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Abstract Ligand-receptor interaction (LRI) prediction has great significance in biological and medical research and facilitates to infer and analyze cell-to-cell communication. However, wet experiments for new LRI discovery are costly and time-consuming. Here, we propose a computational model called THGB to uncover new LRIs. THGB first extracts feature information of Ligand-Receptor (LR) pairs using iFeature. Next, it adopts a tree boosting model to obtain representative LR features. Finally, it devises the histogram-based gradient boosting model to capture high-quality LRIs. To assess the THGB performance, we compared it with three new LRI prediction models (i.e., CellEnBoost, CellGiQ, and CellComNet) and one classical protein-protein interaction inference model PIPR. The results demonstrated that THGB achieved the best overall predictions in terms of six evaluation indictors (i.e., precision, recall, accuracy, F1-score, AUC, and AUPR). To measure the effect of LR feature selection on the prediction, THGB was compared with four feature selection methods (i.e., PCA, NMF, LLE, and TSVD). The results showed that the tree boosting model was more appropriate to select representative LR features and improve LRI prediction. We also conducted ablation study and found that THGB with feature selection outperformed THGB without feature selection. We hope that THGB is a useful tool to find new LRIs and further infer cell-to-cell communication.

Introduction: Long non-coding RNAs (lncRNAs) have been in the clinical use as potential prognostic biomarkers of various types of cancer. Identifying associations between lncRNAs and diseases helps capture the potential biomarkers and design efficient therapeutic options for diseases. Wet experiments for identifying these associations are costly and laborious.Methods: We developed LDA-SABC, a novel boosting-based framework for lncRNA–disease association (LDA) prediction. LDA-SABC extracts LDA features based on singular value decomposition (SVD) and classifies lncRNA–disease pairs (LDPs) by incorporating LightGBM and AdaBoost into the convolutional neural network.Results: The LDA-SABC performance was evaluated under five-fold cross validations (CVs) on lncRNAs, diseases, and LDPs. It obviously outperformed four other classical LDA inference methods (SDLDA, LDNFSGB, LDASR, and IPCAF) through precision, recall, accuracy, F1 score, AUC, and AUPR. Based on the accurate LDA prediction performance of LDA-SABC, we used it to find potential lncRNA biomarkers for lung cancer. The results elucidated that 7SK and HULC could have a relationship with non-small-cell lung cancer (NSCLC) and lung adenocarcinoma (LUAD), respectively.Conclusion: We hope that our proposed LDA-SABC method can help improve the LDA identification.

IntroductionDrug-target interaction prediction is one important step in drug research and development. Experimental methods are time consuming and laborious.MethodsIn this study, we developed a novel DTI prediction method called EnGDD by combining initial feature acquisition, dimensional reduction, and DTI classification based on Gradient boosting neural network, Deep neural network, and Deep Forest.ResultsEnGDD was compared with seven stat-of-the-art DTI prediction methods (BLM-NII, NRLMF, WNNGIP, NEDTP, DTi2Vec, RoFDT, and MolTrans) on the nuclear receptor, GPCR, ion channel, and enzyme datasets under cross validations on drugs, targets, and drug-target pairs, respectively. EnGDD computed the best recall, accuracy, F1-score, AUC, and AUPR under the majority of conditions, demonstrating its powerful DTI identification performance. EnGDD predicted that D00182 and hsa2099, D07871 and hsa1813, DB00599 and hsa2562, D00002 and hsa10935 have a higher interaction probabilities among unknown drug-target pairs and may be potential DTIs on the four datasets, respectively. In particular, D00002 (Nadide) was identified to interact with hsa10935 (Mitochondrial peroxiredoxin3) whose up-regulation might be used to treat neurodegenerative diseases. Finally, EnGDD was used to find possible drug targets for Parkinson's disease and Alzheimer's disease after confirming its DTI identification performance. The results show that D01277, D04641, and D08969 may be applied to the treatment of Parkinson's disease through targeting hsa1813 (dopamine receptor D2) and D02173, D02558, and D03822 may be the clues of treatment for patients with Alzheimer's disease through targeting hsa5743 (prostaglandinendoperoxide synthase 2). The above prediction results need further biomedical validation.DiscussionWe anticipate that our proposed EnGDD model can help discover potential therapeutic clues for various diseases including neurodegenerative diseases.

Abstract Background Long noncoding RNAs (lncRNAs) have dense linkages with various biological processes. Identifying interacting lncRNA-protein pairs contributes to understand the functions and mechanisms of lncRNAs. Wet experiments are costly and time-consuming. Most computational methods failed to observe the imbalanced characterize of lncRNA-protein interaction (LPI) data. More importantly, they were measured based on a unique dataset, which produced the prediction bias. Results In this study, we develop an Ensemble framework (LPI-EnEDT) with Extra tree and Decision Tree classifiers to implement imbalanced LPI data classification. First, five LPI datasets are arranged. Second, lncRNAs and proteins are separately characterized based on Pyfeat and BioTriangle and concatenated as a vector to represent each lncRNA-protein pair. Finally, an ensemble framework with Extra tree and decision tree classifiers is developed to classify unlabeled lncRNA-protein pairs. The comparative experiments demonstrate that LPI-EnEDT outperforms four classical LPI prediction methods (LPI-BLS, LPI-CatBoost, LPI-SKF, and PLIPCOM) under cross validations on lncRNAs, proteins, and LPIs. The average AUC values on the five datasets are 0.8480, 0,7078, and 0.9066 under the three cross validations, respectively. The average AUPRs are 0.8175, 0.7265, and 0.8882, respectively. Case analyses suggest that there are underlying associations between HOTTIP and Q9Y6M1, NRON and Q15717. Conclusions Fusing diverse biological features of lncRNAs and proteins and exploiting an ensemble learning model with Extra tree and decision tree classifiers, this work focus on imbalanced LPI data classification as well as interaction information inference for a new lncRNA (or protein).

Abstract Background Long noncoding RNAs (lncRNAs) have dense linkages with a plethora of important cellular activities. lncRNAs exert functions by linking with corresponding RNA-binding proteins. Since experimental techniques to detect lncRNA-protein interactions (LPIs) are laborious and time-consuming, a few computational methods have been reported for LPI prediction. However, computation-based LPI identification methods have the following limitations: (1) Most methods were evaluated on a single dataset, and researchers may thus fail to measure their generalization ability. (2) The majority of methods were validated under cross validation on lncRNA-protein pairs, did not investigate the performance under other cross validations, especially for cross validation on independent lncRNAs and independent proteins. (3) lncRNAs and proteins have abundant biological information, how to select informative features need to further investigate. Results Under a hybrid framework (LPI-HyADBS) integrating feature selection based on AdaBoost, and classification models including deep neural network (DNN), extreme gradient Boost (XGBoost), and SVM with a penalty Coefficient of misclassification (C-SVM), this work focuses on finding new LPIs. First, five datasets are arranged. Each dataset contains lncRNA sequences, protein sequences, and an LPI network. Second, biological features of lncRNAs and proteins are acquired based on Pyfeat. Third, the obtained features of lncRNAs and proteins are selected based on AdaBoost and concatenated to depict each LPI sample. Fourth, DNN, XGBoost, and C-SVM are used to classify lncRNA-protein pairs based on the concatenated features. Finally, a hybrid framework is developed to integrate the classification results from the above three classifiers. LPI-HyADBS is compared to six classical LPI prediction approaches (LPI-SKF, LPI-NRLMF, Capsule-LPI, LPI-CNNCP, LPLNP, and LPBNI) on five datasets under 5-fold cross validations on lncRNAs, proteins, lncRNA-protein pairs, and independent lncRNAs and independent proteins. The results show LPI-HyADBS has the best LPI prediction performance under four different cross validations. In particular, LPI-HyADBS obtains better classification ability than other six approaches under the constructed independent dataset. Case analyses suggest that there is relevance between ZNF667-AS1 and Q15717. Conclusions Integrating feature selection approach based on AdaBoost, three classification techniques including DNN, XGBoost, and C-SVM, this work develops a hybrid framework to identify new linkages between lncRNAs and proteins.

Abstract Background Long noncoding RNAs (lncRNAs) play important roles in various biological and pathological processes. Discovery of lncRNA–protein interactions (LPIs) contributes to understand the biological functions and mechanisms of lncRNAs. Although wet experiments find a few interactions between lncRNAs and proteins, experimental techniques are costly and time-consuming. Therefore, computational methods are increasingly exploited to uncover the possible associations. However, existing computational methods have several limitations. First, majority of them were measured based on one simple dataset, which may result in the prediction bias. Second, few of them are applied to identify relevant data for new lncRNAs (or proteins). Finally, they failed to utilize diverse biological information of lncRNAs and proteins. Results Under the feed-forward deep architecture based on gradient boosting decision trees (LPI-deepGBDT), this work focuses on classify unobserved LPIs. First, three human LPI datasets and two plant LPI datasets are arranged. Second, the biological features of lncRNAs and proteins are extracted by Pyfeat and BioProt, respectively. Thirdly, the features are dimensionally reduced and concatenated as a vector to represent an lncRNA–protein pair. Finally, a deep architecture composed of forward mappings and inverse mappings is developed to predict underlying linkages between lncRNAs and proteins. LPI-deepGBDT is compared with five classical LPI prediction models (LPI-BLS, LPI-CatBoost, PLIPCOM, LPI-SKF, and LPI-HNM) under three cross validations on lncRNAs, proteins, lncRNA–protein pairs, respectively. It obtains the best average AUC and AUPR values under the majority of situations, significantly outperforming other five LPI identification methods. That is, AUCs computed by LPI-deepGBDT are 0.8321, 0.6815, and 0.9073, respectively and AUPRs are 0.8095, 0.6771, and 0.8849, respectively. The results demonstrate the powerful classification ability of LPI-deepGBDT. Case study analyses show that there may be interactions between GAS5 and Q15717, RAB30-AS1 and O00425, and LINC-01572 and P35637. Conclusions Integrating ensemble learning and hierarchical distributed representations and building a multiple-layered deep architecture, this work improves LPI prediction performance as well as effectively probes interaction data for new lncRNAs/proteins.

Abstract Long noncoding RNAs (lncRNAs) regulate many biological processes by interacting with corresponding RNA-binding proteins. The identification of lncRNA–protein Interactions (LPIs) is significantly important to well characterize the biological functions and mechanisms of lncRNAs. Existing computational methods have been effectively applied to LPI prediction. However, the majority of them were evaluated only on one LPI dataset, thereby resulting in prediction bias. More importantly, part of models did not discover possible LPIs for new lncRNAs (or proteins). In addition, the prediction performance remains limited. To solve with the above problems, in this study, we develop a Deep Forest-based LPI prediction method (LPIDF). First, five LPI datasets are obtained and the corresponding sequence information of lncRNAs and proteins are collected. Second, features of lncRNAs and proteins are constructed based on four-nucleotide composition and BioSeq2vec with encoder-decoder structure, respectively. Finally, a deep forest model with cascade forest structure is developed to find new LPIs. We compare LPIDF with four classical association prediction models based on three fivefold cross validations on lncRNAs, proteins, and LPIs. LPIDF obtains better average AUCs of 0.9012, 0.6937 and 0.9457, and the best average AUPRs of 0.9022, 0.6860, and 0.9382, respectively, for the three CVs, significantly outperforming other methods. The results show that the lncRNA FTX may interact with the protein P35637 and needs further validation.

Abstract The outbreak of a novel febrile respiratory disease called COVID-19, caused by a newfound coronavirus SARS-CoV-2, has brought a worldwide attention. Prioritizing approved drugs is critical for quick clinical trials against COVID-19. In this study, we first manually curated three Virus-Drug Association (VDA) datasets. By incorporating VDAs with the similarity between drugs and that between viruses, we constructed a heterogeneous Virus-Drug network. A novel Random Walk with Restart method (VDA-RWR) was then developed to identify possible VDAs related to SARS-CoV-2. We compared VDA-RWR with three state-of-the-art association prediction models based on fivefold cross-validations (CVs) on viruses, drugs and virus-drug associations on three datasets. VDA-RWR obtained the best AUCs for the three fivefold CVs, significantly outperforming other methods. We found two small molecules coming together on the three datasets, that is, remdesivir and ribavirin. These two chemical agents have higher molecular binding energies of − 7.0 kcal/mol and − 6.59 kcal/mol with the domain bound structure of the human receptor angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein, respectively. Interestingly, for the first time, experimental results suggested that navitoclax could be potentially applied to stop SARS-CoV-2 and remains to further validation.

Coronavirus disease 2019 (COVID-19) is rapidly spreading. Researchers around the world are dedicated to finding the treatment clues for COVID-19. Drug repositioning, as a rapid and cost-effective way for finding therapeutic options from available FDA-approved drugs, has been applied to drug discovery for COVID-19. In this study, we develop a novel drug repositioning method (VDA-KLMF) to prioritize possible anti-SARS-CoV-2 drugs integrating virus sequences, drug chemical structures, known Virus-Drug Associations, and Logistic Matrix Factorization with Kernel diffusion. First, Gaussian kernels of viruses and drugs are built based on known VDAs and nearest neighbors. Second, sequence similarity kernel of viruses and chemical structure similarity kernel of drugs are constructed based on biological features and an identity matrix. Third, Gaussian kernel and similarity kernel are diffused. Forth, a logistic matrix factorization model with kernel diffusion is proposed to identify potential anti-SARS-CoV-2 drugs. Finally, molecular dockings between the inferred antiviral drugs and the junction of SARS-CoV-2 spike protein-ACE2 interface are implemented to investigate the binding abilities between them. VDA-KLMF is compared with two state-of-the-art VDA prediction models (VDA-KATZ and VDA-RWR) and three classical association prediction methods (NGRHMDA, LRLSHMDA, and NRLMF) based on 5-fold cross validations on viruses, drugs, and VDAs on three datasets. It obtains the best recalls, AUCs, and AUPRs, significantly outperforming other five methods under the three different cross validations. We observe that four chemical agents coming together on any two datasets, that is, remdesivir, ribavirin, nitazoxanide, and emetine, may be the clues of treatment for COVID-19. The docking results suggest that the key residues K353 and G496 may affect the binding energies and dynamics between the inferred anti-SARS-CoV-2 chemical agents and the junction of the spike protein-ACE2 interface. Integrating various biological data, Gaussian kernel, similarity kernel, and logistic matrix factorization with kernel diffusion, this work demonstrates that a few chemical agents may assist in drug discovery for COVID-19.

The novel coronavirus pneumonia COVID-19 infected by SARS-CoV-2 has attracted worldwide attention. It is urgent to find effective therapeutic strategies for stopping COVID-19. In this study, a Bounded Nuclear Norm Regularization (BNNR) method is developed to predict anti-SARS-CoV-2 drug candidates. First, three virus-drug association datasets are compiled. Second, a heterogeneous virus-drug network is constructed. Third, complete genomic sequences and Gaussian association profiles are integrated to compute virus similarities; chemical structures and Gaussian association profiles are integrated to calculate drug similarities. Fourth, a BNNR model based on kernel similarity (VDA-GBNNR) is proposed to predict possible anti-SARS-CoV-2 drugs. VDA-GBNNR is compared with four existing advanced methods under fivefold cross-validation. The results show that VDA-GBNNR computes better AUCs of 0.8965, 0.8562, and 0.8803 on the three datasets, respectively. There are 6 anti-SARS-CoV-2 drugs overlapping in any two datasets, that is, remdesivir, favipiravir, ribavirin, mycophenolic acid, niclosamide, and mizoribine. Molecular dockings are conducted for the 6 small molecules and the junction of SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2. In particular, niclosamide and mizoribine show higher binding energy of −8.06 and −7.06 kcal/mol with the junction, respectively. G496 and K353 may be potential key residues between anti-SARS-CoV-2 drugs and the interface junction. We hope that the predicted results can contribute to the treatment of COVID-19.

Growing evidence shows that microbes in human body and body surface play critical roles in the development of many human diseases. Predicting the underlying associations between diseases and microbes is essential for deeply understanding the pathogenesis of diseases. However, biological experiments to find the relationship between microbes and diseases is usually laborious and time-consuming, which presents the need for effective computational tools. In this study, we propose a computational model of node-information-based Link Propagation for Human Microbe-Disease Association prediction (LPHMDA) to prioritize disease-related microbes. LPHMDA and 3 popular methods including KATZHMDA, PBHMDA, and LRLSHMDA were implemented and compared on the Human Microbe-Disease Association Database (HMDAD) based on cross-validation. As a result, LPHMDA achieved an AUC of 0.9135 in leave-one-out cross-validation (LOOCV), outperforming those of the 3 compared methods. In addition, the performances of LPHDMA on the 3-fold CV, 5-fold CV and 10-fold CV were also better than those of the other 3 canonical methods, further demonstrating its superiority. Finally, we took colorectal carcinoma, asthma and obesity as case studies. Interestingly, 9, 9 and 8 of the top 10 novel microbes predicted by LPHMDA to be associated with the 3 diseases respectively could be confirmed by literatures, providing potential disease-associated microbes for further experimental validation. In summary, LPHMDA is an effective method for prioritizing disease-associated microbes.

Microbes with abnormal levels have important impacts on the formation and development of various complex diseases. Identifying possible Microbe-Disease Associations (MDAs) helps to understand the mechanisms of complex diseases. However, experimental methods for MDA identification are costly and time-consuming. In this study, a new computational model, RNMFMDA, was developed to find possible MDAs. RNMFMDA contains two main processes. First, Reliable Negative MDA samples were selected based on Positive-Unlabeled (PU) learning and random walk with restart on the heterogeneous microbe-disease network. Second, Logistic Matrix Factorization with Neighborhood Regularization (LMFNR) was developed to compute the association probabilities for all microbe-disease pairs. To evaluate the performance of the proposed RNMFMDA method, we compared RNMFMDA with five state-of-the-art MDA prediction methods based on five-fold cross-validations on microbes, diseases, and MDAs. As a result, RNMFMDA obtained the best AUCs of 0.6332, 0.8669, and 0.9081, respectively for the three five-fold cross validations, significantly outperforming other models. The promising prediction performance may be attributed to the following three features: highly quality negative MDA sample selection, LMFNR-based MDA prediction model, and various biological information integration. In addition, a few predicted microbe-disease pairs with high association scores are worthy of further experimental validation.

A new coronavirus called SARS-CoV-2 is rapidly spreading around the world. Over 16,558,289 infected cases with 656,093 deaths have been reported by July 29th, 2020, and it is urgent to identify effective antiviral treatment. In this study, potential antiviral drugs against SARS-CoV-2 were identified by drug repositioning through Virus-Drug Association (VDA) prediction. 96 VDAs between 11 types of viruses similar to SARS-CoV-2 and 78 small molecular drugs were extracted and a novel VDA identification model (VDA-RLSBN) was developed to find potential VDAs related to SARS-CoV-2. The model integrated the complete genome sequences of the viruses, the chemical structures of drugs, a regularized least squared classifier (RLS), a bipartite local model, and the neighbor association information. Compared with five state-of-the-art association prediction methods, VDA-RLSBN obtained the best AUC of 0.9085 and AUPR of 0.6630. Ribavirin was predicted to be the best small molecular drug, with a higher molecular binding energy of −6.39 kcal/mol with human angiotensin-converting enzyme 2 (ACE2), followed by remdesivir (−7.4 kcal/mol), mycophenolic acid (−5.35 kcal/mol), and chloroquine (−6.29 kcal/mol). Ribavirin, remdesivir, and chloroquine have been under clinical trials or supported by recent works. In addition, for the first time, our results suggested several antiviral drugs, such as FK506, with molecular binding energies of −11.06 and −10.1 kcal/mol with ACE2 and the spike protein, respectively, could be potentially used to prevent SARS-CoV-2 and remains to further validation. Drug repositioning through virus–drug association prediction can effectively find potential antiviral drugs against SARS-CoV-2.

Patients with carcinoma of unknown primary (CUP) account for 3–5% of all cancer cases. A large number of metastatic cancers require further diagnosis to determine their tissue of origin. However, diagnosis of CUP and identification of its primary site are challenging. Previous studies have suggested that molecular profiling of tissue-specific genes could be useful in inferring the primary tissue of a tumor. The purpose of this study was to evaluate the performance somatic mutations detected in a tumor to identify the cancer tissue of origin. We downloaded the somatic mutation datasets from the International Cancer Genome Consortium project. The random forest algorithm was used to extract features, and a classifier was established based on the logistic regression. Specifically, the somatic mutations of 300 genes were extracted, which are significantly enriched in functions, such as cell-to-cell adhesion. In addition, the prediction accuracy on tissue-of-origin inference for 3,374 cancer samples across 13 cancer types reached 81% in a 10-fold cross-validation. Our method could be useful in the identification of cancer tissue of origin, as well as the diagnosis and treatment of cancers.

Recently, many studies have demonstrated that microRNAs (miRNAs) are new small molecule drug targets. Identifying small molecule-miRNA associations (SMiRs) plays an important role in finding new clues for various human disease therapy. Wet experiments can discover credible SMiR associations; however, this is a costly and time-consuming process. Computational models have therefore been developed to uncover possible SMiR associations. In this study, we designed a new SMiR association prediction model, RWNS. RWNS integrates various biological information, credible negative sample selections, and random walk on a triple-layer heterogeneous network into a unified framework. It includes three procedures: similarity computation, negative sample selection, and SMiR association prediction based on random walk on the constructed small molecule-disease-miRNA association network. To evaluate the performance of RWNS, we used leave-one-out cross-validation (LOOCV) and 5-fold cross validation to compare RWNS with two state-of-the-art SMiR association methods, namely, TLHNSMMA and SMiR-NBI. Experimental results showed that RWNS obtained an AUC value of 0.9829 under LOOCV and 0.9916 under 5-fold cross validation on the SM2miR1 dataset, and it obtained an AUC value of 0.8938 under LOOCV and 0.9899 under 5-fold cross validation on the SM2miR2 dataset. More importantly, RWNS successfully captured 9, 17, and 37 SMiR associations validated by experiments among the predicted top 10, 20, and 50 SMiR candidates with the highest scores, respectively. We inferred that enoxacin and decitabine are associated with mir-21 and mir-155, respectively. Therefore, RWNS can be a powerful tool for SMiR association prediction.

Human blood contains cell-free DNA (cfDNA), with circulating tumor-derived DNAs (ctDNAs) widely used in cancer diagnosis and treatment. However, it is still difficult to efficiently and accurately identify and distinguish specific ctDNAs from normal cfDNA in cancer patient blood samples. In this study, ctDNA fragment length distribution analysis showed that ctDNA fragments are frequently shorter than the normal cfDNAs, which is consistent with previous findings. Interestingly, the ctDNA fragment length was found to be partially associated with the mutant allele frequency, with a low mutant allele frequency (< ~0.6%) associated with a longer ctDNA fragment length when compared to normal cfDNAs. The findings of this study contribute to improving the detection of low-frequency tumor mutations.

Identifying lncRNA–protein interactions (LPIs) is vital to understanding various key biological processes. Wet experiments found a few LPIs, but experimental methods are costly and time-consuming. Therefore, computational methods are increasingly exploited to capture LPI candidates. We introduced relevant data repositories, focused on two types of LPI prediction models: network-based methods and machine learning-based methods. Machine learning-based methods contain matrix factorization-based techniques and ensemble learning-based techniques. To detect the performance of computational methods, we compared parts of LPI prediction models on Leave-One-Out cross-validation (LOOCV) and fivefold cross-validation. The results show that SFPEL-LPI obtained the best performance of AUC. Although computational models have efficiently unraveled some LPI candidates, there are many limitations involved. We discussed future directions to further boost LPI predictive performance.

There are countless microbes in the human body, and they play various roles in the physiological process. There is growing evidence that microbes are closely associated with human diseases. Researching disease-related microbes helps us understand the mechanisms of diseases and provides new strategies for diseases diagnosis and treatment. Many computational models have been proposed to predict disease-related microbes, in this paper, we developed a model of Adaptive Boosting for Human Microbe-Disease Association prediction (ABHMDA) to reveal the associations between diseases and microbes by calculating the relation probability of disease-microbe pair using a strong classifier. Our model could be applied to new diseases without any known related microbes. In order to assess the prediction power of the model, global and local leave-one-out cross validation (LOOCV) were implemented. As shown in the results, the global and local LOOCV values reached 0.8869 and 0.7910, respectively. What’s more, 10, 10, and 8 out of the top 10 microbes predicted to be most likely to be associated with Asthma, Colorectal carcinoma and Type 1 diabetes were all verified by relevant literatures or database HMDAD, respectively. The above results verify the superior predictive performance of ABHMDA.

Background: Identifying possible drug-target interactions (DTIs) has become an important task in drug research and development. Although high-throughput screening is becoming available, experimental methods narrow down the validation space because of extremely high cost, low success rate, and time consumption. Therefore, various computational models have been exploited to infer DTI candidates. Methods: We introduced relevant databases and packages, mainly provided a comprehensive review of computational models for DTI identification, including network-based algorithms and machine learning-based methods. Specially, machine learning-based methods mainly include bipartite local model, matrix factorization, regularized least squares, and deep learning. Results: Although computational methods have obtained significant improvement in the process of DTI prediction, these models have their limitations. We discussed potential avenues for boosting DTI prediction accuracy as well as further directions.

The present study aimed to explore the immune regulatory function of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein and related mechanisms. In a series of protein activity experiments, SARS-CoV-2 N protein promoted proliferation of three immune cell lines: mouse Raw264.7, human Jurkat and human Raji in a dose-dependent manner. A total of 10 µg/ml N protein could significantly change cell cycle progression of the aforementioned three immune cell lines and could promote quick entry of Raw264.7 cells into G2/M phase from S phase to achieve rapid growth. Additionally, the N protein could also stimulate Raw264.7 cells to secrete a number of proinflammatory factors such as TNF-α, IL-6 and IL-10. RNA sequencing analysis indicated that the N protein changed the expression of certain genes involved in immune-related functions and four important signaling pathways, including JAK-STAT, TNF, NF-κB and MAPK signaling pathways, which suggested that the N protein may not only regulate the expression of genes involved in the process of resisting viral infection in macrophages of the immune system, but also change cellular signal processing. [ABSTRACT FROM AUTHOR]