CapsNet-LDA: predicting lncRNA-disease associations using attention mechanism and capsule network based on multi-view data.

Cumulative studies have shown that many long non-coding RNAs (lncRNAs) are crucial in a number of diseases. Predicting potential lncRNA-disease associations (LDAs) can facilitate disease prevention, diagnosis and treatment. Therefore, it is vital to develop practical computational methods for LDA prediction. In this study, we propose a novel predictor named capsule network (CapsNet)-LDA for LDA prediction. CapsNet-LDA first uses a stacked autoencoder for acquiring the informative low-dimensional representations of the lncRNA-disease pairs under multiple views, then the attention mechanism is leveraged to implement an adaptive allocation of importance weights to them, and they are subsequently processed using a CapsNet-based architecture for predicting LDAs. Different from the conventional convolutional neural networks (CNNs) that have some restrictions with the usage of scalar neurons and pooling operations. the CapsNets use vector neurons instead of scalar neurons that have better robustness for the complex combination of features and they use dynamic routing processes for updating parameters. CapsNet-LDA is superior to other five state-of-the-art models on four benchmark datasets, four perturbed datasets and an independent test set in the comparison experiments, demonstrating that CapsNet-LDA has excellent performance and robustness against perturbation, as well as good generalization ability. The ablation studies verify the effectiveness of some modules of CapsNet-LDA. Moreover, the ability of multi-view data to improve performance is proven. Case studies further indicate that CapsNet-LDA can accurately predict novel LDAs for specific diseases.

Dimensionality reduction and visualization of single-cell RNA-seq data with an improved deep variational autoencoder.

Single-cell RNA sequencing (scRNA-seq) is a revolutionary breakthrough that determines the precise gene expressions on individual cells and deciphers cell heterogeneity and subpopulations. However, scRNA-seq data are much noisier than traditional high-throughput RNA-seq data because of technical limitations, leading to many scRNA-seq data studies about dimensionality reduction and visualization remaining at the basic data-stacking stage. In this study, we propose an improved variational autoencoder model (termed DREAM) for dimensionality reduction and a visual analysis of scRNA-seq data. Here, DREAM combines the variational autoencoder and Gaussian mixture model for cell type identification, meanwhile explicitly solving 'dropout' events by introducing the zero-inflated layer to obtain the low-dimensional representation that describes the changes in the original scRNA-seq dataset. Benchmarking comparisons across nine scRNA-seq datasets show that DREAM outperforms four state-of-the-art methods on average. Moreover, we prove that DREAM can accurately capture the expression dynamics of human preimplantation embryonic development. DREAM is implemented in Python, freely available via the GitHub website, https://github.com/Crystal-JJ/DREAM.

Drug repositioning based on weighted local information augmented graph neural network.

Drug repositioning, the strategy of redirecting existing drugs to new therapeutic purposes, is pivotal in accelerating drug discovery. While many studies have engaged in modeling complex drug-disease associations, they often overlook the relevance between different node embeddings. Consequently, we propose a novel weighted local information augmented graph neural network model, termed DRAGNN, for drug repositioning. Specifically, DRAGNN firstly incorporates a graph attention mechanism to dynamically allocate attention coefficients to drug and disease heterogeneous nodes, enhancing the effectiveness of target node information collection. To prevent excessive embedding of information in a limited vector space, we omit self-node information aggregation, thereby emphasizing valuable heterogeneous and homogeneous information. Additionally, average pooling in neighbor information aggregation is introduced to enhance local information while maintaining simplicity. A multi-layer perceptron is then employed to generate the final association predictions. The model's effectiveness for drug repositioning is supported by a 10-times 10-fold cross-validation on three benchmark datasets. Further validation is provided through analysis of the predicted associations using multiple authoritative data sources, molecular docking experiments and drug-disease network analysis, laying a solid foundation for future drug discovery.

A weighted bilinear neural collaborative filtering approach for drug repositioning.

Drug repositioning is an efficient and promising strategy for traditional drug discovery and development. Many research efforts are focused on utilizing deep-learning approaches based on a heterogeneous network for modeling complex drug-disease associations. Similar to traditional latent factor models, which directly factorize drug-disease associations, they assume the neighbors are independent of each other in the network and thus tend to be ineffective to capture localized information. In this study, we propose a novel neighborhood and neighborhood interaction-based neural collaborative filtering approach (called DRWBNCF) to infer novel potential drugs for diseases. Specifically, we first construct three networks, including the known drug-disease association network, the drug-drug similarity and disease-disease similarity networks (using the nearest neighbors). To take the advantage of localized information in the three networks, we then design an integration component by proposing a new weighted bilinear graph convolution operation to integrate the information of the known drug-disease association, the drug's and disease's neighborhood and neighborhood interactions into a unified representation. Lastly, we introduce a prediction component, which utilizes the multi-layer perceptron optimized by the α-balanced focal loss function and graph regularization to model the complex drug-disease associations. Benchmarking comparisons on three datasets verified the effectiveness of DRWBNCF for drug repositioning. Importantly, the unknown drug-disease associations predicted by DRWBNCF were validated against clinical trials and three authoritative databases and we listed several new DRWBNCF-predicted potential drugs for breast cancer (e.g. valrubicin and teniposide) and small cell lung cancer (e.g. valrubicin and cytarabine).

Drug repositioning based on the heterogeneous information fusion graph convolutional network.

In silico reuse of old drugs (also known as drug repositioning) to treat common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked drugs, with potentially lower overall development costs and shorter development timelines. Therefore, there is a pressing need for computational drug repurposing methodologies to facilitate drug discovery. In this study, we propose a new method, called DRHGCN (Drug Repositioning based on the Heterogeneous information fusion Graph Convolutional Network), to discover potential drugs for a certain disease. To make full use of different topology information in different domains (i.e. drug-drug similarity, disease-disease similarity and drug-disease association networks), we first design inter- and intra-domain feature extraction modules by applying graph convolution operations to the networks to learn the embedding of drugs and diseases, instead of simply integrating the three networks into a heterogeneous network. Afterwards, we parallelly fuse the inter- and intra-domain embeddings to obtain the more representative embeddings of drug and disease. Lastly, we introduce a layer attention mechanism to combine embeddings from multiple graph convolution layers for further improving the prediction performance. We find that DRHGCN achieves high performance (the average AUROC is 0.934 and the average AUPR is 0.539) in four benchmark datasets, outperforming the current approaches. Importantly, we conducted molecular docking experiments on DRHGCN-predicted candidate drugs, providing several novel approved drugs for Alzheimer's disease (e.g. benzatropine) and Parkinson's disease (e.g. trihexyphenidyl and haloperidol).

Computational drug repositioning using similarity constrained weight regularization matrix factorization: A case of COVID-19.

Amid the COVID-19 crisis, we put sizeable efforts to collect a high number of experimentally validated drug-virus association entries from literature by text mining and built a human drug-virus association database. To the best of our knowledge, it is the largest publicly available drug-virus database so far. Next, we develop a novel weight regularization matrix factorization approach, termed WRMF, for in silico drug repurposing by integrating three networks: the known drug-virus association network, the drug-drug chemical structure similarity network, and the virus-virus genomic sequencing similarity network. Specifically, WRMF adds a weight to each training sample for reducing the influence of negative samples (i.e. the drug-virus association is unassociated). A comparison on the curated drug-virus database shows that WRMF performs better than a few state-of-the-art methods. In addition, we selected the other two different public datasets (i.e. Cdataset and HMDD V2.0) to assess WRMF's performance. The case study also demonstrated the accuracy and reliability of WRMF to infer potential drugs for the novel virus. In summary, we offer a useful tool including a novel drug-virus association database and a powerful method WRMF to repurpose potential drugs for new viruses.

CMF-Impute: an accurate imputation tool for single-cell RNA-seq data.

MOTIVATION: Single-cell RNA-sequencing (scRNA-seq) technology provides a powerful tool for investigating cell heterogeneity and cell subpopulations by allowing the quantification of gene expression at single-cell level. However, scRNA-seq data analysis remains challenging because of various technical noises such as dropout events (i.e. excessive zero counts in the expression matrix). RESULTS: By taking consideration of the association among cells and genes, we propose a novel collaborative matrix factorization-based method called CMF-Impute to impute the dropout entries of a given scRNA-seq expression matrix. We test CMF-Impute and compare it with the other five state-of-the-art methods on six popular real scRNA-seq datasets of various sizes and three simulated datasets. For simulated datasets, CMF-Impute outperforms other methods in imputing the closest dropouts to the original expression values as evaluated by both the sum of squared error and Pearson correlation coefficient. For real datasets, CMF-Impute achieves the most accurate cell classification results in spite of the choice of different clustering methods like SC3 or T-SNE followed by K-means as evaluated by both adjusted rand index and normalized mutual information. Finally, we demonstrate that CMF-Impute is powerful in reconstructing cell-to-cell and gene-to-gene correlation, and in inferring cell lineage trajectories. AVAILABILITY AND IMPLEMENTATION: CMF-Impute is written as a Matlab package which is available at https://github.com/xujunlin123/CMFImpute.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Drug repositioning based on similarity constrained probabilistic matrix factorization: COVID-19 as a case study.

The novel coronavirus disease 2019 (COVID-19) pandemic has caused a massive health crisis worldwide and upended the global economy. However, vaccines and traditional drug discovery for COVID-19 cost too much in terms of time, manpower, and money. Drug repurposing becomes one of the promising treatment strategies amid the COVID-19 crisis. At present, there are no publicly existing databases for experimentally supported human drug-virus interactions, and most existing drug repurposing methods require the rich information, which is not always available, especially for a new virus. In this study, on the one hand, we put size-able efforts to collect drug-virus interaction entries from literature and build the Human Drug Virus Database (HDVD). On the other hand, we propose a new approach, called SCPMF (similarity constrained probabilistic matrix factorization), to identify new drug-virus interactions for drug repurposing. SCPMF is implemented on an adjacency matrix of a heterogeneous drug-virus network, which integrates the known drug-virus interactions, drug chemical structures, and virus genomic sequences. SCPMF projects the drug-virus interactions matrix into two latent feature matrices for the drugs and viruses, which reconstruct the drug-virus interactions matrix when multiplied together, and then introduces the weighted similarity interaction matrix as constraints for drugs and viruses. Benchmarking comparisons on two different datasets demonstrate that SCPMF has reliable prediction performance and outperforms several recent approaches. Moreover, SCPMF-predicted drug candidates of COVID-19 also confirm the accuracy and reliability of SCPMF.

Single-cell RNA-seq clustering: datasets, models, and algorithms.

Single-cell RNA sequencing (scRNA-seq) technologies allow numerous opportunities for revealing novel and potentially unexpected biological discoveries. scRNA-seq clustering helps elucidate cell-to-cell heterogeneity and uncover cell subgroups and cell dynamics at the group level. Two important aspects of scRNA-seq data analysis were introduced and discussed in the present review: relevant datasets and analytical tools. In particular, we reviewed popular scRNA-seq datasets and discussed scRNA-seq clustering models including K-means clustering, hierarchical clustering, consensus clustering, and so on. Seven state-of-the-art scRNA clustering methods were compared on five public available datasets. Two primary evaluation metrics, the Adjusted Rand Index (ARI) and the Normalized Mutual Information (NMI), were used to evaluate these methods. Although unsupervised models can effectively cluster scRNA-seq data, these methods also have challenges. Some suggestions were provided for future research directions.

scDMAE: A Generative Denoising Model Adopted Mask Strategy for scRNA-Seq Data Recovery.

The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized gene expression studies at the single-cell level. However, the presence of technical noise and data sparsity in scRNA-seq often undermines the accuracy of subsequent analyses. Existing methods for denoising and imputing scRNA-seq data often rely on stringent assumptions about data distribution, limiting the effectiveness of data recovery. In this study, we propose the scDMAE model for denoising and recovery of scRNA-seq data. First, the model fuses gene expression features and topological features to discern the primary expression patterns of genes in cells. Then, an autoencoder with a masking strategy is used to model dropout events and separate potential noise in the data. Finally, the model incorporates the original raw data to recover the true biological expression value. By conducting experiments on various types of scRNA-Seq datasets, scDMAE demonstrates superior performance compared to other comparative methods based on six distinct evaluation metrics in downstream analysis. The scDMAE method can accurately cluster similar cell populations, identify differential genes and infer cell trajectories.

Gel-confined fabrication of fully bio-based filtration membrane for green capture and rapid detection of airborne microbes.

Air filtration has become a desirable route for collecting airborne microbes. However, the potential biotoxicity and sterilization of current air filtration membranes often lead to undesired inactivation of captured microbes, which greatly limits microbial non-traumatic transfer and recovery. Herein, we report a gel-confined phase separation strategy to rationally fabricate a fully bio-based filtration membrane (SGFM) using soluble soybean polysaccharide and gelatin. The versatile SGFM features fascinating honeycomb micro-nano architecture and hierarchical interconnected porous structures for microbial capture, and achieves a lower pressure drop, higher interception efficiency (99.3%), and superior microbial survivability than commercial gelatin filtration membranes. Particularly, the water-dissolvable SGFM can greatly simplify the elution and extraction process after bioaerosol sampling, thereby bringing about maximum sample transfer and vigorous recovery of collected microbes. Meanwhile, green capture coupled with ATP bioluminescence endows the SGFM with rapid and quantitative detection capability for airborne microbes. This work may pave the way for designing green protocols for the detection of bioaerosols.

MDAlmc: A Novel Low-rank Matrix Completion Model for MiRNADisease Association Prediction by Integrating Similarities among MiRNAs and Diseases.

INTRODUCTION: The importance of microRNAs (miRNAs) has been emphasized by an increasing number of studies, and it is well-known that miRNA dysregulation is associated with a variety of complex diseases. Revealing the associations between miRNAs and diseases are essential to disease prevention, diagnosis, and treatment. METHODS: However, traditional experimental methods in validating the roles of miRNAs in diseases could be very expensive, labor-intensive and time-consuming. Thus, there is a growing interest in predicting miRNA-disease associations by computational methods. Though many computational methods are in this category, their prediction accuracy needs further improvement for downstream experimental validation. In this study, we proposed a novel model to predict miRNA-disease associations by low-rank matrix completion (MDAlmc) integrating miRNA functional similarity, disease semantic similarity, and known miRNA-disease associations. In the 5-fold cross-validation, MDAlmc achieved an average AUROC of 0.8709 and AUPRC of 0.4172, better than those of previous models. RESULTS: Among the case studies of three important human diseases, the top 50 predicted miRNAs of 96% (breast tumors), 98% (lung tumors), and 90% (ovarian tumors) have been confirmed by previous literatures. And the unconfirmed miRNAs were also validated to be potential disease-associated miRNAs. CONCLUSION: MDAlmc is a valuable computational resource for miRNA-disease association prediction.

Graph embedding and Gaussian mixture variational autoencoder network for end-to-end analysis of single-cell RNA sequencing data.

Single-cell RNA sequencing (scRNA-seq) is a revolutionary technology to determine the precise gene expression of individual cells and identify cell heterogeneity and subpopulations. However, technical limitations of scRNA-seq lead to heterogeneous and sparse data. Here, we present autoCell, a deep-learning approach for scRNA-seq dropout imputation and feature extraction. autoCell is a variational autoencoding network that combines graph embedding and a probabilistic depth Gaussian mixture model to infer the distribution of high-dimensional, sparse scRNA-seq data. We validate autoCell on simulated datasets and biologically relevant scRNA-seq. We show that interpolation of autoCell improves the performance of existing tools in identifying cell developmental trajectories of human preimplantation embryos. We identify disease-associated astrocytes (DAAs) and reconstruct DAA-specific molecular networks and ligand-receptor interactions involved in cell-cell communications using Alzheimer's disease as a prototypical example. autoCell provides a toolbox for end-to-end analysis of scRNA-seq data, including visualization, clustering, imputation, and disease-specific gene network identification.

Enhancing Drug Repositioning through Local Interactive Learning with Bilinear Attention Networks.

Drug repositioning has emerged as a promising strategy for identifying new therapeutic applications for existing drugs. In this study, we present DRGBCN, a novel computational method that integrates heterogeneous information through a deep bilinear attention network to infer potential drugs for specific diseases. DRGBCN involves constructing a comprehensive drug-disease network by incorporating multiple similarity networks for drugs and diseases. Firstly, we introduce a layer attention mechanism to effectively learn the embeddings of graph convolutional layers from these networks. Subsequently, a bilinear attention network is constructed to capture pairwise local interactions between drugs and diseases. This combined approach enhances the accuracy and reliability of predictions. Finally, a multi-layer perceptron module is employed to evaluate potential drugs. Through extensive experiments on three publicly available datasets, DRGBCN demonstrates better performance over baseline methods in 10-fold cross-validation, achieving an average area under the receiver operating characteristic curve (AUROC) of 0.9399. Furthermore, case studies on bladder cancer and acute lymphoblastic leukemia confirm the practical application of DRGBCN in real-world drug repositioning scenarios. Importantly, our experimental results from the drug-disease network analysis reveal the successful clustering of similar drugs within the same community, providing valuable insights into drug-disease interactions. In conclusion, DRGBCN holds significant promise for uncovering new therapeutic applications of existing drugs, thereby contributing to the advancement of precision medicine.

Inferring Latent MicroRNA-Disease Associations on a Gene-Mediated Tripartite Heterogeneous Multiplexing Network.

MicroRNA (miRNA) is a class of non-coding single-stranded RNA molecules encoded by endogenous genes with a length of about 22 nucleotides. MiRNAs have been successfully identified as differentially expressed in various cancers. There is evidence that disorders of miRNAs are associated with a variety of complex diseases. Therefore, inferring potential miRNA-disease associations (MDAs) is very important for understanding the aetiology and pathogenesis of many diseases and is useful to disease diagnosis, prognosis and treatment. First, We creatively fused multiple similarity subnetworks from multi-sources for miRNAs, genes and diseases by multiplexing technology, respectively. Then, three multiplexed biological subnetworks are connected through the extended binary association to form a tripartite complete heterogeneous multiplexed network (Tri-HM). Finally, because the constructed Tri-HM network can retain subnetworks' original topology and biological functions and expands the binary association and dependence between the three biological entities, rich neighbourhood information is obtained iteratively from neighbours by a non-equilibrium random walk. Through cross-validation, our tri-HM-RWR model obtained an AUC value of 0.8657, and an AUPR value of 0.2139 in the global 5-fold cross-validation, which shows that our model can more fully speculate disease-related miRNAs.

MILNP: Plant lncRNA-miRNA Interaction Prediction Based on Improved Linear Neighborhood Similarity and Label Propagation.

Knowledge of the interactions between long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) is the basis of understanding various biological activities and designing new drugs. Previous computational methods for predicting lncRNA-miRNA interactions lacked for plants, and they suffer from various limitations that affect the prediction accuracy and their applicability. Research on plant lncRNA-miRNA interactions is still in its infancy. In this paper, we propose an accurate predictor, MILNP, for predicting plant lncRNA-miRNA interactions based on improved linear neighborhood similarity measurement and linear neighborhood propagation algorithm. Specifically, we propose a novel similarity measure based on linear neighborhood similarity from multiple similarity profiles of lncRNAs and miRNAs and derive more precise neighborhood ranges so as to escape the limits of the existing methods. We then simultaneously update the lncRNA-miRNA interactions predicted from both similarity matrices based on label propagation. We comprehensively evaluate MILNP on the latest plant lncRNA-miRNA interaction benchmark datasets. The results demonstrate the superior performance of MILNP than the most up-to-date methods. What's more, MILNP can be leveraged for isolated plant lncRNAs (or miRNAs). Case studies suggest that MILNP can identify novel plant lncRNA-miRNA interactions, which are confirmed by classical tools. The implementation is available on https://github.com/HerSwain/gra/tree/MILNP.

Graph neural network and multi-data heterogeneous networks for microbe-disease prediction.

The research on microbe association networks is greatly significant for understanding the pathogenic mechanism of microbes and promoting the application of microbes in precision medicine. In this paper, we studied the prediction of microbe-disease associations based on multi-data biological network and graph neural network algorithm. The HMDAD database provided a dataset that included 39 diseases, 292 microbes, and 450 known microbe-disease associations. We proposed a Microbe-Disease Heterogeneous Network according to the microbe similarity network, disease similarity network, and known microbe-disease associations. Furthermore, we integrated the network into the graph convolutional neural network algorithm and developed the GCNN4Micro-Dis model to predict microbe-disease associations. Finally, the performance of the GCNN4Micro-Dis model was evaluated via 5-fold cross-validation. We randomly divided all known microbe-disease association data into five groups. The results showed that the average AUC value and standard deviation were 0.8954 ± 0.0030. Our model had good predictive power and can help identify new microbe-disease associations. In addition, we compared GCNN4Micro-Dis with three advanced methods to predict microbe-disease associations, KATZHMDA, BiRWHMDA, and LRLSHMDA. The results showed that our method had better prediction performance than the other three methods. Furthermore, we selected breast cancer as a case study and found the top 12 microbes related to breast cancer from the intestinal flora of patients, which further verified the model's accuracy.

D3K: The Dissimilarity-Density-Dynamic Radius K-means Clustering Algorithm for scRNA-Seq Data.

A single-cell sequencing data set has always been a challenge for clustering because of its high dimension and multi-noise points. The traditional K-means algorithm is not suitable for this type of data. Therefore, this study proposes a Dissimilarity-Density-Dynamic Radius-K-means clustering algorithm. The algorithm adds the dynamic radius parameter to the calculation. It flexibly adjusts the active radius according to the data characteristics, which can eliminate the influence of noise points and optimize the clustering results. At the same time, the algorithm calculates the weight through the dissimilarity density of the data set, the average contrast of candidate clusters, and the dissimilarity of candidate clusters. It obtains a set of high-quality initial center points, which solves the randomness of the K-means algorithm in selecting the center points. Finally, compared with similar algorithms, this algorithm shows a better clustering effect on single-cell data. Each clustering index is higher than other single-cell clustering algorithms, which overcomes the shortcomings of the traditional K-means algorithm.

Efficacy and safety of PD-1/PD-L1 inhibitors plus chemotherapy for triple-negative breast cancer: a systematic review and meta-analysis.

OBJECTIVE: The results of PD-1/PD-L1 inhibitor combined with chemotherapy for TNBC are controversial. Therefore, a meta-analysis was conducted to evaluate the efficacy and safety after PD-1/PD-L1 inhibitors plus chemotherapy in TNBC patients. METHODS: We systematically searched seven databases and several mainly oncology conferences for prospective clinical trials of chemotherapy combined with immunotherapy to treat TNBC, and we included pathologic complete response (PCR), progression-free survival (PFS), overall survival (OS) and adverse effects as outcome indicators of the study. RESULTS: We analyzed data from six studies involving 4,187 patients. The efficacy analysis indicated that PD1/PD-L1 inhibitor combined with chemotherapy significantly increased PCR rates in neoadjuvant patients (OR: 1.60; 95% CI: 1.18-2.17; p=0.003). There was no correlation between increases in PCR rates and the expression of PD-L1, but the PCR rate was higher in PD-L1+ patients. Subgroup analysis suggested that the lymph node-positive (OR: 2.52; 95% CI: 1.69-3.77; p<0.001) and ECOG PS 0 (OR: 1.9; 95% CI: 1.42-2.53; p<0.001) subgroups benefited from the combination of PD-1/PD-L1 inhibitor plus chemotherapy. In TNBC receiving advanced rescue treatment, PFS was higher in the group receiving PD-1/PD-L1 inhibitor plus chemotherapy than in the group receiving chemotherapy alone (HR: 0.78; 95% CI: 0.70-0.86; p<0.001). Compared with chemotherapy alone, PD-1/PD-L1 inhibitors combined with chemotherapy did not increase the OS of patients (HR=0.88, 95% CI: 0.76~1.03, p=0.12). In addition, the toxicity analysis showed that more grade 3-4 adverse effects and severe adverse effects occurred in the PD-1/PD-L1 inhibitor combined with chemotherapy group. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with chemotherapy can improve the PCR and PFS rate of TNBC patients, but did not improve the OS, and had a higher risk of AEs.