WSHNN: A Weakly Supervised Hybrid Neural Network for the Identification of DNA-Protein Binding Sites.

INTRODUCTION: Transcription factors are vital biological components that control gene expression, and their primary biological function is to recognize DNA sequences. As related research continues, it was found that the specificity of DNA-protein binding has a significant role in gene expression, regulation, and especially gene therapy. Convolutional Neural Networks (CNNs) have become increasingly popular for predicting DNa-protein-specific binding sites, but their accuracy in prediction needs to be improved. METHODS: We proposed a framework for combining multi-Instance Learning (MIL) and a hybrid neural network named WSHNN. First, we utilized sliding windows to split the DNA sequences into multiple overlapping instances, each instance containing multiple bags. Then, the instances were encoded using a K-mer encoding. Afterward, the scores of all instances in the same bag were calculated separately by a hybrid neural network. RESULTS: Finally, a fully connected network was utilized as the final prediction for that bag. The framework could achieve the performances of 90.73% in Pre, 82.77% in Recall, 87.17% in Acc, 0.8657 in F1-score, and 0.7462 in MCC, respectively. In addition, we discussed the performance of K-mer encoding. Compared with other art-of-the-state efforts, the model has better performance with sequence information. CONCLUSION: From the experimental results, it can be concluded that Bi-directional Long-ShortTerm Memory (Bi-LSTM) can better capture the long-sequence relationships between DNA sequences (the code and data can be visited at https://github.com/baowz12345/Weak_ Super_Network).

Identify Diabetes-related Targets based on ForgeNet_GPC.

BACKGROUND: Research on potential therapeutic targets and new mechanisms of action can greatly improve the efficiency of new drug development. AIMS: Polygenic genetic diseases, such as diabetes, are caused by the interaction of multiple gene loci and environmental factors. OBJECTIVE: In this study, a disease target identification algorithm based on protein recognition is proposed. METHODS: In this method, the related and unrelated targets are collected from literature databases for treating diabetes. The transcribed proteins corresponding to each target are queried in order to construct a protein dataset. Six protein feature extraction algorithms (AAC, CKSAAGP, DDE, DPC, GAAP, and TPC) are utilized to obtain the feature vectors of each protein, which are merged into the full feature vectors. RESULTS: A novel classifier (forgeNet_GPC) based on forgeNet and Gaussian process classifier (GPC) is proposed to classify the proteins. CONCLUSION: In forgeNet_GPC, forgeNet is utilized to select the important features, and GPC is utilized to solve the classification problem. The experimental results reveal that forgeNet_GPC performs better than 22 classifiers in terms of ROC-AUC, PR-AUC, MCC, Youden Index, and Kappa.

Corrigendum: Alzheimer-compound identification based on data fusion and forgeNet_SVM.

[This corrects the article DOI: 10.3389/fnagi.2022.931729.].

Golgi_DF: Golgi proteins classification with deep forest.

Introduction: Golgi is one of the components of the inner membrane system in eukaryotic cells. Its main function is to send the proteins involved in the synthesis of endoplasmic reticulum to specific parts of cells or secrete them outside cells. It can be seen that Golgi is an important organelle for eukaryotic cells to synthesize proteins. Golgi disorders can cause various neurodegenerative and genetic diseases, and the accurate classification of Golgi proteins is helpful to develop corresponding therapeutic drugs. Methods: This paper proposed a novel Golgi proteins classification method, which is Golgi_DF with the deep forest algorithm. Firstly, the classified proteins method can be converted the vector features containing various information. Secondly, the synthetic minority oversampling technique (SMOTE) is utilized to deal with the classified samples. Next, the Light GBM method is utilized to feature reduction. Meanwhile, the features can be utilized in the penultimate dense layer. Therefore, the reconstructed features can be classified with the deep forest algorithm. Results: In Golgi_DF, this method can be utilized to select the important features and identify Golgi proteins. Experiments show that the well-performance than the other art-of-the state methods. Golgi_DF as a standalone tools, all its source codes publicly available at https://github.com/baowz12345/golgiDF. Discussion: Golgi_DF employed reconstructed feature to classify the Golgi proteins. Such method may achieve more available features among the UniRep features.

Oral_voting_transfer: classification of oral microorganisms' function proteins with voting transfer model.

Introduction: The oral microbial group typically represents the human body's highly complex microbial group ecosystem. Oral microorganisms take part in human diseases, including Oral cavity inflammation, mucosal disease, periodontal disease, tooth decay, and oral cancer. On the other hand, oral microbes can also cause endocrine disorders, digestive function, and nerve function disorders, such as diabetes, digestive system diseases, and Alzheimer's disease. It was noted that the proteins of oral microbes play significant roles in these serious diseases. Having a good knowledge of oral microbes can be helpful in analyzing the procession of related diseases. Moreover, the high-dimensional features and imbalanced data lead to the complexity of oral microbial issues, which can hardly be solved with traditional experimental methods. Methods: To deal with these challenges, we proposed a novel method, which is oral_voting_transfer, to deal with such classification issues in the field of oral microorganisms. Such a method employed three features to classify the five oral microorganisms, including Streptococcus mutans, Staphylococcus aureus, abiotrophy adjacent, bifidobacterial, and Capnocytophaga. Firstly, we utilized the highly effective model, which successfully classifies the organelle's proteins and transfers to deal with the oral microorganisms. And then, some classification methods can be treated as the local classifiers in this work. Finally, the results are voting from the transfer classifiers and the voting ones. Results and discussion: The proposed method achieved the well performances in the five oral microorganisms. The oral_voting_transfer is a standalone tool, and all its source codes are publicly available at https://github.com/baowz12345/voting_transfer.

Disease-related compound identification based on deeping learning method.

Acute lung injury (ALI) is a serious respiratory disease, which can lead to acute respiratory failure or death. It is closely related to the pathogenesis of New Coronavirus pneumonia (COVID-19). Many researches showed that traditional Chinese medicine (TCM) had a good effect on its intervention, and network pharmacology could play a very important role. In order to construct "disease-gene-target-drug" interaction network more accurately, deep learning algorithm is utilized in this paper. Two ALI-related target genes (REAL and SATA3) are considered, and the active and inactive compounds of the two corresponding target genes are collected as training data, respectively. Molecular descriptors and molecular fingerprints are utilized to characterize each compound. Forest graph embedded deep feed forward network (forgeNet) is proposed to train. The experimental results show that forgeNet performs better than support vector machines (SVM), random forest (RF), logical regression (LR), Naive Bayes (NB), XGBoost, LightGBM and gcForest. forgeNet could identify 19 compounds in Erhuang decoction (EhD) and Dexamethasone (DXMS) more accurately.

PGRNIG: novel parallel gene regulatory network identification algorithm based on GPU.

Molecular biology has revealed that complex life phenomena can be treated as the result of many gene interactions. Investigating these interactions and understanding the intrinsic mechanisms of biological systems using gene expression data have attracted a lot of attention. As a typical gene regulatory network (GRN) inference method, the S-system has been utilized to deal with small-scale network identification. However, it is extremely difficult to optimize it to infer medium-to-large networks. This paper proposes a novel parallel swarm intelligent algorithm, PGRNIG, to optimize the parameters of the S-system. We employed the clone selection strategy to improve the whale optimization algorithm (CWOA). To enhance the time efficiency of CWOA optimization, we utilized a parallel CWOA (PCWOA) based on the compute unified device architecture (CUDA) platform. Decomposition strategy and L1 regularization were utilized to reduce the search space and complexity of GRN inference. We applied the PGRNIG algorithm on three synthetic datasets and two real time-series expression datasets of the species of Escherichia coli and Saccharomyces cerevisiae. Experimental results show that PGRNIG could infer the gene regulatory network more accurately than other state-of-the-art methods with a convincing computational speed-up. Our findings show that CWOA and PCWOA have faster convergence performances than WOA.

Alzheimer-Compound Identification Based on Data Fusion and forgeNet_SVM.

Rapid screening and identification of potential candidate compounds are very important to understand the mechanism of drugs for the treatment of Alzheimer's disease (AD) and greatly promote the development of new drugs. In order to greatly improve the success rate of screening and reduce the cost and workload of research and development, this study proposes a novel Alzheimer-related compound identification algorithm namely forgeNet_SVM. First, Alzheimer related and unrelated compounds are collected using the data mining method from the literature databases. Three molecular descriptors (ECFP6, MACCS, and RDKit) are utilized to obtain the feature sets of compounds, which are fused into the all_feature set. The all_feature set is input to forgeNet_SVM, in which forgeNet is utilized to provide the importance of each feature and select the important features for feature extraction. The selected features are input to support vector machines (SVM) algorithm to identify the new compounds in Traditional Chinese Medicine (TCM) prescription. The experiment results show that the selected feature set performs better than the all_feature set and three single feature sets (ECFP6, MACCS, and RDKit). The performances of TPR, FPR, Precision, Specificity, F1, and AUC reveal that forgeNet_SVM could identify more accurately Alzheimer-related compounds than other classical classifiers.

Single_cell_GRN: gene regulatory network identification based on supervised learning method and Single-cell RNA-seq data.

Single-cell RNA-seq overcomes the shortcomings of conventional transcriptome sequencing technology and could provide a powerful tool for distinguishing the transcriptome characteristics of various cell types in biological tissues, and comprehensively revealing the heterogeneity of gene expression between cells. Many Intelligent Computing methods have been presented to infer gene regulatory network (GRN) with single-cell RNA-seq data. In this paper, we investigate the performances of seven classifiers including support vector machine (SVM), random forest (RF), Naive Bayesian (NB), GBDT, logical regression (LR), decision tree (DT) and K-Nearest Neighbor (KNN) for solving the binary classification problems of GRN inference with single-cell RNA-seq data (Single_cell_GRN). In SVM, three different kernel functions (linear, polynomial and radial basis function) are utilized, respectively. Three real single-cell RNA-seq datasets from mouse and human are utilized. The experiment results prove that in most cases supervised learning methods (SVM, RF, NB, GBDT, LR, DT and KNN) perform better than unsupervised learning method (GENIE3) in terms of AUC. SVM, RF and KNN have the better performances than other four classifiers. In SVM, linear and polynomial kernels are more fit to model single-cell RNA-seq data.

Gene Regulatory Identification Based on the Novel Hybrid Time-Delayed Method.

Gene regulatory network (GRN) inference with biology data is a difficult and serious issue in the field of system biology. In order to detect the direct associations of GRN more accurately, a novel two-step GRN inference technique based on the time-delayed correlation coefficient (TDCC) and time-delayed complex-valued S-system model (TDCVSS) is proposed. First, a TDCC algorithm is utilized to construct an initial network. Second, a TDCVSS model is utilized to prune the network topology in order to delete false-positive regulatory relationships for each target gene. The complex-valued restricted additive tree and complex-valued differential evolution are proposed to approximate the optimal TDCVSS model. Finally, the overall network could be inferred by integrating the regulations of all target genes. Two real gene expression datasets from E. coli and S. cerevisiae gene networks are utilized to evaluate the performances of our proposed two-step GRN inference algorithm. The results demonstrated that the proposed algorithm could infer GRN more correct than classical methods and time-delayed methods.

A survey on protein-DNA-binding sites in computational biology.

Transcription factors are important cellular components of the process of gene expression control. Transcription factor binding sites are locations where transcription factors specifically recognize DNA sequences, targeting gene-specific regions and recruiting transcription factors or chromatin regulators to fine-tune spatiotemporal gene regulation. As the common proteins, transcription factors play a meaningful role in life-related activities. In the face of the increase in the protein sequence, it is urgent how to predict the structure and function of the protein effectively. At present, protein-DNA-binding site prediction methods are based on traditional machine learning algorithms and deep learning algorithms. In the early stage, we usually used the development method based on traditional machine learning algorithm to predict protein-DNA-binding sites. In recent years, methods based on deep learning to predict protein-DNA-binding sites from sequence data have achieved remarkable success. Various statistical and machine learning methods used to predict the function of DNA-binding proteins have been proposed and continuously improved. Existing deep learning methods for predicting protein-DNA-binding sites can be roughly divided into three categories: convolutional neural network (CNN), recursive neural network (RNN) and hybrid neural network based on CNN-RNN. The purpose of this review is to provide an overview of the computational and experimental methods applied in the field of protein-DNA-binding site prediction today. This paper introduces the methods of traditional machine learning and deep learning in protein-DNA-binding site prediction from the aspects of data processing characteristics of existing learning frameworks and differences between basic learning model frameworks. Our existing methods are relatively simple compared with natural language processing, computational vision, computer graphics and other fields. Therefore, the summary of existing protein-DNA-binding site prediction methods will help researchers better understand this field.

Disease-Ligand Identification Based on Flexible Neural Tree.

In order to screen the disease-related compounds of a traditional Chinese medicine prescription in network pharmacology research accurately, a new virtual screening method based on flexible neural tree (FNT) model, hybrid evolutionary method and negative sample selection algorithm is proposed. A novel hybrid evolutionary algorithm based on the Grammar-guided genetic programming and salp swarm algorithm is proposed to infer the optimal FNT. According to hypertension, diabetes, and Corona Virus Disease 2019, disease-related compounds are collected from the up-to-date literatures. The unrelated compounds are chosen by negative sample selection algorithm. ECFP6, MACCS, Macrocycle, and RDKit are utilized to numerically characterize the chemical structure of each compound collected, respectively. The experiment results show that our proposed method performs better than classical classifiers [Support Vector Machine (SVM), random forest (RF), AdaBoost, decision tree (DT), Gradient Boosting Decision Tree (GBDT), KNN, logic regression (LR), and Naive Bayes (NB)], up-to-date classifier (gcForest), and deep learning method (forgeNet) in terms of AUC, ROC, TPR, FPR, Precision, Specificity, and F1. MACCS method is suitable for the maximum number of classifiers. All methods perform poorly with ECFP6 molecular descriptor.

Phage_UniR_LGBM: Phage Virion Proteins Classification with UniRep Features and LightGBM Model.

Phage, the most prevalent creature on the planet, serves a variety of critical roles. Phage's primary role is to facilitate gene-to-gene communication. The phage proteins can be defined as the virion proteins and the nonvirion ones. Nowadays, experimental identification is a difficult process that necessitates a significant amount of laboratory time and expense. Considering such situation, it is critical to design practical calculating techniques and develop well-performance tools. In this work, the Phage_UniR_LGBM has been proposed to classify the virion proteins. In detailed, such model utilizes the UniRep as the feature and the LightGBM algorithm as the classification model. And then, the training data train the model, and the testing data test the model with the cross-validation. The Phage_UniR_LGBM was compared with the several state-of-the-art features and classification algorithms. The performances of the Phage_UniR_LGBM are 88.51% in Sp,89.89% in Sn, 89.18% in Acc, 0.7873 in MCC, and 0.8925 in F1 score.

Active disease-related compound identification based on capsule network.

Pneumonia, especially corona virus disease 2019 (COVID-19), can lead to serious acute lung injury, acute respiratory distress syndrome, multiple organ failure and even death. Thus it is an urgent task for developing high-efficiency, low-toxicity and targeted drugs according to pathogenesis of coronavirus. In this paper, a novel disease-related compound identification model-based capsule network (CapsNet) is proposed. According to pneumonia-related keywords, the prescriptions and active components related to the pharmacological mechanism of disease are collected and extracted in order to construct training set. The features of each component are extracted as the input layer of capsule network. CapsNet is trained and utilized to identify the pneumonia-related compounds in Qingre Jiedu injection. The experiment results show that CapsNet can identify disease-related compounds more accurately than SVM, RF, gcForest and forgeNet.

Hypertension-Related Drug Activity Identification Based on Novel Ensemble Method.

Hypertension is a chronic disease and major risk factor for cardiovascular and cerebrovascular diseases that often leads to damage to target organs. The prevention and treatment of hypertension is crucially important for human health. In this paper, a novel ensemble method based on a flexible neural tree (FNT) is proposed to identify hypertension-related active compounds. In the ensemble method, the base classifiers are Multi-Grained Cascade Forest (gcForest), support vector machines (SVM), random forest (RF), AdaBoost, decision tree (DT), Gradient Boosting Decision Tree (GBDT), KNN, logical regression, and naïve Bayes (NB). The classification results of nine classifiers are utilized as the input vector of FNT, which is utilized as a nonlinear ensemble method to identify hypertension-related drug compounds. The experiment data are extracted from hypertension-unrelated and hypertension-related compounds collected from the up-to-date literature. The results reveal that our proposed ensemble method performs better than other single classifiers in terms of ROC curve, AUC, TPR, FRP, Precision, Specificity, and F1. Our proposed method is also compared with the averaged and voting ensemble methods. The results reveal that our method could identify hypertension-related compounds more accurately than two classical ensemble methods.

Reverse engineering gene regulatory network based on complex-valued ordinary differential equation model.

BACKGROUND: The growing researches of molecular biology reveal that complex life phenomena have the ability to demonstrating various types of interactions in the level of genomics. To establish the interactions between genes or proteins and understand the intrinsic mechanisms of biological systems have become an urgent need and study hotspot. RESULTS: In order to forecast gene expression data and identify more accurate gene regulatory network, complex-valued version of ordinary differential equation (CVODE) is proposed in this paper. In order to optimize CVODE model, a complex-valued hybrid evolutionary method based on Grammar-guided genetic programming and complex-valued firefly algorithm is presented. CONCLUSIONS: When tested on three real gene expression datasets from E. coli and Human Cell, the experiment results suggest that CVODE model could improve 20-50% prediction accuracy of gene expression data, which could also infer more true-positive regulatory relationships and less false-positive regulations than ordinary differential equation.

Efficient framework for predicting MiRNA-disease associations based on improved hybrid collaborative filtering.

BACKGROUND: Accumulating studies indicates that microRNAs (miRNAs) play vital roles in the process of development and progression of many human complex diseases. However, traditional biochemical experimental methods for identifying disease-related miRNAs cost large amount of time, manpower, material and financial resources. METHODS: In this study, we developed a framework named hybrid collaborative filtering for miRNA-disease association prediction (HCFMDA) by integrating heterogeneous data, e.g., miRNA functional similarity, disease semantic similarity, known miRNA-disease association networks, and Gaussian kernel similarity of miRNAs and diseases. To capture the intrinsic interaction patterns embedded in the sparse association matrix, we prioritized the predictive score by fusing three types of information: similar disease associations, similar miRNA associations, and similar disease-miRNA associations. Meanwhile, singular value decomposition was adopted to reduce the impact of noise and accelerate predictive speed. RESULTS: We then validated HCFMDA with leave-one-out cross-validation (LOOCV) and two types of case studies. In the LOOCV, we achieved 0.8379 of AUC (area under the curve). To evaluate the performance of HCFMDA on real diseases, we further implemented the first type of case validation over three important human diseases: Colon Neoplasms, Esophageal Neoplasms and Prostate Neoplasms. As a result, 44, 46 and 44 out of the top 50 predicted disease-related miRNAs were confirmed by experimental evidence. Moreover, the second type of case validation on Breast Neoplasms indicates that HCFMDA could also be applied to predict potential miRNAs towards those diseases without any known associated miRNA. CONCLUSIONS: The satisfactory prediction performance demonstrates that our model could serve as a reliable tool to guide the following research for identifying candidate miRNAs associated with human diseases.

A graph auto-encoder model for miRNA-disease associations prediction.

Emerging evidence indicates that the abnormal expression of miRNAs involves in the evolution and progression of various human complex diseases. Identifying disease-related miRNAs as new biomarkers can promote the development of disease pathology and clinical medicine. However, designing biological experiments to validate disease-related miRNAs is usually time-consuming and expensive. Therefore, it is urgent to design effective computational methods for predicting potential miRNA-disease associations. Inspired by the great progress of graph neural networks in link prediction, we propose a novel graph auto-encoder model, named GAEMDA, to identify the potential miRNA-disease associations in an end-to-end manner. More specifically, the GAEMDA model applies a graph neural networks-based encoder, which contains aggregator function and multi-layer perceptron for aggregating nodes' neighborhood information, to generate the low-dimensional embeddings of miRNA and disease nodes and realize the effective fusion of heterogeneous information. Then, the embeddings of miRNA and disease nodes are fed into a bilinear decoder to identify the potential links between miRNA and disease nodes. The experimental results indicate that GAEMDA achieves the average area under the curve of $93.56\pm 0.44\%$ under 5-fold cross-validation. Besides, we further carried out case studies on colon neoplasms, esophageal neoplasms and kidney neoplasms. As a result, 48 of the top 50 predicted miRNAs associated with these diseases are confirmed by the database of differentially expressed miRNAs in human cancers and microRNA deregulation in human disease database, respectively. The satisfactory prediction performance suggests that GAEMDA model could serve as a reliable tool to guide the following researches on the regulatory role of miRNAs. Besides, the source codes are available at https://github.com/chimianbuhetang/GAEMDA.

Weakly-Supervised Convolutional Neural Network Architecture for Predicting Protein-DNA Binding.

Although convolutional neural networks (CNN) have outperformed conventional methods in predicting the sequence specificities of protein-DNA binding in recent years, they do not take full advantage of the intrinsic weakly-supervised information of DNA sequences that a bound sequence may contain multiple TFBS(s). Here, we propose a weakly-supervised convolutional neural network architecture (WSCNN), combining multiple-instance learning (MIL) with CNN, to further boost the performance of predicting protein-DNA binding. WSCNN first divides each DNA sequence into multiple overlapping subsequences (instances) with a sliding window, and then separately models each instance using CNN, and finally fuses the predicted scores of all instances in the same bag using four fusion methods, including Max, Average, Linear Regression, and Top-Bottom Instances. The experimental results on in vivo and in vitro datasets illustrate the performance of the proposed approach. Moreover, models built on in vitro data using WSCNN can predict in vivo protein-DNA binding with good accuracy. In addition, we give a quantitative analysis of the importance of the reverse-complement mode in predicting in vivo protein-DNA binding, and explain why not directly use advanced pooling layers to combine MIL with CNN, through a series of experiments.