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‣ A new systematic computational approach to predicting target genes of transcription factors

Dai, Xinbin; He, Ji; Zhao, Xuechun
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Identifying transcription factor target genes (TFTGs) is a vital step towards understanding regulatory mechanisms of gene expression. Methods for the de novo identification of TFTGs are generally based on screening for novel DNA binding sites. However, experimental screening of new binding sites is a technically challenging, laborious and time-consuming task, while computational methods still lack accuracy. We propose a novel systematic computational approach for predicting TFTGs directly on a genome scale. Utilizing gene co-expression data, we modeled the prediction problem as a ‘yes’ or ‘no’ classification task by converting biological sequences into novel reverse-complementary position-sensitive n-gram profiles and implemented the classifiers with support vector machines. Our approach does not necessarily predict new DNA binding sites, which other studies have shown to be difficult and inaccurate. We applied the proposed approach to predict auxin-response factor target genes from published Arabidopsis thaliana co-expression data and obtained satisfactory results. Using ten-fold cross validations, the area under curve value of the receiver operating characteristic reaches around 0.73.

‣ Prediction of novel microRNA genes in cancer-associated genomic regions—a combined computational and experimental approach

Oulas, Anastasis; Boutla, Alexandra; Gkirtzou, Katerina; Reczko, Martin; Kalantidis, Kriton; Poirazi, Panayiota
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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The majority of existing computational tools rely on sequence homology and/or structural similarity to identify novel microRNA (miRNA) genes. Recently supervised algorithms are utilized to address this problem, taking into account sequence, structure and comparative genomics information. In most of these studies miRNA gene predictions are rarely supported by experimental evidence and prediction accuracy remains uncertain. In this work we present a new computational tool (SSCprofiler) utilizing a probabilistic method based on Profile Hidden Markov Models to predict novel miRNA precursors. Via the simultaneous integration of biological features such as sequence, structure and conservation, SSCprofiler achieves a performance accuracy of 88.95% sensitivity and 84.16% specificity on a large set of human miRNA genes. The trained classifier is used to identify novel miRNA gene candidates located within cancer-associated genomic regions and rank the resulting predictions using expression information from a full genome tiling array. Finally, four of the top scoring predictions are verified experimentally using northern blot analysis. Our work combines both analytical and experimental techniques to show that SSCprofiler is a highly accurate tool which can be used to identify novel miRNA gene candidates in the human genome. SSCprofiler is freely available as a web service at http://www.imbb.forth.gr/SSCprofiler.html.

‣ Reduction of dynamical biochemical reactions networks in computational biology

Radulescu, O.; Gorban, A. N.; Zinovyev, A.; Noel, V.
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 19/07/2012 Português
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Biochemical networks are used in computational biology, to model mechanistic details of systems involved in cell signaling, metabolism, and regulation of gene expression. Parametric and structural uncertainty, as well as combinatorial explosion are strong obstacles against analyzing the dynamics of large models of this type. Multiscaleness, an important property of these networks, can be used to get past some of these obstacles. Networks with many well separated time scales, can be reduced to simpler models, in a way that depends only on the orders of magnitude and not on the exact values of the kinetic parameters. The main idea used for such robust simplifications of networks is the concept of dominance among model elements, allowing hierarchical organization of these elements according to their effects on the network dynamics. This concept finds a natural formulation in tropical geometry. We revisit, in the light of these new ideas, the main approaches to model reduction of reaction networks, such as quasi-steady state (QSS) and quasi-equilibrium approximations (QE), and provide practical recipes for model reduction of linear and non-linear networks. We also discuss the application of model reduction to the problem of parameter identification...

‣ Computational Investigation of the pH Dependence of Loop Flexibility and Catalytic Function in Glycoside Hydrolases*

Bu, Lintao; Crowley, Michael F.; Himmel, Michael E.; Beckham, Gregg T.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: Solution pH affects cellulase enzyme activity.

‣ Computational prediction of the localization of microRNAs within their pre-miRNA

Leclercq, Mickael; Diallo, Abdoulaye Banire; Blanchette, Mathieu
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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MicroRNAs (miRNAs) are short RNA species derived from hairpin-forming miRNA precursors (pre-miRNA) and acting as key posttranscriptional regulators. Most computational tools labeled as miRNA predictors are in fact pre-miRNA predictors and provide no information about the putative miRNA location within the pre-miRNA. Sequence and structural features that determine the location of the miRNA, and the extent to which these properties vary from species to species, are poorly understood. We have developed miRdup, a computational predictor for the identification of the most likely miRNA location within a given pre-miRNA or the validation of a candidate miRNA. MiRdup is based on a random forest classifier trained with experimentally validated miRNAs from miRbase, with features that characterize the miRNA–miRNA* duplex. Because we observed that miRNAs have sequence and structural properties that differ between species, mostly in terms of duplex stability, we trained various clade-specific miRdup models and obtained increased accuracy. MiRdup self-trains on the most recent version of miRbase and is easy to use. Combined with existing pre-miRNA predictors, it will be valuable for both de novo mapping of miRNAs and filtering of large sets of candidate miRNAs obtained from transcriptome sequencing projects. MiRdup is open source under the GPLv3 and available at http://www.cs.mcgill.ca/∼blanchem/mirdup/.

‣ Computational identification of novel biochemical systems involved in oxidation, glycosylation and other complex modifications of bases in DNA

Iyer, Lakshminarayan M.; Zhang, Dapeng; Maxwell Burroughs, A.; Aravind, L.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Discovery of the TET/JBP family of dioxygenases that modify bases in DNA has sparked considerable interest in novel DNA base modifications and their biological roles. Using sensitive sequence and structure analyses combined with contextual information from comparative genomics, we computationally characterize over 12 novel biochemical systems for DNA modifications. We predict previously unidentified enzymes, such as the kinetoplastid J-base generating glycosyltransferase (and its homolog GREB1), the catalytic specificity of bacteriophage TET/JBP proteins and their role in complex DNA base modifications. We also predict the enzymes involved in synthesis of hypermodified bases such as alpha-glutamylthymine and alpha-putrescinylthymine that have remained enigmatic for several decades. Moreover, the current analysis suggests that bacteriophages and certain nucleo-cytoplasmic large DNA viruses contain an unexpectedly diverse range of DNA modification systems, in addition to those using previously characterized enzymes such as Dam, Dcm, TET/JBP, pyrimidine hydroxymethylases, Mom and glycosyltransferases. These include enzymes generating modified bases such as deazaguanines related to queuine and archaeosine, pyrimidines comparable with lysidine...

‣ Loop Motions Important to Product Expulsion in the Thermobifida fusca Glycoside Hydrolase Family 6 Cellobiohydrolase from Structural and Computational Studies*

Wu, Miao; Bu, Lintao; Vuong, Thu V.; Wilson, David B.; Crowley, Michael F.; Sandgren, Mats; Ståhlberg, Jerry; Beckham, Gregg T.; Hansson, Henrik
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Background: Family 6 glycoside hydrolases represent an important, diverse enzyme class in cellulolytic organisms.

‣ Quantifying Reproducibility in Computational Biology: The Case of the Tuberculosis Drugome

Garijo, Daniel; Kinnings, Sarah; Xie, Li; Xie, Lei; Zhang, Yinliang; Bourne, Philip E.; Gil, Yolanda
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 27/11/2013 Português
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How easy is it to reproduce the results found in a typical computational biology paper? Either through experience or intuition the reader will already know that the answer is with difficulty or not at all. In this paper we attempt to quantify this difficulty by reproducing a previously published paper for different classes of users (ranging from users with little expertise to domain experts) and suggest ways in which the situation might be improved. Quantification is achieved by estimating the time required to reproduce each of the steps in the method described in the original paper and make them part of an explicit workflow that reproduces the original results. Reproducing the method took several months of effort, and required using new versions and new software that posed challenges to reconstructing and validating the results. The quantification leads to “reproducibility maps” that reveal that novice researchers would only be able to reproduce a few of the steps in the method, and that only expert researchers with advance knowledge of the domain would be able to reproduce the method in its entirety. The workflow itself is published as an online resource together with supporting software and data. The paper concludes with a brief discussion of the complexities of requiring reproducibility in terms of cost versus benefit...

‣ A New Online Computational Biology Curriculum

Searls, David B.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 12/06/2014 Português
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A recent proliferation of Massive Open Online Courses (MOOCs) and other web-based educational resources has greatly increased the potential for effective self-study in many fields. This article introduces a catalog of several hundred free video courses of potential interest to those wishing to expand their knowledge of bioinformatics and computational biology. The courses are organized into eleven subject areas modeled on university departments and are accompanied by commentary and career advice.

‣ Computational Biology: Modeling Chronic Renal Allograft Injury

Stegall, Mark D.; Borrows, Richard
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 03/08/2015 Português
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New approaches are needed to develop more effective interventions to prevent long-term rejection of organ allografts. Computational biology provides a powerful tool to assess the large amount of complex data that is generated in longitudinal studies in this area. This manuscript outlines how our two groups are using mathematical modeling to analyze predictors of graft loss using both clinical and experimental data and how we plan to expand this approach to investigate specific mechanisms of chronic renal allograft injury.

‣ Uma 3−aproximação e uma formulação de PLI para o Problema do Alinhamento Spliced Múltiplo

Mazaro, Regina Beretta
Fonte: Universidade Federal de Mato Grosso do Sul Publicador: Universidade Federal de Mato Grosso do Sul
Tipo: Dissertação de Mestrado
Português
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Com os avanços recentes em áreas específicas da Ciência da Computação como a Biologia Computacional, vários problemas novos envolvendo sequencias vem surgindo, enquanto que problemas tradicionais tornam-se mais difíceis dada a expressiva quantidade de dados gerada nos últimos anos. O interesse aqui ´e no estudo de um problema específico que envolve sequências denominado Problema do Alinhamento Spliced Múltiplo, estendendo um trabalho anteriormente realizado por Kishi e Adi em cima desse mesmo problema. Enquanto que nesse estudo prévio mostrou-se que o Problema do Alinhamento Spliced Múltiplos e NP-completo e foram propostas heurísticas para o problema, o presente trabalho visa sugerir um algoritmo de aproximação e uma formulação de programação linear inteira para ele, possibilitando confrontar essas novas abordagens com as heurísticas já desenvolvidas para o Problema do Alinhamento Spliced Múltiplo. Para isso, foram executados testes com instâncias artificiais e reais, sendo essas ultimas instâncias de um problema tradicional da Bioinformática denominado Problema da Identificação de Genes.; ABSTRACT - Recent advances in specific areas of Computer Science as Computational Biology brought to light several new problems involving sequences...

‣ Computational Biology

Stewart, Craig A.
Fonte: Universidade de Indiana Publicador: Universidade de Indiana
Tipo: Conferência ou Objeto de Conferência
Português
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Presented as part of tutorial Zorn, M., S. Spengler, I. Dubchack, H. Simon, C.A. Stewart. 2000. Computational Biology and High Performance Computing. Tutorial presented at SC2000, Nov 4-10, Dallas, TX. (http://hdl.handle.net/2022/15225)

‣ An intuitionistic approach to scoring DNA sequences against transcription factor binding site motifs

Garc??a Alcalde, Fernando; Blanco Mor??n, Armando; Shepherd, Adrian J.
Fonte: Biomed Central Publicador: Biomed Central
Tipo: Artigo de Revista Científica
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Background Transcription factors (TFs) control transcription by binding to specific regions of DNA called transcription factor binding sites (TFBSs). The identification of TFBSs is a crucial problem in computational biology and includes the subtask of predicting the location of known TFBS motifs in a given DNA sequence. It has previously been shown that, when scoring matches to known TFBS motifs, interdependencies between positions within a motif should be taken into account. However, this remains a challenging task owing to the fact that sequences similar to those of known TFBSs can occur by chance with a relatively high frequency. Here we present a new method for matching sequences to TFBS motifs based on intuitionistic fuzzy sets (IFS) theory, an approach that has been shown to be particularly appropriate for tackling problems that embody a high degree of uncertainty.; Results We propose SCintuit, a new scoring method for measuring sequence-motif affinity based on IFS theory. Unlike existing methods that consider dependencies between positions, SCintuit is designed to prevent overestimation of less conserved positions of TFBSs. For a given pair of bases, SCintuit is computed not only as a function of their combined probability of occurrence...

‣ Uncertainty, Probability, Functionality in contexts of Computational Biology and Bioinformatics

Ricciardi, Luigi M.
Fonte: Universidade da Coruña Publicador: Universidade da Coruña
Tipo: Conferência ou Objeto de Conferência
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[Abstract] The present paper is dedicated to the cherished memory of Professor José Mira Mira, who prematurely passed away on August 13, 2008. In view of his deep scientific interests and professional expertise in bridging natural versus mechanical computation methods, we offer some remarks on the concepts of uncertainty, probability and functionality with special reference to two areas of particular current interest to researchers in the areas of computational biology and bioinformatics. Preliminarily, a sketch of undergraduate and graduate curricula in Computer Science at Federico II Naples University is provided.

‣ Alinhamento múltiplo de proteínas utilizando algoritmos genéticos; Protein multiple sequence alignment using genetic algorithms

Sérgio Jeferson Rafael Ordine
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 03/07/2015 Português
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Uma das ferramentas mais importantes no campo da bioinformática e biologia computacional é o alinhamento múltiplo de sequências (MSA, do inglês Multiple Sequence Alignment). Sua função abrange a criação de árvores filogenéticas, identificação de motifs e domínios conservados, assim como a predição de funções das proteínas e de suas estruturas secundárias e terciárias. Algoritmos genéticos são heurísticas de busca local, utilizadas para problemas de otimização, inspirados nos conceitos da seleção natural: uma popularção de possíveis soluções é criada e iterativamente cruzada e selecionada buscando um resultado mais adequado para o problema sendo tratado. Esta dissertação descreve o estudo realizado no uso de algoritmos genéticos para a resolução do problema de alinhamento múltiplo de proteínas. Como resultado deste trabalho, duas ferramentas foram desenvolvidas: ALGAe, um ambiente para a execução de um algoritmo genético visando o alinhamento múltiplo de proteínas e o Anubis, um visualizador de alinhamentos que permite a comparação entre dois alinhamentos para o mesmo conjunto de proteínas, visando identificar as discrepâncias entre eles.; MSA, that stands for Multiple Sequence Alignment...

‣ Programação por restrições aplicada a problemas de rearranjo de genomas; Constraint programming applied to genome rearrangement problems

Victor de Abreu Iizuka
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 19/12/2012 Português
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A teoria da seleção natural de Darwin afirma que os seres vivos atuais descendem de ancestrais, e ao longo da evolução, mutações genéticas propiciaram o aparecimento de diferentes espécies de seres vivos. Muitas mutações são pontuais, alterando a cadeia de DNA, o que pode impedir que a informação seja expressa, ou pode expressá-la de um modo diferente. A comparação de sequências é o método mais usual de se identificar a ocorrência de mutações pontuais, sendo um dos problemas mais abordados em Biologia Computacional. Rearranjo de Genomas tem como objetivo encontrar o menor número de operações que transformam um genoma em outro. Essas operações podem ser, por exemplo, reversões, transposições, fissões e fusões. O conceito de distância pode ser definido para estes eventos, por exemplo, a distância de reversão é o número mínimo de reversões que transformam um genoma em outro [9] e a distância de transposição é o número mínimo de transposições que transformam um genoma em outro [10]. Nós trataremos os casos em que os eventos de reversão e transposição ocorrem de forma isolada e os casos quando os dois eventos ocorrem simultaneamente, com o objetivo de encontrar o valor exato para a distância. Nós criamos modelos de Programação por Restrições para ordenação por reversões e ordenação por reversões e transposições...

‣ Computational biology approach to uncover hepatitis C virus helicase operation

Flechsig, Holger
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 26/11/2013 Português
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Hepatitis C virus helicase is a molecular motor that splits nucleic acid duplex structures during viral replication, therefore representing a promising target for antiviral treatment. Hence, a detailed understanding of the mechanism by which it operates would facilitate the development of efficient drug-assisted therapies aiming to inhibit helicase activity. Despite extensive investigations performed in the past, a thorough understanding of the activity of this important protein was lacking since the underlying internal conformational motions could not be resolved. Here we review investigations that have been previously performed by us for HCV helicase. Using methods of structure-based computational modelling it became possible to follow entire operation cycles of this motor protein in structurally resolved simulations and uncover the mechanism by which it moves along the nucleic acid and accomplishes strand separation. We also discuss observations from that study in the light of recent experimental studies that confirm our findings.; Comment: 22 pages, 5 figures

‣ Bidirectional Control of Absence Seizures by the Basal Ganglia: A Computational Evidence

Chen, Mingming; Guo, Daqing; Wang, Tiebin; Jing, Wei; Xia, Yang; Xu, Peng; Luo, Cheng; Valdes-Sosa, Pedro A.; Yao, Dezhong
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 10/01/2014 Português
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Absence epilepsy is believed to be associated with the abnormal interactions between the cerebral cortex and thalamus. Besides the direct coupling, anatomical evidence indicates that the cerebral cortex and thalamus also communicate indirectly through an important intermediate bridge--basal ganglia. It has been thus postulated that the basal ganglia might play key roles in the modulation of absence seizures, but the relevant biophysical mechanisms are still not completely established. Using a biophysically based model, we demonstrate here that the typical absence seizure activities can be controlled and modulated by the direct GABAergic projections from the substantia nigra pars reticulata (SNr) to either the thalamic reticular nucleus (TRN) or the specific relay nuclei (SRN) of thalamus, through different biophysical mechanisms. Under certain conditions, these two types of seizure control are observed to coexist in the same network. More importantly, due to the competition between the inhibitory SNr-TRN and SNr-SRN pathways, we find that both decreasing and increasing the activation of SNr neurons from the normal level may considerably suppress the generation of SWDs in the coexistence region. Overall, these results highlight the bidirectional functional roles of basal ganglia in controlling and modulating absence seizures...

‣ Allosteric Communication Pathways and Thermal Rectification in PDZ-2 Protein: A Computational Study

Miño-Galaz, Germán A.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
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Allosteric communication in proteins is a central and yet unsolved problem of structural biochemistry. Previous findings, from computational biology (Ota and Agard, 2005), have proposed that heat diffuses in a protein through cognate protein allosteric pathways. This work studied heat diffusion in the well-known PDZ-2 protein, and confirmed that this protein has two cognate allosteric pathways and that heat flows preferentially through these. Also, a new property was also observed for protein structures - heat diffuses asymmetrically through the structures. The underling structure of this asymmetrical heat flow was a normal length hydrogen bond (~2.85 {\AA}) that acted as a thermal rectifier. In contrast, thermal rectification was compromised in short hydrogen bonds (~2.60 {\AA}), giving rise to symmetrical thermal diffusion. Asymmetrical heat diffusion was due, on a higher scale, to the local, structural organization of residues that, in turn, was also mediated by hydrogen bonds. This asymmetrical/symmetrical energy flow may be relevant for allosteric signal communication directionality in proteins and for the control of heat flow in materials science.; Comment: 29 pages, 8 Figures. All Results Unchanged. Changed Title. Improved Grammar. Added references. Corrected typos. Elimination of the "Knocking" argument for Asp5-Lys91 Interaction in Results and in Discussion sections

‣ PLoS Computational Biology Conference Postcards from ISMB 2010;

Kosloff, Mickey
Fonte: PUBLIC LIBRARY SCIENCE Publicador: PUBLIC LIBRARY SCIENCE
Publicado em //2010 Português
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