments on simulated and real confocal microscope images of flat cells (2D images) show efficacy of the new method.

Description: The Local/Global Alignment (Zemla, 2003), or LGA, is a popular method for the comparison of protein structures. One of the two components of LGA requires us to compute the longest common contiguous segments between two protein structures. That is, given two structures $A=(a_1, ldots , a_n)$ and $B=(b_1, ldots , b_n)$ where $a_k$ , $b_kin mathbb {R}^3$ , we are to find, among all the segments $f=(a_i,ldots ,a_j)$ and $g=(b_i,ldots ,b_j)$ that fulfill a certain criterion regarding their similarity, those of the maximum length. We consider the following criteria: (1) the root mean squared deviation (RMSD) between $f$ and $g$ is to be within a given $tin mathbb {R}$ ; (2) $f$ and $g$ can be superposed such that for each $k$ , $ile kle j$ , $Vert a_k-b_kVert le t$ for a given $tin mathbb {R}$ . We give an algorithm of $O(n;log; n+n{{boldsymbol l}})$ time complexity when the first requirement applies, where ${{boldsymbol l}}$ is the maximum length of the segments fulfilling the criterion. We show an FPTAS which, for any

Description: Noise can induce various dynamical behaviors in nonlinear systems. White noise perturbed systems have been extensively investigated during the last decades. In gene networks, experimentally observed extrinsic noise is colored. As an attempt, we investigate the genetic toggle switch systems perturbed by colored extrinsic noise and with kinetic parameters. Compared with white noise perturbed systems, we show there also exists optimal colored noise strength to induce the best stochastic switch behaviors in the single toggle switch, and the best synchronized switching in the networked systems, which demonstrate that noise-induced optimal switch behaviors are widely in existence. Moreover, under a wide range of system parameter regions, we find there exist wider ranges of white and colored noises strengths to induce good switch and synchronization behaviors, respectively; therefore, white noise is beneficial for switch and colored noise is beneficial for population synchronization. Our observations are very robust to extrinsic stimulus strength, cell density, and diffusion rate. Finally, based on the Waddington’s epigenetic landscape and the Wiener-Khintchine theorem, physical mechanisms underlying the observations are interpreted. Our investigations can provide guidelines for experimental design, and have potential clinical implications in gene therapy and synthetic biology.

Description: Revealing the underlying evolutionary mechanism plays an important role in understanding protein interaction networks in the cell. While many evolutionary models have been proposed, the problem about applying these models to real network data, especially for differentiating which model can better describe evolutionary process for the observed network remains a challenge. The traditional way is to use a model with presumed parameters to generate a network, and then evaluate the fitness by summary statistics, which however cannot capture the complete network structures information and estimate parameter distribution. In this work, we developed a novel method based on Approximate Bayesian Computation and modified Differential Evolution algorithm (ABC-DEP) that is capable of conducting model selection and parameter estimation simultaneously and detecting the underlying evolutionary mechanisms for PPI networks more accurately. We tested our method for its power in differentiating models and estimating parameters on simulated data and found significant improvement in performance benchmark, as compared with a previous method. We further applied our method to real data of protein interaction networks in human and yeast. Our results show duplication attachment model as the predominant evolutionary mechanism for human PPI networks and Scale-Free model as the predominant mechanism for yeast PPI networks.

Description: Single nucleotide polymorphisms, a dominant type of genetic variants, have been used successfully to identify defective genes causing human single gene diseases. However, most common human diseases are complex diseases and caused by gene-gene and gene-environment interactions. Many SNP-SNP interaction analysis methods have been introduced but they are not powerful enough to discover interactions more than three SNPs. The paper proposes a novel method that analyzes all SNPs simultaneously. Different from existing methods, the method regards an individual’s genotype data on a list of SNPs as a point with a unit of energy in a multi-dimensional space, and tries to find a new coordinate system where the energy distribution difference between cases and controls reaches the maximum. The method will find different multiple SNPs combinatorial patterns between cases and controls based on the new coordinate system. The experiment on simulated data shows that the method is efficient. The tests on the real data of age-related macular degeneration (AMD) disease show that it can find out more significant multi-SNP combinatorial patterns than existing methods.

Description: Disulfide connectivity is an important protein structural characteristic. Accurately predicting disulfide connectivity solely from protein sequence helps to improve the intrinsic understanding of protein structure and function, especially in the post-genome era where large volume of sequenced proteins without being functional annotated is quickly accumulated. In this study, a new feature extracted from the predicted protein 3D structural information is proposed and integrated with traditional features to form discriminative features. Based on the extracted features, a random forest regression model is performed to predict protein disulfide connectivity. We compare the proposed method with popular existing predictors by performing both cross-validation and independent validation tests on benchmark datasets. The experimental results demonstrate the superiority of the proposed method over existing predictors. We believe the superiority of the proposed method benefits from both the good discriminative capability of the newly developed features and the powerful modelling capability of the random forest. The web server implementation, called TargetDisulfide, and the benchmark datasets are freely available at: http://csbio.njust.edu.cn/bioinf/TargetDisulfide for academic use.

Description: Proteins are molecules that form the mass of living beings. These proteins exist in dissociated forms like amino-acids and carry out various biological functions, in fact, almost all body reactions occur with the participation of proteins. This is one of the reasons why the analysis of proteins has become a major issue in biology. In a more concrete way, the identification of conserved patterns in a set of related protein sequences can provide relevant biological information about these protein functions. In this paper, we present a novel algorithm based on teaching learning based optimization (TLBO) combined with a local search function specialized to predict common patterns in sets of protein sequences. This population-based evolutionary algorithm defines a group of individuals (solutions) that enhance their knowledge (quality) by means of different learning stages. Thus, if we correctly adapt it to the biological context of the mentioned problem, we can get an acceptable set of quality solutions. To evaluate the performance of the proposed technique, we have used six instances composed of different related protein sequences obtained from the PROSITE database. As we will see, the designed approach makes good predictions and improves the quality of the solutions found by other well-known biological tools.

Description: We introduce Supervised Variational Relevance Learning (Suvrel), a variational method to determine metric tensors to define distance based similarity in pattern classification, inspired in relevance learning. The variational method is applied to a cost function that penalizes large intraclass distances and favors small interclass distances. We find analytically the metric tensor that minimizes the cost function. Preprocessing the patterns by doing linear transformations using the metric tensor yields a dataset which can be more efficiently classified. We test our methods using publicly available datasets, for some standard classifiers. Among these datasets, two were tested by the MAQC-II project and, even without the use of further preprocessing, our results improve on their performance.

Description: Genes can participate in multiple biological processes at a time and thus their expression can be seen as a composition of the contributions from the active processes. Biclustering under a plaid assumption allows the modeling of interactions between transcriptional modules or biclusters (subsets of genes with coherence across subsets of conditions) by assuming an additive composition of contributions in their overlapping areas. Despite the biological interest of plaid models, few biclustering algorithms consider plaid effects and, when they do, they place restrictions on the allowed types and structures of biclusters, and suffer from robustness problems by seizing exact additive matchings. We propose BiP (Biclustering using Plaid models), a biclustering algorithm with relaxations to allow expression levels to change in overlapping areas according to biologically meaningful assumptions (weighted and noise-tolerant composition of contributions). BiP can be used over existing biclustering solutions (seizing their benefits) as it is able to recover excluded areas due to unaccounted plaid effects and detect noisy areas non-explained by a plaid assumption, thus producing an explanatory model of overlapping transcriptional activity. Experiments on synthetic data support BiP’s efficiency and effectiveness. The learned models from expression data unravel meaningful and non-trivial functional interactions between biological processes associated with putative regulatory modules.

Description: We propose a classifier system called iPFPi that predicts the functions of un-annotated proteins. iPFPi assigns an un-annotated protein $P$ the functions of GO annotation terms that are semantically similar to $P$ . An un-annotated protein $P$ and a GO annotation term $T$ are represented by their characteristics. The characteristics of $P$ are GO terms found within the abstracts of biomedical literature associated with $P$ . The characteristics of $T$ are GO terms found within the abstracts of biomedical literature associated with the proteins annotated with the function of $T$ . Let - F$ and $Fprime $ be the important (dominant) sets of characteristic terms representing $T$ and $P$ , respectively. iPFPi would annotate $P$ with the function of $T$ , if $F$ and $Fprime $ are semantically similar. We constructed a novel semantic similarity measure that takes into consideration several factors, such as the dominance degree of each characteristic term $t$ in set $F$

Description: Adverse drug reaction (ADR) is a common clinical problem, sometimes accompanying with high risk of mortality and morbidity. It is also one of the major factors that lead to failure in new drug development. Unfortunately, most of current experimental and computational methods are unable to evaluate clinical safety of drug candidates in early drug discovery stage due to the very limited knowledge of molecular mechanisms underlying ADRs. Therefore, in this study, we proposed a novel naïve Bayesian model for rapid assessment of clinical ADRs with frequency estimation. This model was constructed on a gene-ADR association network, which covered 611 US FDA approved drugs, 14,251 genes, and 1,254 distinct ADR terms. An average detection rate of 99.86 and 99.73 percent were achieved eventually in identification of known ADRs in internal test data set and external case analyses respectively. Moreover, a comparative analysis between the estimated frequencies of ADRs and their observed frequencies was undertaken. It is observed that these two frequencies have the similar distribution trend. These results suggest that the naïve Bayesian model based on gene-ADR association network can serve as an efficient and economic tool in rapid ADRs assessment.

Description: The papers in this special section were presented at the 13th International Workshop on Data Mining in Bioinformatics (BIOKDD???14) was organized in conjunction with the ACM SIGKDD International Conference on Knowledge Discovery and Data Mining that was held on August 24, 2014 in New York, NY. It brought together international researchers in the interacting disciplines of data mining, systems biology, and bioinformatics at the Bloomberg Headquarters venue. The goal of this workshop is to encourage Knowledge Discovery and Data mining (KDD) researchers to take on the numerous challenges that Bioinformatics offers.

Description: The introduction of next-generation sequencing technologies has radically changed the way we view structural genetic events. Microhomology-mediated break-induced replication (MMBIR) is just one of the many mechanisms that can cause genomic destabilization that may lead to cancer. Although the mechanism for MMBIR remains unclear, it has been shown that MMBIR is typically associated with template-switching events. Currently, to our knowledge, there is no existing bioinformatics tool to detect these template-switching events. We have developed MMBIRFinder, a method that detects template-switching events associated with MMBIR from whole-genome sequenced data. MMBIRFinder uses a half-read alignment approach to identify potential regions of interest. Clustering of these potential regions helps narrow the search space to regions with strong evidence. Subsequent local alignments identify the template-switching events with single-nucleotide accuracy. Using simulated data, MMBIRFinder identified 83 percent of the MMBIR regions within a five nucleotide tolerance. Using real data, MMBIRFinder identified 16 MMBIR regions on a normal breast tissue data sample and 51 MMBIR regions on a triple-negative breast cancer tumor sample resulting in detection of 37 novel template-switching events. Finally, we identified template-switching events residing in the promoter region of seven genes that have been implicated in breast cancer. The program is freely available for download at https://github.com/msegar/MMBIRFinder.

Description: Compressing heterogeneous collections of trees is an open problem in computational phylogenetics. In a heterogeneous tree collection, each tree can contain a unique set of taxa. An ideal compression method would allow for the efficient archival of large tree collections and enable scientists to identify common evolutionary relationships over disparate analyses. In this paper, we extend TreeZip to compress heterogeneous collections of trees. TreeZip is the most efficient algorithm for compressing homogeneous tree collections. To the best of our knowledge, no other domain-based compression algorithm exists for large heterogeneous tree collections or enable their rapid analysis. Our experimental results indicate that TreeZip averages 89.03 percent (72.69 percent) space savings on unweighted (weighted) collections of trees when the level of heterogeneity in a collection is moderate. The organization of the TRZ file allows for efficient computations over heterogeneous data. For example, consensus trees can be computed in mere seconds. Lastly, combining the TreeZip compressed (TRZ) file with general-purpose compression yields average space savings of 97.34 percent (81.43 percent) on unweighted (weighted) collections of trees. Our results lead us to believe that TreeZip will prove invaluable in the efficient archival of tree collections, and enables scientists to develop novel methods for relating heterogeneous collections of trees.

Description: The papers in this special section were presented at the 2014 International Conference on Genome Informatics (GIW).

Description: Cluster analysis of biological networks is one of the most important approaches for identifying functional modules and predicting protein functions. Furthermore, visualization of clustering results is crucial to uncover the structure of biological networks. In this paper, ClusterViz, an APP of Cytoscape 3 for cluster analysis and visualization, has been developed. In order to reduce complexity and enable extendibility for ClusterViz, we designed the architecture of ClusterViz based on the framework of Open Services Gateway Initiative. According to the architecture, the implementation of ClusterViz is partitioned into three modules including interface of ClusterViz, clustering algorithms and visualization and export. ClusterViz fascinates the comparison of the results of different algorithms to do further related analysis. Three commonly used clustering algorithms, FAG-EC, EAGLE and MCODE, are included in the current version. Due to adopting the abstract interface of algorithms in module of the clustering algorithms, more clustering algorithms can be included for the future use. To illustrate usability of ClusterViz, we provided three examples with detailed steps from the important scientific articles, which show that our tool has helped several research teams do their research work on the mechanism of the biological networks.

Description: Structural domains are evolutionary and functional units of proteins and play a critical role in comparative and functional genomics. Computational assignment of domain function with high reliability is essential for understanding whole-protein functions. However, functional annotations are conventionally assigned onto full-length proteins rather than associating specific functions to the individual structural domains. In this article, we present Structural Domain Annotation (SDA), a novel computational approach to predict functions for SCOP structural domains. The SDA method integrates heterogeneous information sources, including structure alignment based protein-SCOP mapping features, InterPro2GO mapping information, PSSM Profiles, and sequence neighborhood features, with a Bayesian network. By large-scale annotating Gene Ontology terms to SCOP domains with SDA, we obtained a database of SCOP domain to Gene Ontology mappings, which contains $sim$ 162,000 out of the approximately 166,900 domains in SCOPe 2.03 ( $>$ 97 percent) and their predicted Gene Ontology functions. We have benchmarked SDA using a single-domain protein dataset and an independent dataset from different species. Comparative studies show that SDA significantly outperforms the existing function prediction methods for structural domains in terms of coverage and maximum F-measure.

Description: A major challenge in computational biology is to find simple representations of high-dimensional data that best reveal the underlying structure. In this work, we present an intuitive and easy-to-implement method based on ranked neighborhood comparisons that detects structure in unsupervised data. The method is based on ordering objects in terms of similarity and on the mutual overlap of nearest neighbors. This basic framework was originally introduced in the field of social network analysis to detect actor communities. We demonstrate that the same ideas can successfully be applied to biomedical data sets in order to reveal complex underlying structure. The algorithm is very efficient and works on distance data directly without requiring a vectorial embedding of data. Comprehensive experiments demonstrate the validity of this approach. Comparisons with state-of-the-art clustering methods show that the presented method outperforms hierarchical methods as well as density based clustering methods and model-based clustering. A further advantage of the method is that it simultaneously provides a visualization of the data. Especially in biomedical applications, the visualization of data can be used as a first pre-processing step when analyzing real world data sets to get an intuition of the underlying data structure. We apply this model to synthetic data as well as to various biomedical data sets which demonstrate the high quality and usefulness of the inferred structure.

Description: Proline residues are common source of kinetic complications during folding. The X-Pro peptide bond is the only peptide bond for which the stability of the cis and trans conformations is comparable. The cis-trans isomerization (CTI) of X-Pro peptide bonds is a widely recognized rate-limiting factor, which can not only induces additional slow phases in protein folding but also modifies the millisecond and sub-millisecond dynamics of the protein. An accurate computational prediction of proline CTI is of great importance for the understanding of protein folding, splicing, cell signaling, and transmembrane active transport in both the human body and animals. In our earlier work, we successfully developed a biophysically motivated proline CTI predictor utilizing a novel tree-based consensus model with a powerful metalearning technique and achieved 86.58 percent Q2 accuracy and 0.74 Mcc, which is a better result than the results (70-73 percent Q2 accuracies) reported in the literature on the well-referenced benchmark dataset. In this paper, we describe experiments with novel randomized subspace learning and bootstrap seeding techniques as an extension to our earlier work, the consensus models as well as entropy-based learning methods, to obtain better accuracy through a precise and robust learning scheme for proline CTI prediction.

Description: Efficient search algorithms for finding genomic-range overlaps are essential for various bioinformatics applications. A majority of fast algorithms for searching the overlaps between a query range (e.g., a genomic variant) and a set of N reference ranges (e.g., exons) has time complexity of O ( k + log N ), where k denotes a term related to the length and location of the reference ranges. Here, we present a simple but efficient algorithm that reduces k, based on the maximum reference range length. Specifically, for a given query range and the maximum reference range length, the proposed method divides the reference range set into three subsets: always , potentially , and never overlapping . Therefore, search effort can be reduced by excluding never overlapping subset. We demonstrate that the running time of the proposed algorithm is proportional to potentially overlapping subset size, that is proportional to the maximum reference range length if all the other conditions are the same. Moreover, an implementation of our algorithm was 13.8 to 30.0 percent faster than one of the fastest range search methods available when tested on various genomic-range data sets. The proposed algorithm has been incorporated into a disease-linked variant prioritization pipeline for WGS (http://gnome.tchlab.org) and its implementation is available at http://ml.ssu.ac.kr/gSearch.

Description: The identification of protein complexes in protein-protein interaction (PPI) networks is fundamental for understanding biological processes and cellular molecular mechanisms. Many graph computational algorithms have been proposed to identify protein complexes from PPI networks by detecting densely connected groups of proteins. These algorithms assess the density of subgraphs through evaluation of the sum of individual edges or nodes; thus, incomplete and inaccurate measures may miss meaningful biological protein complexes with functional significance. In this study, we propose a novel method for assessing the compactness of local subnetworks by measuring the number of three node cliques. The present method detects each optimal cluster by growing a seed and maximizing the compactness function. To demonstrate the efficacy of the new proposed method, we evaluate its performance using five PPI networks on three reference sets of yeast protein complexes with five different measurements and compare the performance of the proposed method with four state-of-the-art methods. The results show that the protein complexes generated by the proposed method are of better quality than those generated by four classic methods. Therefore, the new proposed method is effective and useful for detecting protein complexes in PPI networks.

Description: Presents the back cover of this issue of the periodical.

Description: Nonmilitary applications of unmanned air vehicles (UAVs), especially as rescue vehicles to obtain information have increased in recent years. Small UAVs (SUAV) were used in nonmilitary projects, where the focus was on autonomous vehicles; however, microaerial vehicles (MAVs), such as Samarai, make use of radio control, and they were not autonomous vehicles [1]. Autonomous UAVs need sophisticated guidance, control, and navigation systems with conventional aircraft flying processes. Most of current UAVs use ground-station commands for guidance purposes, although autonomous UAVs tend to reduce dependency on ground-station command via autonomous algorithms, such as intelligent methods. Therefore, ground-based air control may not suffice to cover every flying mission. Thus, self-contained, onboard guidance via intelligent methods, such as fuzzy logic, has been considered to achieve this goal. Lockheed Martin???s Intelligent Robotics Laboratory has spent the last 5 years developing an unmanned craft to replicate the air vehicle motion. The idea was based on the motion of maple seed, which whirls softly to the ground after dropping from maple tree. This motion, which is similar to a one-winged helicopter, inspired Lockheed Martin to design a new type of flying vehicles, beneficial in military and nonmilitary surveillance. Maple seeds disperse themselves by auto-rotating passively by using a single wing as they descend from trees, thereby ensuring they are widely scattered. Inspired by these flight concepts, Lockheed Martin Advanced Technology Laboratories developed the Samarai MAV, a 30-cm-radius maple seedlike aircraft that can take off and land vertically and fly laterally, like a helicopter, due to the intrinsic stability of the maple seeds??? nature [2] (Figure 1).

Description: Presents the message from the Associate Editor-in-Chief.

Description: Presents the front cover for this issue of the publication.

Description: Lists upcoming AESS society meetings and conferences.

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Description: Presents letters to the editor for this issue of the publication.

Description: Presents a listing of AESS IEEE Senior Members.

Description: Presents information on the guidelines for the 2016 Robert T. Hill best dissertation award.

Description: A global navigation satellite system (GNSS) receiver processes signals transmitted from the satellites to determine user position, velocity, and time. Compared to conventional receivers, a software GNSS receiver offers better design flexibility and requires fewer dedicated hardware components [1]. An ideal software receiver typically processes all signals in a processor; however, this method is not efficient practically, because it becomes a computational burden for the processor. For this reason, frequent multiplications and operations are offloaded to hardware elements such as a field-programmable gate array (FPGA).

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Description: Presents the 2015 author/subject index for this publication.

Description: Currently, the diverse engineering disciplines involved in a complex product, for example unmanned aerial vehicle (UAV) development, work in isolation without the benefits of accelerated delivery of capabilities more reliable and affordable. Considering the vehicle as a system requires the integration of engineering disciplines, such as mechanical, electrical, control, avionics, and software with potentially disparate design artifacts. This integration allows risk containment by improving the confidence in the system design at earlier stages of the system development.

Description: In recent years, the design of so-called tunable detectors has raised significant interest in the radar community. The class of tunable detectors has been shown to be an effective means to attack detection of mainlobe targets or rejection of coherent repeater interferers in the presence of clutter and/or possible noise-like in-terferers. Tunable detectors allow adjustment of the rate at which the probability of detection Pd decreases as the received signal departs from the nominal one. In this case, a mismatch between the nominal and the actual steering vector is present. We refer to the capability of rejecting or detecting signals as directivity. Existing architectures can be classified according to their directivity as follows [1]: ▸ Robust decision schemes provide good detection performance in the presence of echoes containing signal components not aligned with the nominal (transmitted) signal (as shown in Figure 1, where target returns lie on a direction that is not aligned with the antenna beam boresight). ▸ Selective decision schemes are capable of rejecting signals whose signature is unlikely to correspond to the signal of interest to avoid false alarms.

Description: Small satellites are revolutionizing the space industry [1]. In particular, nanosatellites are very attractive because they enable access to space with a significant reduction of costs for satellite industries, and a shorter development time with respect to large satellites [2], [3]. Moreover, thanks to modern technologies, relatively complex missions can be planned for Earth observation [4], remote sensing [5], communication technology experiments [6], hardware validation and other scientific missions, as well as educational purposes [7]-[10].

Description: Cost estimation is a critical issue in the planning of a large project and may prove to be a vital determinant of final success. Despite its great importance, predicting the cost of developing complex high-technology systems and products, based a good deal on research and development, is difficult and carries a degree of uncertainty in the results. The difficulty of the process has been especially evident in projects for which there was little prior experience. Estimating satellite development costs has been just such an endeavor, in which history shows cost overruns are not uncommon [1].

Description: Whenever a tried-and-true classic beloved by many is revised by a team of authors rather than the original author, the first question that one tends to want answered is, “Have they ruined it?” In this case, the answer is a definitive no. This is a magnificent revision of a classic that will become a classic in its own right. It is the first book new employees who are going to specialize in radar should be handed to read, independent of any area they choose to specialize in. For more senior radar specialists, it is a quick refresher at the high level of the familiar, so specialists can visit a subject area in preparation for an elevator speech or a talk with a manager who has not specialized in radar. Radar is such a broad area of specialization that one cannot be familiar with all aspects of it, particularly as the number of subfields within radar has exploded in the last 20 years. At the elementary level of a non-calculus-based college physics course, Stimsons Introduction to Airborne Radar provides an alternative for first reads of most of the new subfields that have appeared since the previous edition. The graphics in the new edition take advantage of modern developments, so they are much improved. For one who has grown up in a southern household, where recipes have based passed down for generations, the family recipes “smell,” wafting through the kitchen as generations succeed one another. The modern southern kitchen provides the comfort of the old and familiar, with fusion of new species as new traditions are added. The new edition of this book maintains the smell of the old and Stimson's familiar writing style while reflecting the needed fusion with the latest generation's contributions. One wishes other revisions of classic books had been handled with such loving care.

Description: During the course of a space mission unexpected events can occur regardless of rigorous testing. In order to ensure the ability of a spacecraft to recover and adapt to new situations, it may be necessary to update the firmware for resolving the software issues, work around hardware problems, or introduce new features. The importance of remote firmware updates as well as a method to calculate an indicative value of flexibility in space missions is summarized by R. Nilchiani [1].

Description: For the 9th time the international conference “Inertial Sensors and Systems” took place in Karlsruhe, Germany, organized by the Institute of Systems Optimization (ITE) together with the German Institute of Navigation (DGON), cosponsored by the Royal Institute of Navigation (RIN) and by the IEEE Aerospace and Electronic Systems Society (AESS).

Description: The characteristics of a landing landmark are a key concern when an autonomous, vision-based unmanned helicopter is landing. The shape and recognition of the landmark determines the posture parameters of the unmanned helicopter and the accuracy of its autonomous landing. This article analyzes and summarizes the shapes and the detection methods of various landmarks used for autonomous landing of helicopters, as well as their relationship to the posture parameters. The characteristics of different landing landmarks are obtained, and then the development of autonomous landing landmarks is analyzed. Finally, this article offers some directions for the future research of autonomous, vision-based landing of unmanned helicopters.

Description: The rapid growth in the use of software in airborne systems and equipment in the early 1980s resulted in a need for industry-accepted guidance for satisfying airworthiness requirements [1]. To assure the reliability of the software and to ultimately ensure the safety of passengers, the U.S. Federal Aviation Administration (FAA) has imposed software certifcation suited to the development of safety-critical systems. The FAA has accepted guidelines developed by the Radio Technical Commission for Aeronautics (RTCA) that respond to the necessity of reliability and safety, which are vital in this feld: DO-178B/EUROCAE ED-12B (DO-178B), titled Software Considerations in Airborne Systems and Equipment Certifcation [1]. DO-178B prescribes design assurance guidance for airborne software. The aim of DO-178B is to assure that software developed for avionics systems is reliable and safe to use in fight [2].

Description: Prospective authors are requested to submit new, unpublished manuscripts for inclusion in the upcoming event described in this call for papers.

Description: Over-the-horizon radar (OTHR) systems, or skywave propagation systems, use the high frequency (HF) band (3 to 30 MHz) to ???bounce??? or ???refract??? a signal off the ionosphere to detect tracks of interest (TOIs) between 500 and 2000 nautical miles from the transmitter/receiver pair. This range is ???an order of magnitude greater than is possible with conventional line-of-sight radars??? [1]. Since their initial employment, OTHR systems have significantly improved in abilities to detect and track TOIs such as aircraft, ballistic and cruise missiles, and ships [2].

Description: As discussed in Partitioning in Avionics Architectures: Requirements, Mechanisms, and Assurance by Rush by, J. [1], integrated modular avionics (IMA) is an embedded version of a centralized time-shared ???mainframe,??? which provides the hosted applications with the common computing resources and the airborne data network. The features of various IMA systems can be summarized in the following points: 1. high performance shared common computing resources 2. high speed communication network 3. open architecture for both software and hardware.

Description: The ionosphere consists of plasma trapped by Earth's magnetic feld. The plasma consists of heterogeneous structures, which are susceptible to perturbation caused by solar winds. Radio waves passing through the ionosphere experience scintillation due to irregularities in the plasma. This is a problem for satellite-based systems used for communication and navigation because the signals received by ground-based terminals experience reduced signal quality. This effect is greater around the Equator and near the polar cusps. During periods with high solar activity it can cause satellite communication outage. To understand radio wave disturbance in the ionosphere and develop more accurate space weather models, one must measure and quantify the plasma structures and perturbation by using in-situ instruments.

Description: Presents a call for nominations for the IEEE AESS Judith A. Resnik space award.

Description: Microbial interactions play important roles on the structure and function of complex microbial communities. With the rapid accumulation of high-throughput metagenomic or 16S rRNA sequencing data, it is possible to infer complex microbial interactions. Co-occurrence patterns of microbial species among multiple samples are often utilized to infer interactions. There are few methods to consider the temporally interacting patterns among microbial species. In this paper, we present a Graph-regularized Vector Autoregressive (GVAR) model to infer causal relationships among microbial entities. The new model has advantage comparing to the original vector autoregressive (VAR) model. Specifically, GVAR can incorporate similarity information for microbial interaction inference—i.e., GVAR assumed that if two species are similar in the previous stage, they tend to have similar influence on the other species in the next stage. We apply the model on a time series dataset of human gut microbiome which was treated with repeated antibiotics. The experimental results indicate that the new approach has better performance than several other VAR-based models and demonstrate its capability of extracting relevant microbial interactions.

Description: Modeling and simulations approaches have been widely used in computational biology, mathematics, bioinformatics and engineering to represent complex existing knowledge and to effectively generate novel hypotheses. While deterministic modeling strategies are widely used in computational biology, stochastic modeling techniques are not as popular due to a lack of user-friendly tools. This paper presents ENISI SDE, a novel web-based modeling tool with stochastic differential equations. ENISI SDE provides user-friendly web user interfaces to facilitate adoption by immunologists and computational biologists. This work provides three major contributions: (1) discussion of SDE as a generic approach for stochastic modeling in computational biology; (2) development of ENISI SDE, a web-based user-friendly SDE modeling tool that highly resembles regular ODE-based modeling; (3) applying ENISI SDE modeling tool through a use case for studying stochastic sources of cell heterogeneity in the context of CD4+ T cell differentiation. The CD4+ T cell differential ODE model has been published [8] and can be downloaded from biomodels.net. The case study reproduces a biological phenomenon that is not captured by the previously published ODE model and shows the effectiveness of SDE as a stochastic modeling approach in biology in general and immunology in particular and the power of ENISI SDE.

Description: Because most complex genetic diseases are caused by defects of cell signaling, illuminating a signaling cascade is essential for understanding their mechanisms. We present three novel computational algorithms to reconstruct signaling networks between a starting protein and an ending protein using genome-wide protein-protein interaction (PPI) networks and gene ontology (GO) annotation data. A signaling network is represented as a directed acyclic graph in a merged form of multiple linear pathways. An advanced semantic similarity metric is applied for weighting PPIs as the preprocessing of all three methods. The first algorithm repeatedly extends the list of nodes based on path frequency towards an ending protein. The second algorithm repeatedly appends edges based on the occurrence of network motifs which indicate the link patterns more frequently appearing in a PPI network than in a random graph. The last algorithm uses the information propagation technique which iteratively updates edge orientations based on the path strength and merges the selected directed edges. Our experimental results demonstrate that the proposed algorithms achieve higher accuracy than previous methods when they are tested on well-studied pathways of S. cerevisiae . Furthermore, we introduce an interactive web application tool, called P-Finder, to visualize reconstructed signaling networks.

Description: Accurately predicting the binding affinities of large diverse sets of protein-ligand complexes efficiently is a key challenge in computational biomolecular science, with applications in drug discovery, chemical biology, and structural biology. Since a scoring function (SF) is used to score, rank, and identify potential drug leads, the fidelity with which it predicts the affinity of a ligand candidate for a protein’s binding site has a significant bearing on the accuracy of virtual screening. Despite intense efforts in developing conventional SFs, which are either force-field based, knowledge-based, or empirical, their limited predictive accuracy has been a major roadblock toward cost-effective drug discovery. Therefore, in this work, we explore a range of novel SFs employing different machine-learning (ML) approaches in conjunction with a variety of physicochemical and geometrical features characterizing protein-ligand complexes. We assess the scoring accuracies of these new ML SFs as well as those of conventional SFs in the context of the 2007 and 2010 PDBbind benchmark datasets on both diverse and protein-family-specific test sets. We also investigate the influence of the size of the training dataset and the type and number of features used on scoring accuracy. We find that the best performing ML SF has a Pearson correlation coefficient of 0.806 between predicted and measured binding affinities compared to 0.644 achieved by a state-of-the-art conventional SF. We also find that ML SFs benefit more than their conventional counterparts from increases in the number of features and the size of training dataset. In addition, they perform better on novel proteins that they were never trained on before.

Description: One of the key tasks related to proteins is the similarity comparison of protein sequences in the area of bioinformatics and molecular biology, which helps the prediction and classification of protein structure and function. It is a significant and open issue to find similar proteins from a large scale of protein database efficiently. This paper presents a new distance based protein similarity analysis using a new encoding method of protein sequence which is based on fractal dimension. The protein sequences are first represented into the 1-dimensional feature vectors by their biochemical quantities. A series of Hybrid method involving discrete Wavelet transform, Fractal dimension calculation (HWF) with sliding window are then applied to form the feature vector. At last, through the similarity calculation, we can obtain the distance matrix, by which, the phylogenic tree can be constructed. We apply this approach by analyzing the ND5 (NADH dehydrogenase subunit 5) protein cluster data set. The experimental results show that the proposed model is more accurate than the existing ones such as Su’s model, Zhang’s model, Yao’s model and MEGA software, and it is consistent with some known biological facts.

Description: Essential proteins are indispensable for cellular life. It is of great significance to identify essential proteins that can help us understand the minimal requirements for cellular life and is also very important for drug design. However, identification of essential proteins based on experimental approaches are typically time-consuming and expensive. With the development of high-throughput technology in the post-genomic era, more and more protein-protein interaction data can be obtained, which make it possible to study essential proteins from the network level. There have been a series of computational approaches proposed for predicting essential proteins based on network topologies. Most of these topology based essential protein discovery methods were to use network centralities. In this paper, we investigate the essential proteins’ topological characters from a completely new perspective. To our knowledge it is the first time that topology potential is used to identify essential proteins from a protein-protein interaction (PPI) network. The basic idea is that each protein in the network can be viewed as a material particle which creates a potential field around itself and the interaction of all proteins forms a topological field over the network. By defining and computing the value of each protein’s topology potential, we can obtain a more precise ranking which reflects the importance of proteins from the PPI network. The experimental results show that topology potential-based methods TP and TP-NC outperform traditional topology measures: degree centrality (DC), betweenness centrality (BC), closeness centrality (CC), subgraph centrality (SC), eigenvector centrality (EC), information centrality (IC), and network centrality (NC) for predicting essential proteins. In addition, these centrality measures are improved on their performance for identifying essential proteins in biological network when controlled by topology potential.

Description: Mining knowledge from gene expression data is a hot research topic and direction of bioinformatics. Gene selection and sample classification are significant research trends, due to the large amount of genes and small size of samples in gene expression data. Rough set theory has been successfully applied to gene selection, as it can select attributes without redundancy. To improve the interpretability of the selected genes, some researchers introduced biological knowledge. In this paper, we first employ neighborhood system to deal directly with the new information table formed by integrating gene expression data with biological knowledge, which can simultaneously present the information in multiple perspectives and do not weaken the information of individual gene for selection and classification. Then, we give a novel framework for gene selection and propose a significant gene selection method based on this framework by employing reduction algorithm in rough set theory. The proposed method is applied to the analysis of plant stress response. Experimental results on three data sets show that the proposed method is effective, as it can select significant gene subsets without redundancy and achieve high classification accuracy. Biological analysis for the results shows that the interpretability is well.

Description: In order to make multiple copies of a target sequence in the laboratory, the technique of Polymerase Chain Reaction (PCR) requires the design of “primers”, which are short fragments of nucleotides complementary to the flanking regions of the target sequence. If the same primer is to amplify multiple closely related target sequences, then it is necessary to make the primers “degenerate”, which would allow it to hybridize to target sequences with a limited amount of variability that may have been caused by mutations. However, the PCR technique can only allow a limited amount of degeneracy, and therefore the design of degenerate primers requires the identification of reasonably well-conserved regions in the input sequences. We take an existing algorithm for designing degenerate primers that is based on clustering and parallelize it in a web-accessible software package GPUDePiCt, using a shared memory model and the computing power of Graphics Processing Units (GPUs). We test our implementation on large sets of aligned sequences from the human genome and show a multi-fold speedup for clustering using our hybrid GPU/CPU implementation over a pure CPU approach for these sequences, which consist of more than 7,500 nucleotides. We also demonstrate that this speedup is consistent over larger numbers and longer lengths of aligned sequences.

Description: Cell signaling governs the basic cellular activities and coordinates the actions in cell. Abnormal regulations in cell signaling processing are responsible for many human diseases, such as diabetes and cancers. With the accumulation of massive data related to human cell signaling, it is feasible to obtain a human signaling network. Some studies have shown that interesting biological phenomenon and drug-targets could be discovered by applying structural controllability analysis to biological networks. In this work, we apply structural controllability to a human signaling network and detect driver nodes, providing a systematic analysis of the role of different proteins in controlling the human signaling network. We find that the proteins in the upstream of the signaling information flow and the low in-degree proteins play a crucial role in controlling the human signaling network. Interestingly, inputting different control signals on the regulators of the cancer-associated genes could cost less than controlling the cancer-associated genes directly in order to control the whole human signaling network in the sense that less drive nodes are needed. This research provides a fresh perspective for controlling the human cell signaling system.

Description: Traditionally, biological objects such as genes, proteins, and pathways are represented by a convenient identifier, or ID, which is then used to cross reference, link and describe objects in biological databases. Relationships among the objects are often established using non-trivial and computationally complex ID mapping systems or converters, and are stored in authoritative databases such as UniGene, GeneCards, PIR and BioMart. Despite best efforts, such mappings are largely incomplete and riddled with false negatives. Consequently, data integration using record linkage that relies on these mappings produces poor quality of data, inadvertently leading to erroneous conclusions. In this paper, we discuss this largely ignored dimension of data integration, examine how the ubiquitous use of identifiers in biological databases is a significant barrier to knowledge fusion using distributed computational pipelines, and propose two algorithms for ad hoc and restriction free ID mapping of arbitrary types using online resources. We also propose two declarative statements for ID conversion and data integration based on ID mapping on-the-fly.

Description: Array comparative genome hybridization (aCGH) is a widely used methodology to detect copy number variations of a genome in high resolution. Knowing the number of break-points and their corresponding locations in genomic sequences serves different biological needs. Primarily, it helps to identify disease-causing genes that have functional importance in characterizing genome wide diseases. For human autosomes the normal copy number is two, whereas at the sites of oncogenes it increases (gain of DNA) and at the tumour suppressor genes it decreases (loss of DNA). The majority of the current detection methods are deterministic in their set-up and use dynamic programming or different smoothing techniques to obtain the estimates of copy number variations. These approaches limit the search space of the problem due to different assumptions considered in the methods and do not represent the true nature of the uncertainty associated with the unknown break-points in genomic sequences. We propose the Cross-Entropy method, which is a model-based stochastic optimization technique as an exact search method, to estimate both the number and locations of the break-points in aCGH data. We model the continuous scale log-ratio data obtained by the aCGH technique as a multiple break-point problem. The proposed methodology is compared with well established publicly available methods using both artificially generated data and real data. Results show that the proposed procedure is an effective way of estimating number and especially the locations of break-points with high level of precision. Availability: The methods described in this article are implemented in the new R package breakpoint and it is available from the Comprehensive R Archive Network at http://CRAN.R-project.org/package=breakpoint.

Description: Ageing is a highly complex biological process that is still poorly understood. With the growing amount of ageing-related data available on the web, in particular concerning the genetics of ageing, it is timely to apply data mining methods to that data, in order to try to discover novel patterns that may assist ageing research. In this work, we introduce new hierarchical feature selection methods for the classification task of data mining and apply them to ageing-related data from four model organisms: Caenorhabditis elegans (worm), Saccharomyces cerevisiae (yeast), Drosophila melanogaster (fly), and Mus musculus (mouse). The main novel aspect of the proposed feature selection methods is that they exploit hierarchical relationships in the set of features (Gene Ontology terms) in order to improve the predictive accuracy of the Naïve Bayes and 1 -Nearest Neighbour (1-NN) classifiers, which are used to classify model organisms’ genes into pro-longevity or anti-longevity genes. The results show that our hierarchical feature selection methods, when used together with Naïve Bayes and 1-NN classifiers, obtain higher predictive accuracy than the standard (without feature selection) Naïve Bayes and 1-NN classifiers, respectively. We also discuss the biological relevance of a number of Gene Ontology terms very frequently selected by our algorithms in our datasets.

Description: Prediction of essential proteins which are crucial to an organism's survival is important for disease analysis and drug design, as well as the understanding of cellular life. The majority of prediction methods infer the possibility of proteins to be essential by using the network topology. However, these methods are limited to the completeness of available protein-protein interaction (PPI) data and depend on the network accuracy. To overcome these limitations, some computational methods have been proposed. However, seldom of them solve this problem by taking consideration of protein domains. In this work, we first analyze the correlation between the essentiality of proteins and their domain features based on data of 13 species. We find that the proteins containing more protein domain types which rarely occur in other proteins tend to be essential. Accordingly, we propose a new prediction method, named UDoNC, by combining the domain features of proteins with their topological properties in PPI network. In UDoNC, the essentiality of proteins is decided by the number and the frequency of their protein domain types, as well as the essentiality of their adjacent edges measured by edge clustering coefficient. The experimental results on S. cerevisiae data show that UDoNC outperforms other existing methods in terms of area under the curve (AUC). Additionally, UDoNC can also perform well in predicting essential proteins on data of E. coli.