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BACKGROUND: Non-coding RNAs (ncRNAs) are emerging as key regulators and play critical roles in a wide range of tumorigenesis. Recent studies have suggested that long non-coding RNAs (lncRNAs) could interact with microRNAs (miRNAs) and indirectly regulate miRNA targets through competing interactions. Therefore, uncovering the competing endogenous RNA (ceRNA) regulatory mechanism of lncRNAs, miRNAs and mRNAs in post-transcriptional level will aid in deciphering the underlying pathogenesis of human polygenic diseases and may unveil new diagnostic and therapeutic opportunities. However, the functional roles of vast majority of cancer specific ncRNAs and their combinational regulation patterns are still insufficiently understood. RESULTS: Here we develop an integrative framework called CeModule to discover lncRNA, miRNA and mRNA-associated regulatory modules. We fully utilize the matched expression profiles of lncRNAs, miRNAs and mRNAs and establish a model based on joint orthogonality non-negative matrix factorization for identifying modules. Meanwhile, we impose the experimentally verified miRNA-lncRNA interactions, the validated miRNA-mRNA interactions and the weighted gene-gene network into this framework to improve the module accuracy through the network-based penalties. The sparse regularizations are also used to help this model obtain modular sparse solutions. Finally, an iterative multiplicative updating algorithm is adopted to solve the optimization problem. CONCLUSIONS: We applied CeModule to two cancer datasets including ovarian cancer (OV) and uterine corpus endometrial carcinoma (UCEC) obtained from TCGA. The modular analysis indicated that the identified modules involving lncRNAs, miRNAs and mRNAs are significantly associated and functionally enriched in cancer-related biological processes and pathways, which may provide new insights into the complex regulatory mechanism of human diseases at the system level.
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Algoritmos , Regulación Neoplásica de la Expresión Génica , Genómica , Neoplasias/genética , Bases de Datos Genéticas , Femenino , Ontología de Genes , Redes Reguladoras de Genes , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias Ováricas/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los ResultadosRESUMEN
The emergence of network medicine has provided great insight into the identification of disease-related molecules, which could help with the development of personalized medicine. However, the state-of-the-art methods could neither simultaneously consider target information and the known miRNA-disease associations nor effectively explore novel gene-disease associations as a by-product during the process of inferring disease-related miRNAs. Computational methods incorporating multiple sources of information offer more opportunities to infer disease-related molecules, including miRNAs and genes in heterogeneous networks at a system level. In this study, we developed a novel algorithm, named inference of Disease-related MiRNAs based on Heterogeneous Manifold (DMHM), to accurately and efficiently identify miRNA-disease associations by integrating multi-omics data. Graph-based regularization was utilized to obtain a smooth function on the data manifold, which constitutes the main principle of DMHM. The novelty of this framework lies in the relatedness between diseases and miRNAs, which are measured via heterogeneous manifolds on heterogeneous networks integrating target information. To demonstrate the effectiveness of DMHM, we conducted comprehensive experiments based on HMDD datasets and compared DMHM with six state-of-the-art methods. Experimental results indicated that DMHM significantly outperformed the other six methods under fivefold cross validation and de novo prediction tests. Case studies have further confirmed the practical usefulness of DMHM.
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Biología Computacional/métodos , Estudios de Asociación Genética/métodos , MicroARNs/genética , Neoplasias/genética , Algoritmos , Bases de Datos Genéticas , Humanos , MicroARNs/análisis , MicroARNs/metabolismo , Neoplasias/clasificación , Neoplasias/metabolismo , Reproducibilidad de los ResultadosRESUMEN
High-throughput technology has generated large-scale protein interaction data, which is crucial in our understanding of biological organisms. Many complex identification algorithms have been developed to determine protein complexes. However, these methods are only suitable for dense protein interaction networks, because their capabilities decrease rapidly when applied to sparse proteinâ»protein interaction (PPI) networks. In this study, based on penalized matrix decomposition (PMD), a novel method of penalized matrix decomposition for the identification of protein complexes (i.e., PMDpc) was developed to detect protein complexes in the human protein interaction network. This method mainly consists of three steps. First, the adjacent matrix of the protein interaction network is normalized. Second, the normalized matrix is decomposed into three factor matrices. The PMDpc method can detect protein complexes in sparse PPI networks by imposing appropriate constraints on factor matrices. Finally, the results of our method are compared with those of other methods in human PPI network. Experimental results show that our method can not only outperform classical algorithms, such as CFinder, ClusterONE, RRW, HC-PIN, and PCE-FR, but can also achieve an ideal overall performance in terms of a composite score consisting of F-measure, accuracy (ACC), and the maximum matching ratio (MMR).
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Biología Computacional/métodos , Mapeo de Interacción de Proteínas/métodos , Algoritmos , Redes Reguladoras de Genes , HumanosRESUMEN
Proteins play a vital role in various biological processes and achieve their functions through protein-protein interactions (PPIs). Thus, accurate identification of PPI sites is essential. Traditional biological methods for identifying PPIs are costly, labor-intensive, and time-consuming. The development of computational prediction methods for PPI sites offers promising alternatives. Most known deep learning (DL) methods employ layer-wise multi-scale CNNs to extract features from protein sequences. But, these methods usually neglect the spatial positions and hierarchical information embedded within protein sequences, which are actually crucial for PPI site prediction. In this paper, we propose MR2CPPIS, a novel sequence-based DL model that utilizes the multi-scale Res2Net with coordinate attention mechanism to exploit multi-scale features and enhance PPI site prediction capability. We leverage the multi-scale Res2Net to expand the receptive field for each network layer, thus capturing multi-scale information of protein sequences at a granular level. To further explore the local contextual features of each target residue, we employ a coordinate attention block to characterize the precise spatial position information, enabling the network to effectively extract long-range dependencies. We evaluate our MR2CPPIS on three public benchmark datasets (Dset 72, Dset 186, and PDBset 164), achieving state-of-the-art performance. The source codes are available at https://github.com/YyinGong/MR2CPPIS.
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Aprendizaje Profundo , Proteínas/metabolismo , Proteínas/química , Mapeo de Interacción de Proteínas/métodos , Biología Computacional/métodos , Humanos , Bases de Datos de ProteínasRESUMEN
Predicting associations between microRNAs (miRNAs) and diseases from the viewpoint of function modules has become increasingly popular. However, existing methods obtained the relations between diseases and miRNAs only through the construction of similarity networks and neglected the complex network characteristic. In this paper, a new method named combining miRNA function similarities and network topology similarities based on module identification in networks (ComSim-MINE) was developed. Combined similarity is calculated from the harmonic mean between miRNA function similarities and network topology similarities. Experimental results showed that ComSim-MINE can compete with several state-of-the-art weighted function module algorithms, such as ClusterONE, MCODE, NEMO, and SPICi, and achieved the satisfactory results in terms of the composite score of F-measure, sensitivity, and accuracy based on the generated miRNA function interaction network. From the analysis of case studies, some new findings obtained from our proposed method provide clinicians new clues for epidemic diseases, such as COVID-19.
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Inferring potential associations between microRNAs (miRNAs) and human diseases can help people understand the pathogenesis of complex human diseases. Several computational approaches have been presented to discover novel miRNA-disease associations based on a top-ranked association model. However, some top-ranked miRNAs are not easily used to reveal the association between miRNAs and diseases. This study aims to infer miRNA-disease relationship by identifying a functional module. We first construct a miRNA functional similarity network derived from a disease similarity network and a known miRNA-disease relationship network. We then present an improved K-means (i.e., IK-means) algorithm to detect miRNA functional modules and used 243 diseases to validate the performance of our proposed method. Experimental results indicate that the performance of IK-means is better compared with classical K-means algorithms. Case studies on some functional modules further demonstrate the applicability of IK-means in the identification of new miRNA-disease associations.
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Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , MicroARNs/genética , Humanos , MicroARNs/metabolismo , Modelos GenéticosRESUMEN
MicroRNAs (miRNAs) play an essential role in many biological processes by regulating the target genes, especially in the initiation and development of cancers. Therefore, the identification of the miRNA-mRNA regulatory modules is important for understanding the regulatory mechanisms. Most computational methods only used statistical correlations in predicting miRNA-mRNA modules, and neglected the fact there are causal relationships between miRNAs and their target genes. In this paper, we propose a novel approach called CALM(the causal regulatory modules) to identify the miRNA-mRNA regulatory modules through integrating the causal interactions and statistical correlations between the miRNAs and their target genes. Our algorithm largely consists of three steps: it first forms the causal regulatory relationships of miRNAs and genes from gene expression profiles and detects the miRNA clusters according to the GO function information of their target genes, then expands each miRNA cluster by greedy adding(discarding) the target genes to maximize the modularity score. To show the performance of our method, we apply CALM on four datasets including EMT, breast, ovarian, thyroid cancer and validate our results. The experiment results show that our method can not only outperform the compared method, but also achieve ideal overall performance in terms of the functional enrichment.
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Synergistic drug combinations play an important role in the treatment of complex diseases. The identification of effective drug combination is vital to further reduce the side effects and improve therapeutic efficiency. In previous years, in vitro method has been the main route to discover synergistic drug combinations. However, many limitations of time and resource consumption lie within the in vitro method. Therefore, with the rapid development of computational models and the explosive growth of large and phenotypic data, computational methods for discovering synergistic drug combinations are an efficient and promising tool and contribute to precision medicine. It is the key of computational methods how to construct the computational model. Different computational strategies generate different performance. In this review, the recent advancements in computational methods for predicting effective drug combination are concluded from multiple aspects. First, various datasets utilized to discover synergistic drug combinations are summarized. Second, we discussed feature-based approaches and partitioned these methods into two classes including feature-based methods in terms of similarity measure, and feature-based methods in terms of machine learning. Third, we discussed network-based approaches for uncovering synergistic drug combinations. Finally, we analyzed and prospected computational methods for predicting effective drug combinations.
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Biología Computacional , Descubrimiento de Drogas , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Aprendizaje AutomáticoRESUMEN
The discovery of human disease-related miRNA is a challenging problem for complex disease biology research. For existing computational methods, it is difficult to achieve excellent performance with sparse known miRNA-disease association verified by biological experiment. Here, we develop CPTL, a Collective Prediction based on Transduction Learning, to systematically prioritize miRNAs related to disease. By combining disease similarity, miRNA similarity with known miRNA-disease association, we construct a miRNA-disease network for predicting miRNA-disease association. Then, CPTL calculates relevance score and updates the network structure iteratively, until a convergence criterion is reached. The relevance score of node including miRNA and disease is calculated by the use of transduction learning based on its neighbors. The network structure is updated using relevance score, which increases the weight of important links. To show the effectiveness of our method, we compared CPTL with existing methods based on HMDD datasets. Experimental results indicate that CPTL outperforms existing approaches in terms of AUC, precision, recall, and F1-score. Moreover, experiments performed with different number of iterations verify that CPTL has good convergence. Besides, it is analyzed that the varying of weighted parameters affect predicted results. Case study on breast cancer has further confirmed the identification ability of CPTL.
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Biología Computacional/métodos , MicroARNs/genética , Neoplasias/genética , Algoritmos , Redes Reguladoras de Genes/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Aprendizaje Automático , Neoplasias/metabolismo , Curva ROC , Transducción de Señal/genéticaRESUMEN
Identifying overlapping protein complexes in protein-protein interaction (PPI) networks can provide insight into cellular functional organization and thus elucidate underlying cellular mechanisms. Recently, various algorithms for protein complexes detection have been developed for PPI networks. However, majority of algorithms primarily depend on network topological feature and/or gene expression profile, failing to consider the inherent biological meanings between protein pairs. In this paper, we propose a novel method to detect protein complexes using pseudo-clique extension based on fuzzy relation (PCE-FR). Our algorithm operates in three stages: it first forms the nonoverlapping protein substructure based on fuzzy relation and then expands each substructure by adding neighbor proteins to maximize the cohesive score. Finally, highly overlapped candidate protein complexes are merged to form the final protein complex set. Particularly, our algorithm employs the biological significance hidden in protein pairs to construct edge weight for protein interaction networks. The experiment results show that our method can not only outperform classical algorithms such as CFinder, ClusterONE, CMC, RRW, HC-PIN, and ProRank +, but also achieve ideal overall performance in most of the yeast PPI datasets in terms of composite score consisting of precision, accuracy, and separation. We further apply our method to a human PPI network from the HPRD dataset and demonstrate it is very effective in detecting protein complexes compared to other algorithms.
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Algoritmos , Biología Computacional/métodos , Lógica Difusa , Mapeo de Interacción de Proteínas/métodos , Bases de Datos de Proteínas , HumanosRESUMEN
The identification of protein complexes in protein-protein interaction (PPI) networks has greatly advanced our understanding of biological organisms. Existing computational methods to detect protein complexes are usually based on specific network topological properties of PPI networks. However, due to the inherent complexity of the network structures, the identification of protein complexes may not be fully addressed by using single network topological property. In this study, we propose a novel MultiObjective Evolutionary Programming Genetic Algorithm (MOEPGA) which integrates multiple network topological features to detect biologically meaningful protein complexes. Our approach first systematically analyzes the multiobjective problem in terms of identifying protein complexes from PPI networks, and then constructs the objective function of the iterative algorithm based on three common topological properties of protein complexes from the benchmark dataset, finally we describe our algorithm, which mainly consists of three steps, population initialization, subgraph mutation and subgraph selection operation. To show the utility of our method, we compared MOEPGA with several state-of-the-art algorithms on two yeast PPI datasets. The experiment results demonstrate that the proposed method can not only find more protein complexes but also achieve higher accuracy in terms of fscore. Moreover, our approach can cover a certain number of proteins in the input PPI network in terms of the normalized clustering score. Taken together, our method can serve as a powerful framework to detect protein complexes in yeast PPI networks, thereby facilitating the identification of the underlying biological functions.