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Small molecule drugs can be used to target nucleic acids (NA) to regulate biological processes. Computational modeling methods, such as molecular docking or scoring functions, are commonly employed to facilitate drug design. However, the accuracy of the scoring function in predicting the closest-to-native docking pose is often suboptimal. To overcome this problem, a machine learning model, RmsdXNA, was developed to predict the root-mean-square-deviation (RMSD) of ligand docking poses in NA complexes. The versatility of RmsdXNA has been demonstrated by its successful application to various complexes involving different types of NA receptors and ligands, including metal complexes and short peptides. The predicted RMSD by RmsdXNA was strongly correlated with the actual RMSD of the docked poses. RmsdXNA also outperformed the rDock scoring function in ranking and identifying closest-to-native docking poses across different structural groups and on the testing dataset. Using experimental validated results conducted on polyadenylated nuclear element for nuclear expression triplex, RmsdXNA demonstrated better screening power for the RNA-small molecule complex compared to rDock. Molecular dynamics simulations were subsequently employed to validate the binding of top-scoring ligand candidates selected by RmsdXNA and rDock on MALAT1. The results showed that RmsdXNA has a higher success rate in identifying promising ligands that can bind well to the receptor. The development of an accurate docking score for a NA–ligand complex can aid in drug discovery and development advancements. The code to use RmsdXNA is available at the GitHub repository https://github.com/laiheng001/RmsdXNA. [ABSTRACT FROM AUTHOR]

Existing algorithms for learning Boolean networks (BNs) have time complexities of at least O(N · n0.7((κ+1)), where n is the number of variables, N is the number of samples and k is the number of inputs in Boolean functions. Some recent studies propose more efficient methods with O(N ·n2 time complexities. However, these methods can only be used to learn monotonic BNs, and their performances are not satisfactory when the sample size is small. In this paper, we mathematically prove that OR/AND BNs, where the variables are related with logical OR/AND operations, can be found with the time complexity of O(κ.(N+ logn).n2), if there are enough noiseless training samples randomly generated from a uniform distribution. We also demonstrate that our method can successfully learn most BNs, whose variables are not related with exclusive OR and Boolean equality operations, with the same order of time complexity for learning OR/AND BNs, indicating our method has good efficiency for learning general BNs other than monotonic BNs. When the datasets are noisy, our method can still successfully identify most BNs with the same efficiency. When compared with two existing methods with the same settings, our method achieves a better comprehensive performance than both of them, especially for small training sample sizes. More importantly, our method can be used to learn all BNs. However, of the two methods that are compared, one can only be used to learn monotonic BNs, and the other one has a much worse time complexity than our method. In conclusion, our results demonstrate that Boolean networks can be learned with improved time complexities. [ABSTRACT FROM AUTHOR]

Specific binding between proteins plays a crucial role in molecular functions and biological processes. Protein binding interfaces and their atomic contacts are typically defined by simple criteria, such as distance-based definitions that only use some threshold of spatial distance in previous studies. These definitions neglect the nearby atomic organization of contact atoms, and thus detect predominant contacts which are interrupted by other atoms. It is questionable whether such kinds of interrupted contacts are as important as other contacts in protein binding. To tackle this challenge, we propose a new definition called beta (β) atomic contacts. Our definition, founded on the β-skeletons in computational geometry, requires that there is no other atom in the contact spheres defined by two contact atoms; this sphere is similar to the van der Waals spheres of atoms. The statistical analysis on a large dataset shows that β contacts are only a small fraction of conventional distance-based contacts. To empirically quantify the importance of β contacts, we design βACV, an SVM classifier with β contacts as input, to classify homodimers from crystal packing. We found that our βACV is able to achieve the state-of-the-art classification performance superior to SVM classifiers with distance-based contacts as input. Our βACV also outperforms several existing methods when being evaluated on several datasets in previous works. The promising empirical performance suggests that β contacts can truly identify critical specific contacts in protein binding interfaces. β contacts thus provide a new model for more precise description of atomic organization in protein quaternary structures than distance-based contacts. [ABSTRACT FROM AUTHOR]

Motivation: In silico methods provide efficient ways to predict possible interactions between drugs and targets. Supervised learning approach, bipartite local model (BLM), has recently been shown to be effective in prediction of drug–target interactions. However, for drug-candidate compounds or target-candidate proteins that currently have no known interactions available, its pure ‘local’ model is not able to be learned and hence BLM may fail to make correct prediction when involving such kind of new candidates.Results: We present a simple procedure called neighbor-based interaction-profile inferring (NII) and integrate it into the existing BLM method to handle the new candidate problem. Specifically, the inferred interaction profile is treated as label information and is used for model learning of new candidates. This functionality is particularly important in practice to find targets for new drug-candidate compounds and identify targeting drugs for new target-candidate proteins. Consistent good performance of the new BLM–NII approach has been observed in the experiment for the prediction of interactions between drugs and four categories of target proteins. Especially for nuclear receptors, BLM–NII achieves the most significant improvement as this dataset contains many drugs/targets with no interactions in the cross-validation. This demonstrates the effectiveness of the NII strategy and also shows the great potential of BLM–NII for prediction of compound–protein interactions.Contact: jpmei@ntu.edu.sgSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

The prevalence of tandem repeats in eukaryotic genomes and their association with a number of genetic diseases has raised considerable interest in locating these repeats. Over the last 10–15 years, numerous tools have been developed for searching tandem repeats, but differences in the search algorithms adopted and difficulties with parameter settings have confounded many users resulting in widely varying results. In this review, we have systematically separated the algorithmic aspect of the search tools from the influence of the parameter settings. We hope that this will give a better understanding of how the tools differ in algorithmic performance, their inherent constraints and how one should approach in evaluating and selecting them. [ABSTRACT FROM PUBLISHER]

Epitope residues located on viral surface proteins are of immense interest in immunology and related applications such as vaccine development, disease diagnosis and drug design. Most tools rely on sequence-based statistical comparisons, such as information entropy of residue positions in aligned columns to infer location and properties of epitope sites. To facilitate cross-structural comparisons of epitopes on viral surface proteins, a python-based extraction tool implemented with Jupyter notebook is presented (Jupytope). Given a viral antigen structure of interest, a list of known epitope sites and a reference structure, the corresponding epitope structural properties can quickly be obtained. The tool integrates biopython modules for commonly used software such as NACCESS, DSSP as well as residue depth and outputs a list of structure-derived properties such as dihedral angles, solvent accessibility, residue depth and secondary structure that can be saved in several convenient data formats. To ensure correct spatial alignment, Jupytope takes a list of given epitope sites and their corresponding reference structure and aligns them before extracting the desired properties. Examples are demonstrated for epitopes of Influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) viral strains. The extracted properties assist detection of two Influenza subtypes and show potential in distinguishing between four major clades of SARS-CoV2, as compared with randomized labels. The tool will facilitate analytical and predictive works on viral epitopes through the extracted structural information. Jupytope and extracted datasets are available at https://github.com/shamimarashid/Jupytope. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs) play significant roles in varieties of physiological and pathological processes.The premise of the lncRNA functional study is that the lncRNAs are identified correctly. Recently, deep learning method like convolutional neural network (CNN) has been successfully applied to identify the lncRNAs. However, the traditional CNN considers little relationships among samples via an indirect way. Results: Inspired by the Siamese Neural Network (SNN), here we propose a novel network named Class Similarity Network in coding RNA and lncRNA classification. Class Similarity Network considers more relationships among input samples in a direct way. It focuses on exploring the potential relationships between input samples and samples from both the same class and the different classes. To achieve this, Class Similarity Network trains the parameters specific to each class to obtain the high-level features and represents the general similarity to each class in a node. The comparison results on the validation dataset under the same conditions illustrate the superiority of our Class Similarity Network to the baseline CNN. Besides, our method performs effectively and achieves state-of-the-art performances on two test datasets. Conclusions: We construct Class Similarity Network in coding RNA and lncRNA classification, which is shown to work effectively on two different datasets by achieving accuracy, precision, and F1-score as 98.43%, 0.9247, 0.9374, and 97.54%, 0.9990, 0.9860, respectively. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) play significant roles in various physiological and pathological processes via their interactions with biomolecules like DNA, RNA and protein. The existing in silico methods used for predicting the functions of lncRNA mainly rely on calculating the similarity of lncRNA or investigating whether an lncRNA can interact with a specific biomolecule or disease. In this work, we explored the functions of lncRNA from a different perspective: we presented a tool for predicting the interaction biomolecule type for a given lncRNA. For this purpose, we first investigated the main molecular mechanisms of the interactions of lncRNA–RNA, lncRNA–protein and lncRNA–DNA. Then, we developed an ensemble deep learning model: lncIBTP (lncRNA Interaction Biomolecule Type Prediction). This model predicted the interactions between lncRNA and different types of biomolecules. On the 5-fold cross-validation, the lncIBTP achieves average values of 0.7042 in accuracy, 0.7903 and 0.6421 in macro-average area under receiver operating characteristic curve and precision–recall curve, respectively, which illustrates the model effectiveness. Besides, based on the analysis of the collected published data and prediction results, we hypothesized that the characteristics of lncRNAs that interacted with DNA may be different from those that interacted with only RNA. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs) can exert functions via forming triplex with DNA. The current methods in predicting the triplex formation mainly rely on mathematic statistic according to the base paring rules. However, these methods have two main limitations: (1) they identify a large number of triplex-forming lncRNAs, but the limited number of experimentally verified triplex-forming lncRNA indicates that maybe not all of them can form triplex in practice, and (2) their predictions only consider the theoretical relationship while lacking the features from the experimentally verified data. Results: In this work, we develop an integrated program named TriplexFPP (Triplex Forming Potential Prediction), which is the first machine learning model in DNA:RNA triplex prediction. TriplexFPP predicts the most likely triplex-forming lncRNAs and DNA sites based on the experimentally verified data, where the high-level features are learned by the convolutional neural networks. In the fivefold cross validation, the average values of Area Under the ROC curves and PRC curves for removed redundancy triplex-forming lncRNA dataset with threshold 0.8 are 0.9649 and 0.9996, and these two values for triplex DNA sites prediction are 0.8705 and 0.9671, respectively. Besides, we also briefly summarize the cis and trans targeting of triplexes lncRNAs. Conclusions: The TriplexFPP is able to predict the most likely triplex-forming lncRNAs from all the lncRNAs with computationally defined triplex forming capacities and the potential of a DNA site to become a triplex. It may provide insights to the exploration of lncRNA functions. [ABSTRACT FROM AUTHOR]

Motivation Human microbes play critical roles in drug development and precision medicine. How to systematically understand the complex interaction mechanism between human microbes and drugs remains a challenge nowadays. Identifying microbe–drug associations can not only provide great insights into understanding the mechanism, but also boost the development of drug discovery and repurposing. Considering the high cost and risk of biological experiments, the computational approach is an alternative choice. However, at present, few computational approaches have been developed to tackle this task. Results In this work, we leveraged rich biological information to construct a heterogeneous network for drugs and microbes, including a microbe similarity network, a drug similarity network and a microbe–drug interaction network. We then proposed a novel graph convolutional network (GCN)-based framework for predicting human M icrobe– D rug A ssociations, named GCNMDA. In the hidden layer of GCN, we further exploited the Conditional Random Field (CRF), which can ensure that similar nodes (i.e. microbes or drugs) have similar representations. To more accurately aggregate representations of neighborhoods, an attention mechanism was designed in the CRF layer. Moreover, we performed a random walk with restart-based scheme on both drug and microbe similarity networks to learn valuable features for drugs and microbes, respectively. Experimental results on three different datasets showed that our GCNMDA model consistently achieved better performance than seven state-of-the-art methods. Case studies for three microbes including SARS-CoV-2 and two antimicrobial drugs (i.e. Ciprofloxacin and Moxifloxacin) further confirmed the effectiveness of GCNMDA in identifying potential microbe–drug associations. Availability and implementation Python codes and dataset are available at: https://github.com/longyahui/GCNMDA. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background: The evolution of influenza A viruses leads to the antigenic changes. Serological diagnosis of the antigenicity is usually labor-intensive, time-consuming and not suitable for early-stage detection. Computational prediction of the antigenic relationship between emerging and old strains of influenza viruses using viral sequences can facilitate large-scale antigenic characterization, especially for those viruses requiring high biosafety facilities, such as H5 and H7 influenza A viruses. However, most computational models require carefully designed subtype-specific features, thereby being restricted to only one subtype. Methods: In this paper, we propose a Context-FreeEncoding Scheme (CFreeEnS) for pairs of protein sequences, which encodes a protein sequence dataset into a numeric matrix and then feeds the matrix into a downstream machine learning model. CFreeEnS is not only free from subtype-specific selected features but also able to improve the accuracy of predicting the antigenicity of influenza. Since CFreeEnS is subtype-free, it is applicable to predicting the antigenicity of diverse influenza subtypes, hopefully saving the biologists from conducting serological assays for highly pathogenic strains. Results: The accuracy of prediction on each subtype tested (A/H1N1, A/H3N2, A/H5N1, A/H9N2) is over 85%, and can be as high as 91.5%. This outperforms existing methods that use carefully designed subtype-specific features. Furthermore, we tested the CFreeEnS on the combined dataset of the four subtypes. The accuracy reaches 84.6%, much higher than the best performance 75.1% reported by other subtype-free models, i.e. regional band-based model and residue-based model, for predicting the antigenicity of influenza. Also, we investigate the performance of CFreeEnS when the model is trained and tested on different subtypes (i.e. transfer learning). The prediction accuracy using CFreeEnS is 84.3% when the model is trained on the A/H1N1 dataset and tested on the A/H5N1, better than the 75.2% using a regional band-based model. Conclusions: The CFreeEnS not only improves the prediction of antigenicity on datasets with only one subtype but also outperforms existing methods when tested on a combined dataset with four subtypes of influenza viruses. [ABSTRACT FROM AUTHOR]

Dengue fever is a febrile illness caused by Dengue Virus, which belongs to the Flaviviridae family. Among its proteome, the nonstructural protein 5 (NS5) is the biggest and most conserved. It has a primer-independent RNA-dependent RNA polymerase (RdRp) domain at its C-Terminus. Zou et al. studied the biological relevance of the two conserved cavities (named A and B) within the NS5 proteins of dengue virus (DENV) and West Nile Virus (WNV) using mutagenesis and revertant analysis and found four mutations located at cavity B having effects on viral replication. They recommended Cavity B, but not Cavity A as a potential target for drugs against flavivirus RdRp. In this study, we virtually screened the MayBridge drug fragments dataset for potential small molecule binders of cavity B using both AutoDock Vina, the standard docking tool, and QuickVina 2, our previously developed tool. We selected 16 fragments that appeared in the top 100 docking results of each of the representative structures of NS5. Visual inspection suggests that they have reasonable binding poses. The 16 predicted fragments are plausible drug candidates and should be considered for further validation, optimization, and linking to come up with a suitable inhibitor of dengue virus. [ABSTRACT FROM AUTHOR]

Extracellular signals are captured and transmitted by signaling proteins inside a cell. An important type of cellular responses to the signals is the cell fate decision, e.g., apoptosis. However, the underlying mechanisms of cell fate regulation are still unclear, thus comprehensive and detailed kinetic models are not yet available. Alternatively, data-driven models are promising to bridge signaling data with the phenotypic measurements of cell fates. The traditional linear model for data-driven modeling of signaling pathways has its limitations because it assumes that the a cell fate is proportional to the activities of signaling proteins, which is unlikely in the complex biological systems. Therefore, we propose a power-law model to relate the activities of all the measured signaling proteins to the probabilities of cell fates. In our experiments, we compared our nonlinear power-law model with the linear model on three cancer datasets with phosphoproteomics and cell fate measurements, which demonstrated that the nonlinear model has superior performance on cell fates prediction. By in silico simulation of virtual protein knock-down, the proposed model is able to reveal drug effects which can complement traditional approaches such as binding affinity analysis. Moreover, our model is able to capture cell line specific information to distinguish one cell line from another in cell fate prediction. Our results show that the power-law data-driven model is able to perform better in cell fate prediction and provide more insights into the signaling pathways for cancer cell fates than the linear model. [ABSTRACT FROM AUTHOR]

Studies using machine learning (ML) approaches have reported high diagnostic accuracies for glaucoma detection. However, none assessed model performance across ethnicities. The aim of the study is to externally validate ML models for glaucoma detection from optical coherence tomography (OCT) data. We performed a prospective, cross-sectional study, where 514 Asians (257 glaucoma/257 controls) were enrolled to construct ML models for glaucoma detection, which was then tested on 356 Asians (183 glaucoma/173 controls) and 138 Caucasians (57 glaucoma/81 controls). We used the retinal nerve fibre layer (RNFL) thickness values produced by the compensation model, which is a multiple regression model fitted on healthy subjects that corrects the RNFL profile for anatomical factors and the original OCT data (measured) to build two classifiers, respectively. Both the ML models (area under the receiver operating [AUC] = 0.96 and accuracy = 92%) outperformed the measured data (AUC = 0.93; P < 0.001) for glaucoma detection in the Asian dataset. However, in the Caucasian dataset, the ML model trained with compensated data (AUC = 0.93 and accuracy = 84%) outperformed the ML model trained with original data (AUC = 0.83 and accuracy = 79%; P < 0.001) and measured data (AUC = 0.82; P < 0.001) for glaucoma detection. The performance with the ML model trained on measured data showed poor reproducibility across different datasets, whereas the performance of the compensated data was maintained. Care must be taken when ML models are applied to patient cohorts of different ethnicities. [ABSTRACT FROM AUTHOR]

Motivation: Protein complexes are of great importance for unraveling the secrets of cellular organization and function. The AP-MS technique has provided an effective high-throughput screening to directly measure the co-complex relationship among multiple proteins, but its performance suffers from both false positives and false negatives. To computationally predict complexes from AP-MS data, most existing approaches either required the additional knowledge from known complexes (supervised learning), or had numerous parameters to tune.Method: In this article, we propose a novel unsupervised approach, without relying on the knowledge of existing complexes. Our method probabilistically calculates the affinity between two proteins, where the affinity score is evaluated by a co-complexed score or C2S in brief. In particular, our method measures the log-likelihood ratio of two proteins being co-complexed to being drawn randomly, and we then predict protein complexes by applying hierarchical clustering algorithm on the C2S score matrix.Results: Compared with existing approaches, our approach is computationally efficient and easy to implement. It has just one parameter to set and its value has little effect on the results. It can be applied to different species as long as the AP-MS data are available. Despite its simplicity, it is competitive or superior in performance over many aspects when compared with the state-of-the-art predictions performed by supervised or unsupervised approaches.Availability: The predicted complex sets in this article are available in the Supplementary information or by sending email to asckkwoh@ntu.edu.sgContact: xlli@i2r.a-star.edu.sgSupplementary information: Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 pandemic has alerted people of the threat caused by viruses. Vaccine is the most effective way to prevent the disease from spreading. The interaction between antibodies and antigens will clear the infectious organisms from the host. Identifying B-cell epitopes is critical in vaccine design, development of disease diagnostics and antibody production. However, traditional experimental methods to determine epitopes are time-consuming and expensive, and the predictive performance using the existing in silico methods is not satisfactory. This paper develops a general framework to predict variable-length linear B-cell epitopes specific for human-adapted viruses with machine learning approaches based on Protvec representation of peptides and physicochemical properties of amino acids. QR decomposition is incorporated during the embedding process that enables our models to handle variable-length sequences. Experimental results on large immune epitope datasets validate that our proposed model's performance is superior to the state-of-the-art methods in terms of AUROC (0.827) and AUPR (0.831) on the testing set. Moreover, sequence analysis also provides the results of the viral category for the corresponding predicted epitopes with high precision. Therefore, this framework is shown to reliably identify linear B-cell epitopes of human-adapted viruses given protein sequences and could provide assistance for potential future pandemics and epidemics. [ABSTRACT FROM AUTHOR]

We used diffusion modelling to predict vulnerability to decline in psychomotor vigilance task ( PVT) performance following a night of total sleep deprivation ( SD). A total of 135 healthy young adults (69 women, age = 21.9 ± 1.7 years) participated in several within-subject cross-over design studies that incorporated the PVT. Participants were classified as vulnerable (lower tertile) or non-vulnerable (upper tertile) according to their change in lapse rate [lapse = reaction time ( RT) ≥ 500 ms] between the evening before ( ESD) and the morning after SD. RT data were fitted using Ratcliff's diffusion model. Although both groups showed significant change in RT during SD, there was no significant group difference in RT during the ESD session. In contrast, during ESD, the mean diffusion drift of vulnerable subjects was significantly lower than for non-vulnerable subjects. Mean drift and non-decision times were both adversely affected by sleep deprivation. Both mean drift and non-decision time showed significant state × vulnerability interaction. Diffusion modelling appears to have promise in predicting vulnerability to vigilance decline induced by a night of total sleep deprivation. [ABSTRACT FROM AUTHOR]

Motivation Graphs or networks are widely utilized to model the interactions between different entities (e.g. proteins, drugs, etc.) for biomedical applications. Predicting potential interactions/links in biomedical networks is important for understanding the pathological mechanisms of various complex human diseases, as well as screening compound targets for drug discovery. Graph neural networks (GNNs) have been utilized for link prediction in various biomedical networks, which rely on the node features extracted from different data sources, e.g. sequence, structure and network data. However, it is challenging to effectively integrate these data sources and automatically extract features for different link prediction tasks. Results In this article, we propose a novel Pre-Training Graph Neural Networks-based framework named PT-GNN to integrate different data sources for link prediction in biomedical networks. First, we design expressive deep learning methods [e.g. convolutional neural network and graph convolutional network (GCN)] to learn features for individual nodes from sequence and structure data. Second, we further propose a GCN-based encoder to effectively refine the node features by modelling the dependencies among nodes in the network. Third, the node features are pre-trained based on graph reconstruction tasks. The pre-trained features can be used for model initialization in downstream tasks. Extensive experiments have been conducted on two critical link prediction tasks, i.e. synthetic lethality (SL) prediction and drug–target interaction (DTI) prediction. Experimental results demonstrate PT-GNN outperforms the state-of-the-art methods for SL prediction and DTI prediction. In addition, the pre-trained features benefit improving the performance and reduce the training time of existing models. Availability and implementation Python codes and dataset are available at: https://github.com/longyahui/PT-GNN. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

• We integrated various data sources and constructed two heterogeneous network. • A novel GAT-based framework named HGATMDA was proposed for DTI prediction. • A self-enhanced attention mechanism was designed to learn node representations. • Comprehensive experiments demonstrated the performance of HGATMDA. Coronavirus Disease-19 (COVID-19) has lead global epidemics with high morbidity and mortality. However, there are currently no proven effective drugs targeting COVID-19. Identifying drug-virus associations can not only provide insights into the understanding of drug-virus interaction mechanism, but also guide and facilitate the screening of compound candidates for antiviral drug discovery. Since conventional experiment methods are time-consuming, laborious and expensive, computational methods to identify potential drug candidates for viruses (e.g., COVID-19) provide an alternative strategy. In this work, we propose a novel framework of Heterogeneous Graph Attention Networks for Drug-Virus Association predictions, named HGATDVA. First, we fully incorporate multiple sources of biomedical data, e.g., drug chemical information, virus genome sequences and viral protein sequences, to construct abundant features for drugs and viruses. Second, we construct two drug-virus heterogeneous graphs. For each graph, we design a self-enhanced graph attention network (SGAT) to explicitly model the dependency between a node and its local neighbors and derive the graph-specific representations for nodes. Third, we further develop a neural network architecture with tri-aggregator to aggregate the graph-specific representations to generate the final node representations. Extensive experiments were conducted on two datasets, i.e., DrugVirus and MDAD, and the results demonstrated that our model outperformed 7 state-of-the-art methods. Case study on SARS-CoV-2 validated the effectiveness of our model in identifying potential drugs for viruses. [ABSTRACT FROM AUTHOR]

Graph is a natural data structure for describing complex systems, which contains a set of objects and relationships. Ubiquitous real-life biomedical problems can be modeled as graph analytics tasks. Machine learning, especially deep learning, succeeds in vast bioinformatics scenarios with data represented in Euclidean domain. However, rich relational information between biological elements is retained in the non-Euclidean biomedical graphs, which is not learning friendly to classic machine learning methods. Graph representation learning aims to embed graph into a low-dimensional space while preserving graph topology and node properties. It bridges biomedical graphs and modern machine learning methods and has recently raised widespread interest in both machine learning and bioinformatics communities. In this work, we summarize the advances of graph representation learning and its representative applications in bioinformatics. To provide a comprehensive and structured analysis and perspective, we first categorize and analyze both graph embedding methods (homogeneous graph embedding, heterogeneous graph embedding, attribute graph embedding) and graph neural networks. Furthermore, we summarize their representative applications from molecular level to genomics, pharmaceutical and healthcare systems level. Moreover, we provide open resource platforms and libraries for implementing these graph representation learning methods and discuss the challenges and opportunities of graph representation learning in bioinformatics. This work provides a comprehensive survey of emerging graph representation learning algorithms and their applications in bioinformatics. It is anticipated that it could bring valuable insights for researchers to contribute their knowledge to graph representation learning and future-oriented bioinformatics studies. [ABSTRACT FROM AUTHOR]

Accurate estimation of remaining useful life (RUL) of industrial equipment can enable advanced maintenance schedules, increase equipment availability and reduce operational costs. However, existing deep learning methods for RUL prediction are not completely successful due to the following two reasons. First, relying on a single objective function to estimate the RUL will limit the learned representations and thus affect the prediction accuracy. Second, while longer sequences are more informative for modelling the sensor dynamics of equipment, existing methods are less effective to deal with very long sequences, as they mainly focus on the latest information. To address these two problems, we develop a novel attention-based sequence to sequence with auxiliary task (ATS2S) model. In particular, our model jointly optimizes both reconstruction loss to empower our model with predictive capabilities (by predicting next input sequence given current input sequence) and RUL prediction loss to minimize the difference between the predicted RUL and actual RUL. Furthermore, to better handle longer sequences, we employ the attention mechanism to focus on all the important input information during the training process. Finally, we propose a new dual-latent feature representation to integrate the encoder features and decoder hidden states, to capture rich semantic information in data. We conduct extensive experiments on four real datasets to evaluate the efficacy of the proposed method. Experimental results show that our proposed method can achieve superior performance over 13 state-of-the-art methods consistently. [ABSTRACT FROM AUTHOR]

Epigenomics and transcriptomics data from high-throughput sequencing techniques such as RNA-seq and ChIP-seq have been successfully applied in predicting gene transcript expression. However, the locations of chromatin loops in the genome identified by techniques such as Chromatin Interaction Analysis with Paired End Tag sequencing (ChIA-PET) have never been used for prediction tasks. Here, we developed machine learning models to investigate if ChIA-PET could contribute to transcript and exon usage prediction. In doing so, we used a large set of transcription factors as well as ChIA-PET data. We developed different Gradient Boosting Trees models according to the different tasks with the integrated datasets from three cell lines, including GM12878, HeLaS3 and K562. We validated the models via 10-fold cross validation, chromosome-split validation and cross-cell validation. Our results show that both transcript and splicing-derived exon usage can be effectively predicted with at least 0.7512 and 0.7459 of accuracy, respectively, on all cell lines from all kinds of validations. Examining the predictive features, we found that RNA Polymerase II ChIA-PET was one of the most important features in both transcript and exon usage prediction, suggesting that chromatin loop anchors are predictive of both transcript and exon usage. [ABSTRACT FROM AUTHOR]

Background: The pandemic 2009-H1N1 influenza virus circulated in the human population and caused thousands deaths worldwide. Studies on pandemic influenza vaccines have shown that T cell recognition to conserved epitopes and cross-reactive T cell responses are important when new strains emerge, especially in the absence of antibody cross-reactivity. In this work, using HLA-B"4405 and DM1-TCR structure model, we systematically generated high confidence conserved 2009-H1N1 T cell epitope candidates and investigated their potential crossreactivity against H5N1 avian flu virus. Results: Molecular docking analysis of differential DM1-TCR recognition of the 2009-H1N1 epitope candidates yielded a mosaic epitope (KEKMNTEFW) and potential H5N1 HA cross-reactive epitopes that could be applied as multivalent peptide towards influenza A vaccine development. Structural models of TCR cross-recognition between 2009-H1N1 and 2004-H5N1 revealed steric and topological effects of TCR contact residue mutations on TCR binding affinity. Conclusions: The results are novel with regard to HA epitopes and useful for developing possible vaccination strategies against the rapidly changing influenza viruses. Yet, the challenge of identifying epitope candidates that result in heterologous T cell immunity under natural influenza infection conditions can only be overcome if more structural data on the TCR repertoire become available. [ABSTRACT FROM AUTHOR]

Many cellular functions involve protein complexes that are formed by multiple interacting proteins. Tandem Affinity Purification (TAP) is a popular experimental method for detecting such multi-protein interactions. However, current computational methods that predict protein complexes from TAP data require converting the co-complex relationships in TAP data into binary interactions. The resulting pairwise protein-protein interaction (PPI) network is then mined for densely connected regions that are identified as putative protein complexes. Converting the TAP data into PPI data not only introduces errors but also loses useful information about the underlying multi-protein relationships that can be exploited to detect the internal organization (i.e., core-attachment structures) of protein complexes. In this article, we propose a method called CACHET that detects protein complexes with ore-ttament structures directly from bipartitAP data. CACHET models the TAP data as a bipartite graph in which the two vertex sets are the baits and the preys, respectively. The edges between the two vertex sets represent bait-prey relationships. CACHET first focuses on detecting high-quality protein-complex cores from the bipartite graph. To minimize the effects of false positive interactions, the bait-prey relationships are indexed with reliability scores. Only non-redundant, reliable bicliques computed from the TAP bipartite graph are regarded as protein-complex cores. CACHET constructs protein complexes by including attachment proteins into the cores. We applied CACHET on large-scale TAP datasets and found that CACHET outperformed existing methods in terms of prediction accuracy (i.e., F-measure and functional homogeneity of predicted complexes). In addition, the protein complexes predicted by CACHET are equipped with core-attachment structures that provide useful biological insights into the inherent functional organization of protein complexes. Our can be found at ; binary executables can also be found there. is also available at . [ABSTRACT FROM AUTHOR]

Protein-ligand docking is a computational method to identify the binding mode of a ligand and a target protein, and predict the corresponding binding affinity using a scoring function. This method has great value in drug design. After decades of development, scoring functions nowadays typically can identify the true binding mode, but the prediction of binding affinity still remains a major problem. Here we present CScore, a data-driven scoring function using a modified Cerebellar Model Articulation Controller (CMAC) learning architecture, for accurate binding affinity prediction. The performance of CScore in terms of correlation between predicted and experimental binding affinities is benchmarked under different validation approaches. CScore achieves a prediction with R = 0.7668 and RMSE = 1.4540 when tested on an independent dataset. To the best of our knowledge, this result outperforms other scoring functions tested on the same dataset. The performance of CScore varies on different clusters under the leave-cluster-out validation approach, but still achieves competitive result. Lastly, the target-specified CScore achieves an even better result with R = 0.8237 and RMSE = 1.0872, trained on a much smaller but more relevant dataset for each target. The large dataset of protein-ligand complexes structural information and advances of machine learning techniques enable the data-driven approach in binding affinity prediction. CScore is capable of accurate binding affinity prediction. It is also shown that CScore will perform better if sufficient and relevant data is presented. As there is growth of publicly available structural data, further improvement of this scoring scheme can be expected. [ABSTRACT FROM AUTHOR]

Summary: Objective: The hidden vector state (HVS) model is an extension of the basic discrete Markov model in which context is encoded as a stack-oriented state vector. It has been applied successfully for protein–protein interactions extraction. However, the HVS model, being a statistically based approach, requires large-scale annotated corpora in order to reliably estimate model parameters. This is normally difficult to obtain in practical applications. Methods and materials: In this paper, we present two novel semi-supervised learning approaches, one based on classification and the other based on expectation-maximization, to train the HVS model from both annotated and un-annotated corpora. Results and conclusion: Experimental results show the improved performance over the baseline system using the HVS model trained solely from the annotated corpus, which gives the support to the feasibility and efficiency of our approaches. [Copyright &y& Elsevier]

Abstract: Experimental approaches for identifying T-cell epitopes are time-consuming, costly and not applicable to the large scale screening. Computer modeling methods can help to minimize the number of experiments required, enable a systematic scanning for candidate major histocompatibility complex (MHC) binding peptides and thus speed up vaccine development. We developed a prediction system based on a novel data representation of peptide/MHC interaction and support vector machines (SVM) for prediction of peptides that promiscuously bind to multiple Human Leukocyte Antigen (HLA, human MHC) alleles belonging to a HLA supertype. Ten-fold cross-validation results showed that the overall performance of SVM models is improved in comparison to our previously published methods based on hidden Markov models (HMM) and artificial neural networks (ANN), also confirmed by blind testing. At specificity 0.90, sensitivity values of SVM models were 0.90 and 0.92 for HLA-A2 and -A3 dataset respectively. Average area under the receiver operating curve (A ROC) of SVM models in blind testing are 0.89 and 0.92 for HLA-A2 and -A3 datasets. A ROC of HLA-A2 and -A3 SVM models were 0.94 and 0.95, validated using a full overlapping study of 9-mer peptides from human papillomavirus type 16 E6 and E7 proteins. In addition, a large-scale experimental dataset has been used to validate HLA-A2 and -A3 SVM models. The SVM prediction models were integrated into a web-based computational system MULTIPRED1, accessible at antigen.i2r.a-star.edu.sg/multipred1/. [Copyright &y& Elsevier]

The paper aims to propose a new approach towards human posture reconstruction and animation from monocular video sequences that contain any kind of human postures and movements. This is a way towards low cost motion capture and at the same time it avoids many limitations of those classical methods. A parameterized human skeleton model based on anatomy is adopted where the angular constraints are encoded in the joints. Criterion Function is defined to represent the residuals between feature points in the monocular image and the corresponding points resulted from projecting the human model to the projection plane. By transforming each segment of the human model to achieve the minimum value of the Criterion Function, the proper human posture that resembles the one represented by the monocular image can be generated. Different kinds of adjustments are utilized to adjust the body parts into the proper locations and orientations in 3D space without camera calibration. In order to find the optimal solution effectively in a high-dimensional parameter space by considering all the parameters simultaneously, the method of Genetic Algorithms is proposed. A procedure is developed to recover the whole body posture, and then a human animation system is developed to animate a series of human movements from monocular image sequences, during which information between consecutive frames is considered to improve the accuracy. Our technique makes it feasible to reconstruct any possible human postures, and experimental results from many monocular images and video sequences are encouraging. [ABSTRACT FROM AUTHOR]

Motivation Synthetic Lethality (SL) plays an increasingly critical role in the targeted anticancer therapeutics. In addition, identifying SL interactions can create opportunities to selectively kill cancer cells without harming normal cells. Given the high cost of wet-lab experiments, in silico prediction of SL interactions as an alternative can be a rapid and cost-effective way to guide the experimental screening of candidate SL pairs. Several matrix factorization-based methods have recently been proposed for human SL prediction. However, they are limited in capturing the dependencies of neighbors. In addition, it is also highly challenging to make accurate predictions for new genes without any known SL partners. Results In this work, we propose a novel graph contextualized attention network named GCATSL to learn gene representations for SL prediction. First, we leverage different data sources to construct multiple feature graphs for genes, which serve as the feature inputs for our GCATSL method. Second, for each feature graph, we design node-level attention mechanism to effectively capture the importance of local and global neighbors and learn local and global representations for the nodes, respectively. We further exploit multi-layer perceptron (MLP) to aggregate the original features with the local and global representations and then derive the feature-specific representations. Third, to derive the final representations, we design feature-level attention to integrate feature-specific representations by taking the importance of different feature graphs into account. Extensive experimental results on three datasets under different settings demonstrated that our GCATSL model outperforms 14 state-of-the-art methods consistently. In addition, case studies further validated the effectiveness of our proposed model in identifying novel SL pairs. Availabilityand implementation Python codes and dataset are freely available on GitHub (https://github.com/longyahui/GCATSL) and Zenodo (https://zenodo.org/record/4522679) under the MIT license. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Disease–gene association through genome-wide association study (GWAS) is an arduous task for researchers. Investigating single nucleotide polymorphisms that correlate with specific diseases needs statistical analysis of associations. Considering the huge number of possible mutations, in addition to its high cost, another important drawback of GWAS analysis is the large number of false positives. Thus, researchers search for more evidence to cross-check their results through different sources. To provide the researchers with alternative and complementary low-cost disease–gene association evidence, computational approaches come into play. Since molecular networks are able to capture complex interplay among molecules in diseases, they become one of the most extensively used data for disease–gene association prediction. In this survey, we aim to provide a comprehensive and up-to-date review of network-based methods for disease gene prediction. We also conduct an empirical analysis on 14 state-of-the-art methods. To summarize, we first elucidate the task definition for disease gene prediction. Secondly, we categorize existing network-based efforts into network diffusion methods, traditional machine learning methods with handcrafted graph features and graph representation learning methods. Thirdly, an empirical analysis is conducted to evaluate the performance of the selected methods across seven diseases. We also provide distinguishing findings about the discussed methods based on our empirical analysis. Finally, we highlight potential research directions for future studies on disease gene prediction. [ABSTRACT FROM AUTHOR]

Motivation Influenza viruses are persistently threatening public health, causing annual epidemics and sporadic pandemics. The evolution of influenza viruses remains to be the main obstacle in the effectiveness of antiviral treatments due to rapid mutations. Previous work has been investigated to reveal the determinants of virulence of the influenza A virus. To further facilitate flu surveillance, explicit detection of influenza virulence is crucial to protect public health from potential future pandemics. Results In this article, we propose a weighted ensemble convolutional neural network (CNN) for the virulence prediction of influenza A viruses named VirPreNet that uses all eight segments. Firstly, mouse lethal dose 50 is exerted to label the virulence of infections into two classes, namely avirulent and virulent. A numerical representation of amino acids named ProtVec is applied to the eight-segments in a distributed manner to encode the biological sequences. After splittings and embeddings of influenza strains, the ensemble CNN is constructed as the base model on the influenza dataset of each segment, which serves as the VirPreNet's main part. Followed by a linear layer, the initial predictive outcomes are integrated and assigned with different weights for the final prediction. The experimental results on the collected influenza dataset indicate that VirPreNet achieves state-of-the-art performance combining ProtVec with our proposed architecture. It outperforms baseline methods on the independent testing data. Moreover, our proposed model reveals the importance of PB2 and HA segments on the virulence prediction. We believe that our model may provide new insights into the investigation of influenza virulence. Availability and implementation Codes and data to generate the VirPreNet are publicly available at https://github.com/Rayin-saber/VirPreNet. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

The development of deep sequencing technologies has led to the discovery of novel transcripts. Many in silico methods have been developed to assess the coding potential of these transcripts to further investigate their functions. Existing methods perform well on distinguishing majority long noncoding RNAs (lncRNAs) and coding RNAs (mRNAs) but poorly on RNAs with small open reading frames (sORFs). Here, we present DeepCPP (deep neural network for coding potential prediction), a deep learning method for RNA coding potential prediction. Extensive evaluations on four previous datasets and six new datasets constructed in different species show that DeepCPP outperforms other state-of-the-art methods, especially on sORF type data, which overcomes the bottleneck of sORF mRNA identification by improving more than 4.31, 37.24 and 5.89% on its accuracy for newly discovered human, vertebrate and insect data, respectively. Additionally, we also revealed that discontinuous k-mer, and our newly proposed nucleotide bias and minimal distribution similarity feature selection method play crucial roles in this classification problem. Taken together, DeepCPP is an effective method for RNA coding potential prediction. [ABSTRACT FROM AUTHOR]

Data-driven fault classification methods are receiving great attention as they can be applied to many real-world applications. However, they work under the assumption that training data and testing data are drawn from the same distribution. Practical scenarios have varying operating conditions, which results in a domain-shift problem that significantly deteriorates the diagnosis performance. Recently, domain adaptation (DA) has been explored to address the domain-shift problem by transferring the knowledge from labeled source domain (e.g., source working condition) to unlabeled target domain (e.g., target working condition). Yet, all the existing methods are working under single-source single-target (1S1T) settings. Hence, a new model needs to be trained for each new target domain. This shows limited scalability in handling multiple working conditions since different models should be trained for different target working conditions, which is clearly not a viable solution in practice. To address this problem, we propose a novel adversarial multiple-target DA (AMDA) method for single-source multiple-target (1SmT) scenario, where the model can generalize to multiple-target domains concurrently. Adversarial adaptation is applied to transform the multiple-target domain features to be invariant from the single-source-domain features. This leads to a scalable model with a novel capability of generalizing to multiple-target domains. Extensive experiments on two public datasets and one self-collected dataset have demonstrated that the proposed method outperforms state-of-the-art methods consistently. Our source codes and data are available at https://github.com/mohamedr002/AMDA. [ABSTRACT FROM AUTHOR]

Ensemble clustering has been a popular research topic in data mining and machine learning. Despite its significant progress in recent years, there are still two challenging issues in the current ensemble clustering research. First, most of the existing algorithms tend to investigate the ensemble information at the object-level, yet often lack the ability to explore the rich information at higher levels of granularity. Second, they mostly focus on the direct connections (e.g., direct intersection or pair-wise co-occurrence) in the multiple base clusterings, but generally neglect the multiscale indirect relationship hidden in them. To address these two issues, this paper presents a novel ensemble clustering approach based on fast propagation of cluster-wise similarities via random walks. We first construct a cluster similarity graph with the base clusters treated as graph nodes and the cluster-wise Jaccard coefficient exploited to compute the initial edge weights. Upon the constructed graph, a transition probability matrix is defined, based on which the random walk process is conducted to propagate the graph structural information. Specifically, by investigating the propagating trajectories starting from different nodes, a new cluster-wise similarity matrix can be derived by considering the trajectory relationship. Then, the newly obtained cluster-wise similarity matrix is mapped from the cluster-level to the object-level to achieve an enhanced co-association matrix, which is able to simultaneously capture the object-wise co-occurrence relationship as well as the multiscale cluster-wise relationship in ensembles. Finally, two novel consensus functions are proposed to obtain the consensus clustering result. Extensive experiments on a variety of real-world datasets have demonstrated the effectiveness and efficiency of our approach. [ABSTRACT FROM AUTHOR]

Motivation Human microbes get closely involved in an extensive variety of complex human diseases and become new drug targets. In silico methods for identifying potential microbe–drug associations provide an effective complement to conventional experimental methods, which can not only benefit screening candidate compounds for drug development but also facilitate novel knowledge discovery for understanding microbe–drug interaction mechanisms. On the other hand, the recent increased availability of accumulated biomedical data for microbes and drugs provides a great opportunity for a machine learning approach to predict microbe–drug associations. We are thus highly motivated to integrate these data sources to improve prediction accuracy. In addition, it is extremely challenging to predict interactions for new drugs or new microbes, which have no existing microbe–drug associations. Results In this work, we leverage various sources of biomedical information and construct multiple networks (graphs) for microbes and drugs. Then, we develop a novel ensemble framework of graph attention networks with a hierarchical attention mechanism for microbe–drug association prediction from the constructed multiple microbe–drug graphs, denoted as EGATMDA. In particular, for each input graph, we design a graph convolutional network with node-level attention to learn embeddings for nodes (i.e. microbes and drugs). To effectively aggregate node embeddings from multiple input graphs, we implement graph-level attention to learn the importance of different input graphs. Experimental results under different cross-validation settings (e.g. the setting for predicting associations for new drugs) showed that our proposed method outperformed seven state-of-the-art methods. Case studies on predicted microbe–drug associations further demonstrated the effectiveness of our proposed EGATMDA method. Availability Source codes and supplementary materials are available at: https://github.com/longyahui/EGATMDA/ Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background: A large body of evidence shows that miRNA regulates the expression of its target genes at post-transcriptional level and the dysregulation of miRNA is related to many complex human diseases. Accurately discovering disease-related miRNAs is conductive to the exploring of the pathogenesis and treatment of diseases. However, because of the limitation of time-consuming and expensive experimental methods, predicting miRNA-disease associations by computational models has become a more economical and effective mean. Results: Inspired by the work of predecessors, we proposed an improved computational model based on random forest (RF) for identifying miRNA-disease associations (IRFMDA). First, the integrated similarity of diseases and the integrated similarity of miRNAs were calculated by combining the semantic similarity and Gaussian interaction profile kernel (GIPK) similarity of diseases, the functional similarity and GIPK similarity of miRNAs, respectively. Then, the integrated similarity of diseases and the integrated similarity of miRNAs were combined to represent each miRNA-disease relationship pair. Next, the miRNA-disease relationship pairs contained in the HMDD (v2.0) database were considered positive samples, and the randomly constructed miRNA-disease relationship pairs not included in HMDD (v2.0) were considered negative samples. Next, the feature selection based on the variable importance score of RF was performed to choose more useful features to represent samples to optimize the model's ability of inferring miRNA-disease associations. Finally, a RF regression model was trained on reduced sample space to score the unknown miRNA-disease associations. The AUCs of IRFMDA under local leave-one-out cross-validation (LOOCV), global LOOCV and 5-fold cross-validation achieved 0.8728, 0.9398 and 0.9363, which were better than several excellent models for predicting miRNA-disease associations. Moreover, case studies on oesophageal cancer, lymphoma and lung cancer showed that 94 (oesophageal cancer), 98 (lymphoma) and 100 (lung cancer) of the top 100 disease-associated miRNAs predicted by IRFMDA were supported by the experimental data in the dbDEMC (v2.0) database. Conclusions: Cross-validation and case studies demonstrated that IRFMDA is an excellent miRNA-disease association prediction model, and can provide guidance and help for experimental studies on the regulatory mechanism of miRNAs in complex human diseases in the future. [ABSTRACT FROM AUTHOR]

The molecular components with the functional interdependencies in human cell form complicated biological network. Diseases are mostly caused by the perturbations of the composite of the interaction multi-biomolecules, rather than an abnormality of a single biomolecule. Furthermore, new biological functions and processes could be revealed by discovering novel biological entity relationships. Hence, more and more biologists focus on studying the complex biological system instead of the individual biological components. The emergence of heterogeneous information network (HIN) offers a promising way to systematically explore complicated and heterogeneous relationships between various molecules for apparently distinct phenotypes. In this review, we first present the basic definition of HIN and the biological system considered as a complex HIN. Then, we discuss the topological properties of HIN and how these can be applied to detect network motif and functional module. Afterwards, methodologies of discovering relationships between disease and biomolecule are presented. Useful insights on how HIN aids in drug development and explores human interactome are provided. Finally, we analyze the challenges and opportunities for uncovering combinatorial patterns among pharmacogenomics and cell-type detection based on single-cell genomic data. [ABSTRACT FROM AUTHOR]

This paper focuses on scalability and robustness of spectral clustering for extremely large-scale datasets with limited resources. Two novel algorithms are proposed, namely, ultra-scalable spectral clustering (U-SPEC) and ultra-scalable ensemble clustering (U-SENC). In U-SPEC, a hybrid representative selection strategy and a fast approximation method for $K$ K -nearest representatives are proposed for the construction of a sparse affinity sub-matrix. By interpreting the sparse sub-matrix as a bipartite graph, the transfer cut is then utilized to efficiently partition the graph and obtain the clustering result. In U-SENC, multiple U-SPEC clusterers are further integrated into an ensemble clustering framework to enhance the robustness of U-SPEC while maintaining high efficiency. Based on the ensemble generation via multiple U-SEPC's, a new bipartite graph is constructed between objects and base clusters and then efficiently partitioned to achieve the consensus clustering result. It is noteworthy that both U-SPEC and U-SENC have nearly linear time and space complexity, and are capable of robustly and efficiently partitioning 10-million-level nonlinearly-separable datasets on a PC with 64 GB memory. Experiments on various large-scale datasets have demonstrated the scalability and robustness of our algorithms. The MATLAB code and experimental data are available at https://www.researchgate.net/publication/330760669. [ABSTRACT FROM AUTHOR]

Motivation Influenza viruses are persistently threatening public health, causing annual epidemics and sporadic pandemics. The evolution of influenza viruses remains to be the main obstacle in the effectiveness of antiviral treatments due to rapid mutations. The goal of this work is to predict whether mutations are likely to occur in the next flu season using historical glycoprotein hemagglutinin sequence data. One of the major challenges is to model the temporality and dimensionality of sequential influenza strains and to interpret the prediction results. Results In this article, we propose an efficient and robust time-series mutation prediction model (Tempel) for the mutation prediction of influenza A viruses. We first construct the sequential training samples with splittings and embeddings. By employing recurrent neural networks with attention mechanisms, Tempel is capable of considering the historical residue information. Attention mechanisms are being increasingly used to improve the performance of mutation prediction by selectively focusing on the parts of the residues. A framework is established based on Tempel that enables us to predict the mutations at any specific residue site. Experimental results on three influenza datasets show that Tempel can significantly enhance the predictive performance compared with widely used approaches and provide novel insights into the dynamics of viral mutation and evolution. Availability and implementation The datasets, source code and supplementary documents are available at: https://drive.google.com/drive/folders/15WULR5%5f%5f6k47iRotRPl3H7ghi3RpeNXH. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Background: Accumulated evidence shows that the abnormal regulation of long non-coding RNA (lncRNA) is associated with various human diseases. Accurately identifying disease-associated lncRNAs is helpful to study the mechanism of lncRNAs in diseases and explore new therapies of diseases. Many lncRNA-disease association (LDA) prediction models have been implemented by integrating multiple kinds of data resources. However, most of the existing models ignore the interference of noisy and redundancy information among these data resources. Results: To improve the ability of LDA prediction models, we implemented a random forest and feature selection based LDA prediction model (RFLDA in short). First, the RFLDA integrates the experiment-supported miRNA-disease associations (MDAs) and LDAs, the disease semantic similarity (DSS), the lncRNA functional similarity (LFS) and the lncRNA-miRNA interactions (LMI) as input features. Then, the RFLDA chooses the most useful features to train prediction model by feature selection based on the random forest variable importance score that takes into account not only the effect of individual feature on prediction results but also the joint effects of multiple features on prediction results. Finally, a random forest regression model is trained to score potential lncRNA-disease associations. In terms of the area under the receiver operating characteristic curve (AUC) of 0.976 and the area under the precision-recall curve (AUPR) of 0.779 under 5-fold cross-validation, the performance of the RFLDA is better than several state-of-the-art LDA prediction models. Moreover, case studies on three cancers demonstrate that 43 of the 45 lncRNAs predicted by the RFLDA are validated by experimental data, and the other two predicted lncRNAs are supported by other LDA prediction models. Conclusions: Cross-validation and case studies indicate that the RFLDA has excellent ability to identify potential disease-associated lncRNAs. [ABSTRACT FROM AUTHOR]

Influenza viruses are persistently threatening public health, causing annual epidemics and sporadic pandemics due to rapid viral evolution. Vaccines are used to prevent influenza infections but the composition of the influenza vaccines have to be updated regularly to ensure its efficacy. Computational tools and analyses have become increasingly important in guiding the process of vaccine selection. By constructing time-series training samples with splittings and embeddings, we develop a computational method for predicting suitable strains as the recommendation of the influenza vaccines using recurrent neural networks (RNNs). The Encoder-decoder architecture of RNN model enables us to perform sequence-to-sequence prediction. We employ this model to predict the prevalent sequence of the H3N2 viruses sampled from 2006 to 2017. The identity between our predicted sequence and recommended vaccines is greater than 98% and the P epitope < 0. 2 indicates their antigenic similarity. The multi-step vaccine prediction further demonstrates the robustness of our method which achieves comparable results in contrast to single step prediction. The results show significant matches of the recommended vaccine strains to the circulating strains. We believe it would facilitate the process of vaccine selection and surveillance of seasonal influenza epidemics. [ABSTRACT FROM AUTHOR]

Background: Influenza reassortment, a mechanism where influenza viruses exchange their RNA segments by co-infecting a single cell, has been implicated in several major pandemics since 19th century. Owing to the significant impact on public health and social stability, great attention has been received on the identification of influenza reassortment. Methods: We proposed a novel computational method named HopPER (Host-prediction-based Probability Estimation of Reassortment), that sturdily estimates reassortment probabilities through host tropism prediction using 147 new features generated from seven physicochemical properties of amino acids. We conducted the experiments on a range of real and synthetic datasets and compared HopPER with several state-of-the-art methods. Results: It is shown that 280 out of 318 candidate reassortants have been successfully identified. Additionally, not only can HopPER be applied to complete genomes but its effectiveness on incomplete genomes is also demonstrated. The analysis of evolutionary success of avian, human and swine viruses generated through reassortment across different years using HopPER further revealed the reassortment history of the influenza viruses. Conclusions: Our study presents a novel method for the prediction of influenza reassortment. We hope this method could facilitate rapid reassortment detection and provide novel insights into the evolutionary patterns of influenza viruses. [ABSTRACT FROM AUTHOR]

• Singapore influenza A and B virus strains from 2012-2015 are mainly part of the global influenza virus circulation and evolution. • Several amino acid sites within influenza A/H3N2 are able to computationally discriminate strains from outpatients and hospitalized patients. • Compared with the HA of influenza B, the HA of influenza A/H1N1 may have evolved towards enhanced binding ability to both human and avian receptors. • Our findings enhance our understanding on the comparative evolution, mutations, receptor-binding preference of Singapore influenza strains. This study compared the genomes of influenza viruses that caused mild infections among outpatients and severe infections among hospitalized patients in Singapore, and characterized their molecular evolution and receptor-binding specificity. The complete genomes of influenza A/H1N1, A/H3N2 and B viruses that caused mild infections among outpatients and severe infections among inpatients in Singapore during 2012–2015 were sequenced and characterized. Using various bioinformatics approaches, we elucidated their evolutionary, mutational and structural patterns against the background of global and vaccine strains. The phylogenetic trees of the 8 gene segments revealed that the outpatient and inpatient strains overlapped with representative global and vaccine strains. We observed a cluster of inpatients with A/H3N2 strains that were closely related to vaccine strain A/Texas/50/2012(H3N2). Several protein sites could accurately discriminate between outpatient versus inpatient strains, with site 221 in neuraminidase (NA) achieving the highest accuracy for A/H3N2. Interestingly, amino acid residues of inpatient but not outpatient isolates at those sites generally matched the corresponding residues in vaccine strains, except at site 145 of hemagglutinin (HA). This would be especially relevant for future surveillance of A/H3N2 strains in relation to their antigenicity and virulence. Furthermore, we observed a trend in which the HA proteins of influenza A/H3N2 and A/H1N1 exhibited enhanced ability to bind both avian and human host cell receptors. In contrast, the binding ability to each receptor was relatively stable for the HA of influenza B. Overall, our findings extend our understanding of the molecular and structural evolution of influenza virus strains in Singapore within the global context of these dynamic viruses. [ABSTRACT FROM AUTHOR]

Motivation Promoters are short DNA consensus sequences that are localized proximal to the transcription start sites of genes, allowing transcription initiation of particular genes. However, the precise prediction of promoters remains a challenging task because individual promoters often differ from the consensus at one or more positions. Results In this study, we present a new multi-layer computational approach, called MULTiPly, for recognizing promoters and their specific types. MULTiPly took into account the sequences themselves, including both local information such as k-tuple nucleotide composition, dinucleotide-based auto covariance and global information of the entire samples based on bi-profile Bayes and k -nearest neighbour feature encodings. Specifically, the F-score feature selection method was applied to identify the best unique type of feature prediction results, in combination with other types of features that were subsequently added to further improve the prediction performance of MULTiPly. Benchmarking experiments on the benchmark dataset and comparisons with five state-of-the-art tools show that MULTiPly can achieve a better prediction performance on 5-fold cross-validation and jackknife tests. Moreover, the superiority of MULTiPly was also validated on a newly constructed independent test dataset. MULTiPly is expected to be used as a useful tool that will facilitate the discovery of both general and specific types of promoters in the post-genomic era. Availability and implementation The MULTiPly webserver and curated datasets are freely available at http://flagshipnt.erc.monash.edu/MULTiPly/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Computational prediction of drug–target interactions (DTIs) has become an essential task in the drug discovery process. It narrows down the search space for interactions by suggesting potential interaction candidates for validation via wet-lab experiments that are well known to be expensive and time-consuming. In this article, we aim to provide a comprehensive overview and empirical evaluation on the computational DTI prediction techniques, to act as a guide and reference for our fellow researchers. Specifically, we first describe the data used in such computational DTI prediction efforts. We then categorize and elaborate the state-of-the-art methods for predicting DTIs. Next, an empirical comparison is performed to demonstrate the prediction performance of some representative methods under different scenarios. We also present interesting findings from our evaluation study, discussing the advantages and disadvantages of each method. Finally, we highlight potential avenues for further enhancement of DTI prediction performance as well as related research directions. [ABSTRACT FROM AUTHOR]

H1N1 is the earliest emerging subtype of influenza A viruses with available genomic sequences, has caused several pandemics and seasonal epidemics, resulting in millions of deaths and enormous economic losses. Timely determination of new antigenic variants is crucial for the vaccine selection and flu prevention. In this study, we chronologically divided the H1N1 strains into several periods in terms of the epidemics and pandemics. Computational models have been constructed to predict antigenic variants based on epidemic and pandemic periods. By sequence analysis, we demonstrated the diverse mutation patterns of HA1 protein on different periods and that an individual model built upon each period can not represent the variations of H1N1 virus. A stacking model was established for the prediction of antigenic variants, combining all the variation patterns across periods, which would help assess a new influenza strain’s antigenicity. Three different feature extraction methods, i.e. residue-based, regional band-based and epitope region-based, were applied on the stacking model to verify its feasibility and robustness. The results showed the capability of determining antigenic variants prediction with accuracy as high as 0.908 which performed better than any of the single models. The prediction performance using the stacking model indicates clear distinctions of mutation patterns and antigenicity between epidemic and pandemic strains. It would also facilitate rapid determination of antigenic variants and influenza surveillance. [ABSTRACT FROM AUTHOR]

Avian influenza viruses from migratory birds have managed to cross host species barriers and infected various hosts like human and swine. Epidemics and pandemics might occur when influenza viruses are adapted to humans, causing deaths and enormous economic loss. Receptor-binding specificity of the virus is one of the key factors for the transmission of influenza viruses across species. The determination of host tropism and understanding of molecular properties would help identify the mechanism why zoonotic influenza viruses can cross species barrier and infect humans. In this study, we have constructed computational models for host tropism prediction on human-adapted subtypes of influenza HA proteins using random forest. The feature vectors of the prediction models were generated based on seven physicochemical properties of amino acids from influenza sequences of three major hosts. Feature aggregation and associative rules were further applied to select top 20 features and extract host-associated physicochemical signatures on the combined model of nonspecific subtypes. The prediction model achieved high performance (Accuracy = 0. 9 4 8 , Precision = 0. 9 5 4 , MCC = 0. 9 2 2). Support and confidence rates were calculated for the host class-association rules. The results indicated that secondary structure and normalized Van der Waals volume were identified as more important physicochemical signatures in determining the host tropism. [ABSTRACT FROM AUTHOR]

Experimental prediction of drug-target interactions is expensive, time-consuming and tedious. Fortunately, computational methods help narrow down the search space for interaction candidates to be further examined via wet-lab techniques. Nowadays, the number of attributes/features for drugs and targets, as well as the amount of their interactions, are increasing, making these computational methods inefficient or occasionally prohibitive. This motivates us to derive a reduced feature set for prediction. In addition, since ensemble learning techniques are widely used to improve the classification performance, it is also worthwhile to design an ensemble learning framework to enhance the performance for drug-target interaction prediction. In this paper, we propose a framework for drug-target interaction prediction leveraging both feature dimensionality reduction and ensemble learning. First, we conducted feature subspacing to inject diversity into the classifier ensemble. Second, we applied three different dimensionality reduction methods to the subspaced features. Third, we trained homogeneous base learners with the reduced features and then aggregated their scores to derive the final predictions. For base learners, we selected two classifiers, namely Decision Tree and Kernel Ridge Regression , resulting in two variants of ensemble models, EnsemDT and EnsemKRR , respectively. In our experiments, we utilized AUC (Area under ROC Curve) as an evaluation metric. We compared our proposed methods with various state-of-the-art methods under 5-fold cross validation. Experimental results showed EnsemKRR achieving the highest AUC (94.3%) for predicting drug-target interactions. In addition, dimensionality reduction helped improve the performance of EnsemDT . In conclusion, our proposed methods produced significant improvements for drug-target interaction prediction. [ABSTRACT FROM AUTHOR]

Summary Ligand binding pockets in proteins contain water molecules, which play important roles in modulating protein-ligand interactions. Available crystallographic data for the 5′ mRNA cap-binding pocket of the translation initiation factor protein eIF4E shows several structurally conserved waters, which also persist in molecular dynamics simulations. These waters engage an intricate hydrogen-bond network between the cap and protein. Two crystallographic waters in the cleft of the pocket show a high degree of conservation and bridge two residues, which are part of an evolutionarily conserved scaffold. This appears to be a preformed recognition module for the cap with the two structural waters facilitating an efficient interaction. This is also recapitulated in a new crystal structure of the apo protein. These findings open new windows for the design and screening of compounds targeting eIF4E. [ABSTRACT FROM AUTHOR]