MNMST: topology of cell networks leverages identification of spatial domains from spatial transcriptomics data.

Advances in spatial transcriptomics provide an unprecedented opportunity to reveal the structure and function of biology systems. However, current algorithms fail to address the heterogeneity and interpretability of spatial transcriptomics data. Here, we present a multi-layer network model for identifying spatial domains in spatial transcriptomics data with joint learning. We demonstrate that spatial domains can be precisely characterized and discriminated by the topological structure of cell networks, facilitating identification and interpretability of spatial domains, which outperforms state-of-the-art baselines. Furthermore, we prove that network model offers an effective and efficient strategy for integrative analysis of spatial transcriptomics data from various platforms.

Learning Consistency and Specificity of Cells From Single-Cell Multi-Omic Data.

Advancements in single-cell technologies concomitantly develop the epigenomic and transcriptomic profiles at the cell levels, providing opportunities to explore the potential biological mechanisms. Even though significant efforts have been dedicated to them, it remains challenging for the integration analysis of multi-omic data of single-cell because of the heterogeneity, complicated coupling and interpretability of data. To handle these issues, we propose a novel self-representation Learning-based Multi-omics data Integrative Clustering algorithm (sLMIC) for the integration of single-cell epigenomic profiles (DNA methylation or scATAC-seq) and transcriptomic (scRNA-seq), which the consistent and specific features of cells are explicitly extracted facilitating the cell clustering. Specifically, sLMIC constructs a graph for each type of single-cell data, thereby transforming omics data into multi-layer networks, which effectively removes heterogeneity of omic data. Then, sLMIC employs the low-rank and exclusivity constraints to separate the self-representation of cells into two parts, i.e., the shared and specific features, which explicitly characterize the consistency and diversity of omic data, providing an effective strategy to model the structure of cell types. Feature extraction and cell clustering are jointly formulated as an overall objective function, where latent features of data are obtained under the guidance of cell clustering. The extensive experimental results on 13 multi-omics datasets of single-cell from diverse organisms and tissues indicate that sLMIC observably exceeds the advanced algorithms regarding various measurements.

Contrastive and adversarial regularized multi-level representation learning for incomplete multi-view clustering.

Incomplete multi-view clustering is a significant task in machine learning, given that complex systems in nature and society cannot be fully observed; it provides an opportunity to exploit the structure and functions of underlying systems. Current algorithms are criticized for failing either to balance data restoration and clustering or to capture the consistency of the representation of various views. To address these problems, a novel Multi-level Representation Learning Contrastive and Adversarial Learning (aka MRL_CAL) for incomplete multi-view clustering is proposed, in which data restoration, consistent representation, and clustering are jointly learned by exploiting features in various subspaces. Specifically, MRL_CAL employs v auto-encoder to obtain a low-level specific-view representation of instances, which restores data by estimating the distribution of the original incomplete data with adversarial learning. Then, MRL_CAL extracts a high-level representation of instances, in which the consistency of various views and labels of clusters is incorporated with contrastive learning. In this case, MRL_CAL simultaneously learns multi-level features of instances in various subspaces, which not only overcomes the confliction of representations but also improves the quality of features. Finally, MRL_CAL transforms incomplete multi-view clustering into an overall objective, where features are learned under the guidance of clustering. Extensive experimental results indicate that MRL_CAL outperforms state-of-the-art algorithms in terms of various measurements, implying that the proposed method is promising for incomplete multi-view clustering.

Learning deep representation and discriminative features for clustering of multi-layer networks.

The multi-layer network consists of the interactions between different layers, where each layer of the network is depicted as a graph, providing a comprehensive way to model the underlying complex systems. The layer-specific modules of multi-layer networks are critical to understanding the structure and function of the system. However, existing methods fail to characterize and balance the connectivity and specificity of layer-specific modules in networks because of the complicated inter- and intra-coupling of various layers. To address the above issues, a joint learning graph clustering algorithm (DRDF) for detecting layer-specific modules in multi-layer networks is proposed, which simultaneously learns the deep representation and discriminative features. Specifically, DRDF learns the deep representation with deep nonnegative matrix factorization, where the high-order topology of the multi-layer network is gradually and precisely characterized. Moreover, it addresses the specificity of modules with discriminative feature learning, where the intra-class compactness and inter-class separation of pseudo-labels of clusters are explored as self-supervised information, thereby providing a more accurate method to explicitly model the specificity of the multi-layer network. Finally, DRDF balances the connectivity and specificity of layer-specific modules with joint learning, where the overall objective of the graph clustering algorithm and optimization rules are derived. The experiments on ten multi-layer networks showed that DRDF not only outperforms eight baselines on graph clustering but also enhances the robustness of algorithms.

Multi-View Clustering With Graph Learning for scRNA-Seq Data.

Advances in single-cell biotechnologies have generated the single-cell RNA sequencing (scRNA-seq) of gene expression profiles at cell levels, providing an opportunity to study cellular distribution. Although significant efforts developed in their analysis, many problems remain in studying cell types distribution because of the heterogeneity, high dimensionality, and noise of scRNA-seq. In this study, a multi-view clustering with graph learning algorithm (MCGL) for scRNA-seq data is proposed, which consists of multi-view learning, graph learning, and cell type clustering. In order to avoid a single feature space of scRNA-seq being inadequate to comprehensively characterize the functions of cells, MCGL constructs the multiple feature spaces and utilizes multi-view learning to comprehensively characterize scRNA-seq data from different perspectives. MCGL adaptively learns the similarity graphs of cells that overcome the dependence on fixed similarity, transforming scRNA-seq analysis into the analysis of multi-view clustering. MCGL decomposes the networks of cells into view-specific and common networks in multi-view learning, which better characterizes the topological relationship of cells. MCGL simultaneously utilizes multiple types of cell-cell networks and fully exploits the connection relationship between cells through the complementarity between networks to improve clustering performance. The graph learning, graph factorization, and cell-type clustering processes are accomplished simultaneously under one optimization framework. The performance of the MCGL algorithm is validated with ten scRNA-seq datasets from different scales, and experimental results imply that the proposed algorithm significantly outperforms fourteen state-of-the-art scRNA-seq algorithms.

Multi-View Clustering for Integration of Gene Expression and Methylation Data With Tensor Decomposition and Self-Representation Learning.

The accumulated DNA methylation and gene expression provide a great opportunity to exploit the epigenetic patterns of genes, which is the foundation for revealing the underlying mechanisms of biological systems. Current integrative algorithms are criticized for undesirable performance because they fail to address the heterogeneity of expression and methylation data, and the intrinsic relations among them. To solve this issue, a novel multi-view clustering with self-representation learning and low-rank tensor constraint (MCSL-LTC) is proposed for the integration of gene expression and DNA methylation data, which are treated as complementary views. Specifically, MCSL-LTC first learns the low-dimensional features for each view with the linear projection, and then these features are fused in a unified tensor space with low-rank constraints. In this case, the complementary information of various views is precisely captured, where the heterogeneity of omic data is avoided, thereby enhancing the consistency of different views. Finally, MCSL-LTC obtains a consensus cluster of genes reflecting the structure and features of various views. Experimental results demonstrate that the proposed approach outperforms state-of-the-art baselines in terms of accuracy on both the social and cancer data, which provides an effective and efficient method for the integration of heterogeneous genomic data.

Joint Learning of Feature Extraction and Clustering for Large-Scale Temporal Networks.

Temporal networks are ubiquitous in nature and society, and tracking the dynamics of networks is fundamental for investigating the mechanisms of systems. Dynamic communities in temporal networks simultaneously reflect the topology of the current snapshot (clustering accuracy) and historical ones (clustering drift). Current algorithms are criticized for their inability to characterize the dynamics of networks at the vertex level, independence of feature extraction and clustering, and high time complexity. In this study, we solve these problems by proposing a novel joint learning model for dynamic community detection in temporal networks (also known as jLMDC) via joining feature extraction and clustering. This model is formulated as a constrained optimization problem. Vertices are classified into dynamic and static groups by exploring the topological structure of temporal networks to fully exploit their dynamics at each time step. Then, jLMDC updates the features of dynamic vertices by preserving features of static ones during optimization. The advantage of jLMDC is that features are extracted under the guidance of clustering, promoting performance, and saving the running time of the algorithm. Finally, we extend jLMDC to detect the overlapping dynamic community in temporal networks. The experimental results on 11 temporal networks demonstrate that jLMDC improves accuracy up to 8.23% and saves 24.89% of running time on average compared to state-of-the-art methods.

Clustering of Multilayer Networks Using Joint Learning Algorithm With Orthogonality and Specificity of Features.

Complex systems in nature and society consist of various types of interactions, where each type of interaction belongs to a layer, resulting in the so-called multilayer networks. Identifying specific modules for each layer is of great significance for revealing the structure-function relations in multilayer networks. However, the available approaches are criticized undesirable because they fail to explicitly the specificity of modules, and balance the specificity and connectivity of modules. To overcome these drawbacks, we propose an accurate and flexible algorithm by joint learning matrix factorization and sparse representation (jMFSR) for specific modules in multilayer networks, where matrix factorization extracts features of vertices and sparse representation discovers specific modules. To exploit the discriminative latent features of vertices in multilayer networks, jMFSR incorporates linear discriminant analysis (LDA) into non-negative matrix factorization (NMF) to learn features of vertices that distinguish the categories. To explicitly measure the specificity of features, jMFSR decomposes features of vertices into common and specific parts, thereby enhancing the quality of features. Then, jMFSR jointly learns feature extraction, common-specific feature factorization, and clustering of multilayer networks. The experiments on 11 datasets indicate that jMFSR significantly outperforms state-of-the-art baselines in terms of various measurements.

Network-Based Structural Learning Nonnegative Matrix Factorization Algorithm for Clustering of scRNA-Seq Data.

Single-cell RNA sequencing (scRNA-seq) measures expression profiles at the single-cell level, which sheds light on revealing the heterogeneity and functional diversity among cell populations. The vast majority of current algorithms identify cell types by directly clustering transcriptional profiles, which ignore indirect relations among cells, resulting in an undesirable performance on cell type discovery and trajectory inference. Therefore, there is a critical need for inferring cell types and trajectories by exploiting the interactions among cells. In this study, we propose a network-based structural learning nonnegative matrix factorization algorithm (aka SLNMF) for the identification of cell types in scRNA-seq, which is transformed into a constrained optimization problem. SLNMF first constructs the similarity network for cells and then extracts latent features of the cells by exploiting the topological structure of the cell-cell network. To improve the clustering performance, the structural constraint is imposed on the model to learn the latent features of cells by preserving the structural information of the networks, thereby significantly improving the performance of algorithms. Finally, we track the trajectory of cells by exploring the relationships among cell types. Fourteen scRNA-seq datasets are adopted to validate the performance of algorithms with the number of single cells varying from 49 to 26,484. The experimental results demonstrate that SLNMF significantly outperforms fifteen state-of-the-art methods with 15.32% improvement in terms of accuracy, and it accurately identifies the trajectories of cells. The proposed model and methods provide an effective strategy to analyze scRNA-seq data. (The software is coded using matlab, and is freely available for academic https://github.com/xkmaxidian/SLNMF).

Layer-Specific Modules Detection in Cancer Multi-Layer Networks.

Multi-layer networks provide an effective and efficient tool to model and characterize complex systems with multiple types of interactions, which differ greatly from the traditional single-layer networks. Graph clustering in multi-layer networks is highly non-trivial since it is difficult to balance the connectivity of clusters and the connection of various layers. The current algorithms for the layer-specific clusters are criticized for the low accuracy and sensitivity to the perturbation of networks. To overcome these issues, a novel algorithm for the layer-specific module in multi-layer networks based on nonnegative matrix factorization (LSNMF) is proposed by explicitly exploring the specific features of vertices. LSNMF first extract features of vertices in multi-layer networks by using nonnegative matrix factorization (NMF) and then decompose features of vertices into the common and specific components. The orthogonality constraint is imposed on the specific components to ensure the specificity of features of vertices, which provides a better strategy to characterize and model the structure of layer-specific modules. The extensive experiments demonstrate that the proposed algorithm dramatically outperforms state-of-the-art baselines in terms of various measurements. Furthermore, LSNMF efficiently extracts stage-specific modules, which are more likely to enrich the known functions, and also associate with the survival time of patients.

Multifunctionalized alginate/polydopamine cryogel for hemostasis, antibacteria and promotion of wound healing.

Hemostasis and anti-infection are crucial for emergency treatment of severe trauma. Developing functional biomaterial with efficient hemostasis, antibacterial activity and wound healing is of great social significance and clinical value to fast stop bleeding and save lives, but it is still challenged. Here we designed a series of multifunctionalized SA/PDA cryogels by using two-step cross-linking of dopamine and sodium alginate. The resulting interpenetrating network structure had good swelling ratio, excellent mechanical and shape memory properties. Compared with cotton gauze and gelatin sponge, the cryogels exhibited excellent activation of coagulation cascade, more blood cells and platelet adhesion. Due to the action of polydopamine, the cryogel also showed good antioxidant activity and photothermal antibacterial ability assisted by near-infrared radiation, as well as better wound healing performance than gelatin sponge and Tegaderm™ film. Moreover, in the tests of mouse tail docking model, rat femoral artery hemostasis model and non-compressible rabbit liver defect model, the treatment by SA/PDA cryogels presented less blood loss and shorter hemostasis time than cotton gauze and gelatin sponge. Therefore, SA/PDA cryogels with simple preparation process, low cost, and good biocompatibility would be applied in the variety of great clinical applications in bleeding control, anti-infection and wound healing, etc.

Learning discriminative and structural samples for rare cell types with deep generative model.

Cell types (subpopulations) serve as bio-markers for the diagnosis and therapy of complex diseases, and single-cell RNA-sequencing (scRNA-seq) measures expression of genes at cell level, paving the way for the identification of cell types. Although great efforts have been devoted to this issue, it remains challenging to identify rare cell types in scRNA-seq data because of the few-shot problem, lack of interpretability and separation of generating samples and clustering of cells. To attack these issues, a novel deep generative model for leveraging the small samples of cells (aka scLDS2) is proposed by precisely estimating the distribution of different cells, which discriminate the rare and non-rare cell types with adversarial learning. Specifically, to enhance interpretability of samples, scLDS2 generates the sparse faked samples of cells with $\ell _1$-norm, where the relations among cells are learned, facilitating the identification of cell types. Furthermore, scLDS2 directly obtains cell types from the generated samples by learning the block structure such that cells belonging to the same types are similar to each other with the nuclear-norm. scLDS2 joins the generation of samples, classification of the generated and truth samples for cells and feature extraction into a unified generative framework, which transforms the rare cell types detection problem into a classification problem, paving the way for the identification of cell types with joint learning. The experimental results on 20 datasets demonstrate that scLDS2 significantly outperforms 17 state-of-the-art methods in terms of various measurements with 25.12% improvement in adjusted rand index on average, providing an effective strategy for scRNA-seq data with rare cell types. (The software is coded using python, and is freely available for academic https://github.com/xkmaxidian/scLDS2).

YTHDF1 alleviates sepsis by upregulating WWP1 to induce NLRP3 ubiquitination and inhibit caspase-1-dependent pyroptosis.

Pyroptosis is inflammation-associated caspase-1-dependent programmed cell death, which confers a crucial role in sepsis. The present study intends to investigate the regulatory network and function of the microarray-predicted YTHDF1 in caspase-1-dependent pyroptosis of sepsis. Peripheral blood of patients with sepsis was collected to determine WWP1 and YTHDF1 expression. An in vitro sepsis cell model was induced in RAW264.7 cells using lipopolysaccharide (LPS) and ATP and an in vivo septic mouse model by cecal ligation and perforation (CLP). After gain- and loss-of-function assays in vitro and in vivo, TNF-α and IL-1ß levels and the cleavage of gasdermin-D (GSDMD) were detected by ELISA and Western blot assay, followed by determination of lactate dehydrogenase (LDH) activity. Immunoprecipitation and meRIP assay were performed to detect the ubiquitination of NLRP3 and the m6A modification of WWP1 mRNA. The binding of WWP1 to YTHDF1 was explored using RIP-RT-qPCR and dual luciferase gene reporter assay. It was noted that WWP1 and YTHDF1 were downregulated in clinical sepsis samples, LPS + ATP-treated RAW264.7 cells, and CLP-induced mice. The ubiquitination of NLRP3 was promoted after overexpression of WWP1. WWP1 translation could be promoted by YTHDF1. Then, WWP1 or YTHDF1 overexpression diminished LDH activity, NLRP3 inflammasomes and caspase-1-mediated cleavage of GSDMD in LPS + ATP-induced RAW264.7 cells. Overexpressed YTHDF1 restrained inflammatory response in CLP-induced mice. Collectively, the alleviatory effect of m6A reader protein YTHDF1 may be achieved through promotion of NLRP3 ubiquitination and inhibition of caspase-1-dependent pyroptosis by upregulating WWP1.

Learning deep features and topological structure of cells for clustering of scRNA-sequencing data.

Single-cell RNA sequencing (scRNA-seq) measures gene transcriptome at the cell level, paving the way for the identification of cell subpopulations. Although deep learning has been successfully applied to scRNA-seq data, these algorithms are criticized for the undesirable performance and interpretability of patterns because of the noises, high-dimensionality and extraordinary sparsity of scRNA-seq data. To address these issues, a novel deep learning subspace clustering algorithm (aka scGDC) for cell types in scRNA-seq data is proposed, which simultaneously learns the deep features and topological structure of cells. Specifically, scGDC extends auto-encoder by introducing a self-representation layer to extract deep features of cells, and learns affinity graph of cells, which provide a better and more comprehensive strategy to characterize structure of cell types. To address heterogeneity of scRNA-seq data, scGDC projects cells of various types onto different subspaces, where types, particularly rare cell types, are well discriminated by utilizing generative adversarial learning. Furthermore, scGDC joins deep feature extraction, structural learning and cell type discovery, where features of cells are extracted under the guidance of cell types, thereby improving performance of algorithms. A total of 15 scRNA-seq datasets from various tissues and organisms with the number of cells ranging from 56 to 63 103 are adopted to validate performance of algorithms, and experimental results demonstrate that scGDC significantly outperforms 14 state-of-the-art methods in terms of various measurements (on average 25.51% by improvement), where (rare) cell types are significantly associated with topology of affinity graph of cells. The proposed model and algorithm provide an effective strategy for the analysis of scRNA-seq data (The software is coded using python, and is freely available for academic https://github.com/xkmaxidian/scGDC).

Effect of Mobile Internet on Attitude and Self-Efficacy of Patients with Coronary Heart Disease Diagnosed by 12-Lead Holter ECG.

OBJECTIVE: To explore the effect of mobile Internet on attitude and self-efficacy of patients with coronary heart disease (CHD) diagnosed by 12-lead Holter ECG. METHODS: The clinical data of 62 patients with CHD who underwent routine ECG examination (control group I) and 12-lead dynamic electrocardiogram (control group II) in our hospital (June 2017-December 2020) were retrospectively analyzed, and the clinical data of another 62 patients with CHD who received 12-lead Holter ECG examination combined with mobile Internet in our hospital at the same time (study group) were retrospectively analyzed. The clinical observation indexes of the three groups were compared. RESULTS: No obvious difference in general data among groups (P > 0.05). Compared with the control group I, the positive detection rate (PDR) of the study group and the control group II was obviously higher (P < 0.05), and the PDR of the study group was obviously higher than that of the control group II, without remarkable difference between both groups (P > 0.05). Compared with the control group, the scores of CAS-R of the study group were obviously higher (P < 0.05), and self-efficacy of daily life, health behaviors, medication compliance, and compliance behavior of the study group was obviously better (P < 0.05). The diagnostic efficacy was derived by ROC curve analysis, 12-lead Holter ECG combined with mobile Internet + routine ECG > 12-lead Holter ECG combined with mobile Internet > 12-lead Holter ECG > routine ECG. CONCLUSION: Compared with the routine ECG, the sensitivity of 12-lead Holter ECG in the diagnosis of CHD is conspicuously higher. Meanwhile, 12-lead Holter ECG combined with mobile Internet can enhance the diagnostic efficiency and improve patients' perceived control attitude and self-efficacy.

Network-based integrative analysis of single-cell transcriptomic and epigenomic data for cell types.

Advances in single-cell biotechnologies simultaneously generate the transcriptomic and epigenomic profiles at cell levels, providing an opportunity for investigating cell fates. Although great efforts have been devoted to either of them, the integrative analysis of single-cell multi-omics data is really limited because of the heterogeneity, noises and sparsity of single-cell profiles. In this study, a network-based integrative clustering algorithm (aka NIC) is present for the identification of cell types by fusing the parallel single-cell transcriptomic (scRNA-seq) and epigenomic profiles (scATAC-seq or DNA methylation). To avoid heterogeneity of multi-omics data, NIC automatically learns the cell-cell similarity graphs, which transforms the fusion of multi-omics data into the analysis of multiple networks. Then, NIC employs joint non-negative matrix factorization to learn the shared features of cells by exploiting the structure of learned cell-cell similarity networks, providing a better way to characterize the features of cells. The graph learning and integrative analysis procedures are jointly formulated as an optimization problem, and then the update rules are derived. Thirteen single-cell multi-omics datasets from various tissues and organisms are adopted to validate the performance of NIC, and the experimental results demonstrate that the proposed algorithm significantly outperforms the state-of-the-art methods in terms of various measurements. The proposed algorithm provides an effective strategy for the integrative analysis of single-cell multi-omics data (The software is coded using Matlab, and is freely available for academic https://github.com/xkmaxidian/NIC ).

Predicting combinations of drugs by exploiting graph embedding of heterogeneous networks.

BACKGROUND: Drug combination, offering an insight into the increased therapeutic efficacy and reduced toxicity, plays an essential role in the therapy of many complex diseases. Although significant efforts have been devoted to the identification of drugs, the identification of drug combination is still a challenge. The current algorithms assume that the independence of feature selection and drug prediction procedures, which may result in an undesirable performance. RESULTS: To address this issue, we develop a novel Semi-supervised Heterogeneous Network Embedding algorithm (called SeHNE) to predict the combination patterns of drugs by exploiting the graph embedding. Specifically, the ATC similarity of drugs, drug-target, and protein-protein interaction networks are integrated to construct the heterogeneous networks. Then, SeHNE jointly learns drug features by exploiting the topological structure of heterogeneous networks and predicting drug combination. One distinct advantage of SeHNE is that features of drugs are extracted under the guidance of classification, which improves the quality of features, thereby enhancing the performance of prediction of drugs. Experimental results demonstrate that the proposed algorithm is more accurate than state-of-the-art methods on various data, implying that the joint learning is promising for the identification of drug combination. CONCLUSIONS: The proposed model and algorithm provide an effective strategy for the prediction of combinatorial patterns of drugs, implying that the graph-based drug prediction is promising for the discovery of drugs.

An Integrative Framework of Heterogeneous Genomic Data for Cancer Dynamic Modules Based on Matrix Decomposition.

Cancer progression is dynamic, and tracking dynamic modules is promising for cancer diagnosis and therapy. Accumulated genomic data provide us an opportunity to investigate the underlying mechanisms of cancers. However, as far as we know, no algorithm has been designed for dynamic modules by integrating heterogeneous omics data. To address this issue, we propose an integrative framework for dynamic module detection based on regularized nonnegative matrix factorization method (DrNMF) by integrating the gene expression and protein interaction network. To remove the heterogeneity of genomic data, we divide the samples of expression profiles into groups to construct gene co-expression networks. To characterize the dynamics of modules, the temporal smoothness framework is adopted, in which the gene co-expression network at the previous stage and protein interaction network are incorporated into the objective function of DrNMF via regularization. The experimental results demonstrate that DrNMF is superior to state-of-the-art methods in terms of accuracy. For breast cancer data, the obtained dynamic modules are more enriched by the known pathways, and can be used to predict the stages of cancers and survival time of patients. The proposed model and algorithm provide an effective integrative analysis of heterogeneous genomic data for cancer progression.