Computational Biology Journal The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Survey of Engineering Models for Systems Biology Mon, 18 Jan 2016 13:36:47 +0000 In recent years, the field of systems biology has emerged from a confluence of an increase both in molecular biotechnology and in computing storage and power. As a discipline, systems biology shares many characteristics with engineering. However, before the benefits of engineering-based modeling formalisms and analysis tools can be applied to systems biology, the engineering discipline(s) most related to systems biology must be identified. In this paper, we identify the cell as an embedded computing system and, as such, demonstrate that systems biology shares many aspects in common with computer systems engineering, electrical engineering, and chemical engineering. This realization solidifies the grounds for using modeling formalisms from these engineering subdisciplines to be applied to biological systems. While we document several examples where this is already happening, our goal is that identifying the cell as an embedded computing system would motivate and facilitate further discovery through more widespread use of the modeling formalisms described here. Gregory T. Reeves and Curtis E. Hrischuk Copyright © 2016 Gregory T. Reeves and Curtis E. Hrischuk. All rights reserved. Structural Differences in KIR3DL1 and LILRB1 Interaction with HLA-B and the Loading Peptide Polymorphisms: In Silico Evidences Mon, 16 Nov 2015 08:37:30 +0000 KIR3DL1 and LILRB1 interact with HLA class I. Using KIR3DL1/HLA-B interaction to set up the procedure, structural immune-informatics approaches have been performed in LILRB1/HLA-B alleles’ combination also considering the contribution of the HLA bound peptide. All KIR3DL1 alleles interact strongly with HLA-B alleles carrying Bw4 epitope and negative charged amino acid residues in peptide position P8 disrupt KIR3DL1 binding. HLA-B alleles carrying Ile 194 show a higher strength of interaction with LILRB1 in all the analyzed haplotypes. Finally, we hypothesize a contribution of the amino acid at position 1 of the HLA bound peptide in the modulation of HLA-B/LILRB1 interaction. Alba Grifoni, Atanas Patronov, Carla Montesano, Vittorio Colizzi, and Massimo Amicosante Copyright © 2015 Alba Grifoni et al. All rights reserved. Asymmetric Behavior of Thymidylate Synthase Dimer Subunits in Denaturating Solvent Observed with Molecular Dynamics Wed, 11 Mar 2015 13:35:01 +0000 A molecular dynamics simulations of the thymidylate synthase denaturation in chaotrope solvents (urea, guanidinium hydrochloride) were performed on 600 ns timescale. It appeared that this dimeric enzyme undergoes partial unfolding asymmetrically. It was shown also that urea is a better denaturant in the MD condition, as compared to guanidinium chloride. The unfolding occurs first at the external helices (AA 88-118) and follows by the AA 188-200 region. The present results correspond to the suggested in the literature activity of thymidylate synthase through a half-the-site mechanism. Filip Leonarski, Monika Świniarska, and Andrzej Leś Copyright © 2015 Filip Leonarski et al. All rights reserved. Simplified Algorithms for Determining Cycle Shift between qPCR Fluorescence Curves Tue, 03 Feb 2015 09:34:17 +0000 The polymerase chain reaction is a central component of current molecular biology. It is a cyclic process, in each early cycle of which the template DNA approximately doubles. An indicator which fluoresces when bound to DNA quantifies the DNA present at the end of each cycle, giving rise to a fluorescence curve which is characteristically sigmoid in shape. The fluorescence curve quantifies the amount of DNA initially present; the more the initial DNA, the earlier the rise in the fluorescence. Accordingly the amount of DNA initially present in two samples can be compared: the sample with the less DNA gives rise to a relatively delayed fluorescence curve and the ratio of the DNAs can be deduced from the separation of the curves. There is, however, a second determinant of this separation, the fold increase in DNA per cycle: ideally a twofold increase but frequently less. Current guidelines recommend that this be determined experimentally by carrying out PCR on a series of dilutions. If the value of the fold increase is known, then the algorithm for determining the separation can be reduced to a relatively simple computation, rather than employing a multidimensional nonlinear optimization such as the Marquardt-Levenberg as currently employed. Michael E. Jones, George C. Mayne, Tingting Wang, David I. Watson, and Damian J. Hussey Copyright © 2015 Michael E. Jones et al. All rights reserved. Mining Association Rules in Dengue Gene Sequence with Latent Periodicity Thu, 29 Jan 2015 11:26:03 +0000 The mining of periodic patterns in dengue database is an interesting research problem that can be used for predicting the future evolution of dengue viruses. In this paper, we propose an algorithm called Recurrence Finder (RECFIN) that uses the suffix tree for detecting the periodic patterns of dengue gene sequence. Also, the RECFIN finds the presence of palindrome which indicates the possibilities of formation of proteins. Further, this paper computes the periodicity of nucleic acid and amino acid sequences of any length. The periodicity based association rules are used to diagnose the type of dengue. The time complexity of the proposed algorithm is O(n2). We demonstrate the effectiveness of the proposed approach by comparing the experimental results performed on dengue virus serotypes dataset with NCBI-BLAST algorithm. Marimuthu Thangam and Balamurugan Vanniappan Copyright © 2015 Marimuthu Thangam and Balamurugan Vanniappan. All rights reserved. Identification of Plant Homologues of Dual Specificity Yak1-Related Kinases Mon, 08 Dec 2014 09:50:15 +0000 Currently, Dual Specificity YAK1-Related Kinases (MNB/DYRK) were found in slime molds, protista, fungi, and animals, but the existence of plant homologues is still unclear. In the present study, we have identified 14 potential plant homologues with the previously unknown functions, based on the strong sequence similarity. The results of bioinformatics analysis revealed their correspondence to DYRK1A, DYRK1B, DYRK3, and DYRK4. For two plant homologues of animal DYRK1A from Physcomitrella patens and Arabidopsis thaliana spatial structures of catalytic domains were predicted, as well as their complexes with ADP and selective inhibitor d15. Comparative analysis of 3D-structures of the human DYRK1A and plant homologues, their complexes with the specific inhibitors, and results of molecular dynamics confirm their structural and functional similarity with high probability. Preliminary data indicate the presence of potential MNB/DYRK specific phosphorylation sites in such proteins associated with plant cytoskeleton as plant microtubule-associated proteins WVD2 and WDL1, and FH5 and SCAR2 involved in the organization and polarity of the actin cytoskeleton and some kinesin-like microtubule motor proteins. Pavel Karpov, Aleksey Raevsky, Maxim Korablyov, and Yaroslav Blume Copyright © 2014 Pavel Karpov et al. All rights reserved. Identification of Synchronized Role of Transcription Factors, Genes, and Enzymes in Arabidopsis thaliana under Four Abiotic Stress Responsive Pathways Tue, 26 Aug 2014 05:55:39 +0000 Microarray datasets are widely used resources to predict and characterize functional entities of the whole genomics. The study initiated here aims to identify overexpressed stress responsive genes using microarray datasets applying in silico approaches. The target also extended to build a protein-protein interaction model of regulatory genes with their upstream and downstream connection in Arabidopsis thaliana. Four microarray datasets generated treating abiotic stresses like salinity, cold, drought, and abscisic acid (ABA) were chosen. Retrieved datasets were firstly filtered based on their expression comparing to control. Filtered datasets were then used to create an expression hub. Extensive literature mining helped to identify the regulatory molecules from the expression hub. The study brought out 42 genes/TF/enzymes as the role player during abiotic stress response. Further bioinformatics study and also literature mining revealed that thirty genes from those forty-two were highly correlated in all four datasets and only eight from those thirty genes were determined as highly responsive to the above abiotic stresses. Later their protein-protein interaction (PPI), conserved sequences, protein domains, and GO biasness were studied. Some web based tools and software like String database, Gene Ontology, InterProScan, NCBI BLASTn suite, etc. helped to extend the study arena. Samsad Razzaque, Rabab Mahdi, and Aparna Islam Copyright © 2014 Samsad Razzaque et al. All rights reserved. Intelligent CAD System for Automatic Detection of Mitotic Cells from Breast Cancer Histology Slide Images Based on Teaching-Learning-Based Optimization Sun, 24 Aug 2014 09:38:34 +0000 This paper introduces a computer-assisted diagnosis (CAD) system for automatic mitosis detection from breast cancer histopathology slide images. In this system, a new approach for reducing the number of false positives is proposed based on Teaching-Learning-Based optimization (TLBO). The proposed CAD system is implemented on the histopathology slide images acquired by Aperio XT scanner (scanner A). In TLBO algorithm, the number of false positives (falsely detected nonmitosis candidates as mitosis ones) is defined as a cost function and, by minimizing it, many of nonmitosis candidates will be removed. Then some color and texture (textural) features such as those derived from cooccurrence and run-length matrices are extracted from the remaining candidates and finally mitotic cells are classified using a specific support vector machine (SVM) classifier. The simulation results have proven the claims about the high performance and efficiency of the proposed CAD system. Ramin Nateghi, Habibollah Danyali, Mohammad Sadegh Helfroush, and Ashkan Tashk Copyright © 2014 Ramin Nateghi et al. All rights reserved. A Transcriptome Post-Scaffolding Method for Assembling High Quality Contigs Wed, 28 May 2014 07:32:27 +0000 With the rapid development of high throughput sequencing technologies, new transcriptomes can be sequenced for little cost with high coverage. Sequence assembly approaches have been modified to meet the requirements for de novo transcriptomes, which have complications not found in traditional genome assemblies such as variation in coverage for each candidate mRNA and alternative splicing. As a consequence, de novo assembly strategies tend to generate a large number of redundant contigs due to sequence variations, which adversely affects downstream analysis and experiments. In this work we proposed TransPS, a transcriptome post-scaffolding method, to generate high quality, nonredundant de novo transcriptomes. TransPS shows promising results on the test transcriptome datasets, where redundancy is greatly reduced by more than 50% and, at the same time, coverage is improved considerably. The web server and source code are available. Mingming Liu, Zach N. Adelman, Kevin M. Myles, and Liqing Zhang Copyright © 2014 Mingming Liu et al. All rights reserved. Restricted Boltzmann Machines for Classification of Hepatocellular Carcinoma Mon, 14 Apr 2014 09:19:28 +0000 Multiple antigen miniarrays can provide accurate tools for cancer detection and diagnosis. These miniarrays can be validated by examining their operating characteristics in classifying individuals as either cancer patients or normal (non-cancer) subjects. We describe the use of restricted Boltzmann machines for this classification problem, relative to diagnosis of hepatocellular carcinoma. In this setting, we find that its operating characteristics are similar to a logistic regression standard and suggest that restricted Boltzmann machines merit further consideration for classification problems. James A. Koziol, Eng M. Tan, Liping Dai, Pengfei Ren, and Jian-Ying Zhang Copyright © 2014 James A. Koziol et al. All rights reserved. Bifurcation Analysis for Phage Lambda with Binding Energy Uncertainty Mon, 03 Feb 2014 13:13:49 +0000 In a phage genetic switch model, bistable dynamical behavior can be destroyed due to the bifurcation caused by inappropriately chosen model parameters. Since the values of many parameters with biological significance often cannot be accurately acquired, it is thus of fundamental importance to analyze how and to which extent the system dynamics is influenced by model parameters, especially those parameters pertaining to binding energies. In this paper, we apply a Jacobian method to investigate the relation between bifurcation and parameter uncertainties on a phage OR model. By introducing bistable range as a measure of system robustness, we find that RNA polymerase binding energies have the minimum bistable ranges among all the binding energies, which implies that the uncertainties on these parameters tend to demolish the bistability more easily. Moreover, parameters describing mutual prohibition between proteins Cro and CI have finite bistable ranges, whereas those describing self-prohibition have infinity bistable ranges. Hence, the former are more sensitive to parameter uncertainties than the latter. These results help to understand the influence of parameter uncertainties on the bifurcation and thus bistability. Ning Xu, Xue Lei, Ping Ao, and Jun Zhang Copyright © 2014 Ning Xu et al. All rights reserved. A Composite Synergistic Systems Model for Exploring the Efficacies of Different Chemotherapeutic Strategies in Cancer Mon, 09 Dec 2013 13:18:11 +0000 Different chemotherapeutic strategies like Maximum Tolerable Dosing (MTD), Metronomic Chemotherapy (MCT), and Antiangiogenic (AAG) drug are available; however, the selection of the best therapeutic strategy for an individual patient remains uncertain till now. Several analytical models are proposed for each of the chemotherapeutic strategies; however, no single analytical model is available which can make a comparative assessment regarding the long-term therapeutic efficacy among these strategies. This, in turn, may limit the clinical application of such analytical models. To address this issue here we developed a composite synergistic system (CSS) model. Through this CSS model, comparative assessment among the MTD, MCT, and AAG drug therapy can be assessed. Moreover, these chemotherapeutic strategies along with different supportive therapies like Hematopoietic Stem Cell transplantation (HSC), cellular immunotherapy as well as different combinations among these therapeutic strategies can be assessed. Fitting of initial clinical data of individual clinical cases to this analytical model followed by simulation runs may help in making such decision. Analytical assessments suggest that with the considered tumor condition MCT alone could be more effective one than any other therapeutics and/or their combinations for controlling the long-term tumor burden. Probir Kumar Dhar and Durjoy Majumder Copyright © 2013 Probir Kumar Dhar and Durjoy Majumder. All rights reserved. SCBI_MapReduce, a New Ruby Task-Farm Skeleton for Automated Parallelisation and Distribution in Chunks of Sequences: The Implementation of a Boosted Blast+ Sun, 27 Oct 2013 17:54:14 +0000 Current genomic analyses often require the managing and comparison of big data using desktop bioinformatic software that was not developed regarding multicore distribution. The task-farm SCBI_MAPREDUCE is intended to simplify the trivial parallelisation and distribution of new and legacy software and scripts for biologists who are interested in using computers but are not skilled programmers. In the case of legacy applications, there is no need of modification or rewriting the source code. It can be used from multicore workstations to heterogeneous grids. Tests have demonstrated that speed-up scales almost linearly and that distribution in small chunks increases it. It is also shown that SCBI_MAPREDUCE takes advantage of shared storage when necessary, is fault-tolerant, allows for resuming aborted jobs, does not need special hardware or virtual machine support, and provides the same results than a parallelised, legacy software. The same is true for interrupted and relaunched jobs. As proof-of-concept, distribution of a compiled version of BLAST+ in the SCBI_DISTRIBUTED_BLAST gem is given, indicating that other blast binaries can be used while maintaining the same SCBI_DISTRIBUTED_BLAST code. Therefore, SCBI_MAPREDUCE suits most parallelisation and distribution needs in, for example, gene and genome studies. Darío Guerrero-Fernández, Juan Falgueras, and M. Gonzalo Claros Copyright © 2013 Darío Guerrero-Fernández et al. All rights reserved. Two-Stage Approach for Protein Superfamily Classification Thu, 27 Jun 2013 11:43:09 +0000 We deal with the problem of protein superfamily classification in which the family membership of newly discovered amino acid sequence is predicted. Correct prediction is a matter of great concern for the researchers and drug analyst which helps them in discovery of new drugs. As this problem falls broadly under the category of pattern classification problem, we have made all efforts to optimize feature extraction in the first stage and classifier design in the second stage with an overall objective to maximize the performance accuracy of the classifier. In the feature extraction phase, Genetic Algorithm- (GA-) based wrapper approach is used to select few eigenvectors from the principal component analysis (PCA) space which are encoded as binary strings in the chromosome. On the basis of position of 1’s in the chromosome, the eigenvectors are selected to build the transformation matrix which then maps the original high-dimension feature space to lower dimension feature space. Using PCA-NSGA-II (non-dominated sorting GA), the nondominated solutions obtained from the Pareto front solve the trade-off problem by compromising between the number of eigenvectors selected and the accuracy obtained by the classifier. In the second stage, recursive orthogonal least square algorithm (ROLSA) is used for training radial basis function network (RBFN) to select optimal number of hidden centres as well as update the output layer weighting matrix. This approach can be applied to large data set with much lower requirements of computer memory. Thus, very small architectures having few number of hidden centres are obtained showing higher level of performance accuracy. Swati Vipsita and Santanu Ku. Rath Copyright © 2013 Swati Vipsita and Santanu Ku. Rath. All rights reserved. Assessing the Impact of Drug Resistance on the Transmission Dynamics of Typhoid Fever Thu, 06 Jun 2013 14:43:36 +0000 Typhoid fever continues to be a major public health problem in the developing world. Antibiotic therapy has been the main stay of treating typhoid fever for decades. The emergence of drug-resistant typhoid strain in the last two decades has been a major problem in tackling this scourge. A mathematical model for investigating the impact of drug resistance on the transmission dynamics of typhoid fever is developed. The reproductive number for the model has been computed. Numerical results in this study suggest that when a typhoid outbreak occurs with more drug-sensitive cases than drug-resistant cases, then it may take 10–15 months for symptomatic drug-resistant cases to outnumber all typhoid cases, and it may take an average of 15–20 months for nonsymptomatic drug-resistant cases to outnumber all drug-sensitive cases. S. Mushayabasa, C. P. Bhunu, and E. T. Ngarakana-Gwasira Copyright © 2013 S. Mushayabasa et al. All rights reserved. Transition and Transversion on the Common Trinucleotide Circular Code Wed, 29 May 2013 16:39:06 +0000 In 1996, a trinucleotide circular code which is maximum, self-complementary, and , called , was identified statistically on a large gene population of eukaryotes and prokaryotes (Arquès and Michel (1996)). Transition and transversions I and II are classical molecular evolution processes. A comprehensive computer analysis of these three evolution processes in the code shows some new results; in particular (i) transversion I on the 2nd position of any subset of trinucleotides of generates trinucleotide circular codes which are always and (ii) transversion II on the three positions of any subset of trinucleotides of yields no trinucleotide circular codes. These new results extend our theory of circular code in genes to its evolution under transition and transversion. Emmanuel Benard and Christian J. Michel Copyright © 2013 Emmanuel Benard and Christian J. Michel. All rights reserved. An Approach for Model Reduction of Biochemical Networks Wed, 08 May 2013 14:51:15 +0000 Biochemical networks are not only complex but also extremely large. The dynamic biological model of great complexity resulting in a large number of parameters is a main difficulty for optimization and control processes. In practice, it is highly desirable to further simplify the structure of biological models for the sake of reducing computational cost or simplification for the task of system analysis. This paper considers the S-system model used for describing the response of biochemical networks. By introducing the technique of singular value decomposition (SVD), we are able to identify the major state variables and parameters and eliminate unimportant metabolites and the corresponding signal transduction pathways. The model reduction by multiobjective analysis integrates the criteria of reactive weight, sensitivity, and flux analyses to obtain a reduced model in a systematic way. The resultant model is closed to the original model in performance but with a simpler structure. Representative numerical examples are illustrated to prove feasibility of the proposed method. Yen-Chang Liu, Chun-Liang Lin, and Chia-Hua Chuang Copyright © 2013 Yen-Chang Liu et al. All rights reserved. Efficient Basis Change for Sparse-Grid Interpolating Polynomials with Application to T-Cell Sensitivity Analysis Thu, 11 Apr 2013 16:49:58 +0000 Sparse-grid interpolation provides good approximations to smooth functions in high dimensions based on relatively few function evaluations, but in standard form it is expressed in Lagrange polynomials. Here, we give a block-diagonal factorization of the basis-change matrix to give an efficient conversion of a sparse-grid interpolant to a tensored orthogonal polynomial (or gPC) representation. We describe how to use this representation to give an efficient method for estimating Sobol' sensitivity coefficients and apply this method to analyze and efficiently approximate a complex model of T-cell signaling events. Gregery T. Buzzard Copyright © 2013 Gregery T. Buzzard. All rights reserved. Graph-Theoretic Models of Mutations in the Nucleotide Binding Domain 1 of the Cystic Fibrosis Transmembrane Conductance Regulator Wed, 03 Apr 2013 13:33:01 +0000 Cystic fibrosis is one of the most common inherited diseases and is caused by a mutation in a membrane protein, the cystic fibrosis transmembrane conductance regulator (CFTR). This protein serves as a chloride channel and regulates the viscosity of mucus lining the ducts of a number of organs. Although much has been learned about the consequences of mutations on the energy landscape and the resulting disrupted folding pathway of CFTR, a level of understanding needed to correct the misfolding has not been achieved. The most common mutations of CFTR are located in one of two nucleotide binding domains, namely, the nucleotide binding domain 1 (NBD1). We model NBD1 using a nested graph model. The vertices in the lowest layer each represent an atom in the structure of an amino acid residue, while the vertices in the mid layer each represent the residue. The vertices in the top layer each represent a subdomain of the nucleotide binding domain. We use this model to quantify the effects of a single point mutation on the protein domain. We compare the wildtype structure with eight of the most common mutations. The graph-theoretic model provides insight into how a single point mutation can have such profound structural consequences. Debra J. Knisley, Jeff R. Knisley, and Andrew Cade Herron Copyright © 2013 Debra J. Knisley et al. All rights reserved. Calculated Vibrational Properties of Ubisemiquinones Thu, 10 Jan 2013 17:06:45 +0000 Density functional theory has been used to calculate harmonic normal mode vibrational frequencies for unlabeled and isotope-labeled ubisemiquinones in both the gas phase and in several solvents. It is shown that four methoxy group conformations are likely to be present in solution at room temperature. Boltzmann weighted infrared and Raman spectra for the four conformers were calculated, and composite spectra that are the sum of the Boltzmann weighted spectra were produced. These composite spectra were compared to experimental FTIR and resonance Raman spectra, and it is shown that the calculated band frequencies, relative band intensities, and and isotope-induced band shifts are in excellent agreement with experiment. The calculations show that the C=O and C=C modes of ubisemiquinone strongly mix with methoxy methyl CH bending vibrations, and that the degree of mixing is altered upon isotope labeling, resulting in complicated changes in mode frequencies, intensities, and composition upon isotope labeling. Upon consideration of the calculated potential energy distributions of the normal modes of ubisemiquinone, and how they change upon isotope labeling, an explanation of some puzzling features in previously published Raman spectra is provided. Hari P. Lamichhane and Gary Hastings Copyright © 2013 Hari P. Lamichhane and Gary Hastings. All rights reserved.