Medical image segmentation plays a crucial role in clinical diagnosis, lesion quantification, and preoperative planning. However, existing Mamba-based architectures, which rely on fixed-direction sequence modeling and flatten images into one-dimensional (1D) sequences, struggle to capture hierarchical anatomical features and spatial dependencies, thereby limiting their representational capacity for complex medical structures. To address these limitations, we propose EccoMamba (Enhanced Cross-hierarchical Continuity Orthogonal Mamba), a U-shaped encoder--decoder framework designed for medical image segmentation. In the encoder's downsampling path, we introduce a Hierarchical Aggregation Enhancement (HAE) module that integrates multi-scale convolutions with hierarchical attention mechanisms. The attention branch further incorporates cross-channel interactions, allowing the model to selectively enhance semantically relevant features while suppressing irrelevant background responses. For skip connections, we design a Structural Continuity Orthogonal (SCO) module to preserve spatial continuity by modeling cross-dimensional dependencies via orthogonal Axial Shifts (AS), thereby mitigating directional bias and improving anatomical consistency. Extensive experiments on four benchmark datasets---ISIC 2018, ISIC 2017, Synapse, and ACDC---show that EccoMamba consistently outperforms state-of-the-art methods in both segmentation accuracy and structural fidelity.

Accurate prediction of compound protein interactions (CPIs) is crucial for drug discovery. However, existing deep learning-based methods suffer from hidden biases and poor cross-domain generalization, leading to spurious correlations and inadequate representation of unseen compound-protein pairs. To address these limitations, we propose FuseMine, a multimodal deep learning framework that jointly leverages molecular structures and biological sequences for reliable CPI prediction. Specifically, FuseMine adopts a dual-representation strategy for each molecule. It employs a convolutional encoder to capture structural features, combined with pretrained large language models for extracting semantic information from sequences. We propose a novel Multi-modal Feature Orchestration Aggregation (MFOA) module that enables deep and synergistic fusion between the structural features and the sequential semantics of molecules, effectively capturing the complementary patterns across modalities. Additionally, we design a Reduction Differential Feature Mining (RDFM) module to further enhance the representation of discriminative features, thereby improving the model’s generalization capability. Extensive experiments on multiple benchmark datasets demonstrate that our framework consistently outperforms state-of-the-art methods in both intra-domain and cross-domain scenarios. These results highlight the synergistic value of combining structural and sequential data for CPIs.

Single-cell multi-omics data reveal complex cellular states and deepen our understanding of tissue cell phenotypes and functions. However, data analysis remains challenging due to the discrete nature and high noise level of the data, as well as the lack of modality. Here, we propose scMultiNet, a multi-task deep adversarial neural network that can integrate different tasks to analyze single-cell multi-modal data. In particular, we achieve joint training of multi-modal integration and cross-modal prediction tasks by introducing a cross-modal bi-prediction module and a multi-head self-attention module. Data denoising is further enhanced by integrating an indicator matrix that constrains and precisely reconstructs the original expression values. Extensive simulations and real data experiments demonstrate that scMultiNet outperforms existing state-of-the-art methods in dimensionality reduction, visualization, clustering, batch elimination, data denoising, multi-modal integration, single-cell cross-modality translation, and in revealing cell type-specific biological insights. In addition, we demonstrate that scMultiNet can effectively transfer the complex relationships between modalities from one batch to another. In summary, scMultiNet stands as a comprehensive end-to-end framework, ideally suited for analyzing single-cell multi-omics data.

MOTIVATION: Accurately identifying compound-protein interactions (CPIs) is critical for accelerating drug discovery. Recent deep learning methods have achieved impressive results, yet they primarily focus on local structures and neighborhood information, often overlooking high-order interaction patterns shared among similar molecules. RESULTS: In this paper, we propose HKD-CPI, a high-order knowledge-enhanced inductive framework designed to improve generalization to unseen compound-protein pairs. Specifically, HKD-CPI introduces a molecular graph tokenization mechanism that aligns compound molecular graph features with token embeddings from sequence-pretrained large language models (LLMs), effectively infusing sequence-derived semantics into structural representations. To capture shared interaction patterns among functionally similar biomolecules, we construct a hypergraph-based representation to model high-order relationships between feature-similar compound/protein groups and their binding partners. Furthermore, a knowledge distillation strategy is further adopted to transfer high-order interaction knowledge from the hypergraph to a lightweight student model, enabling efficient and robust CPI prediction. Extensive experiments demonstrate that HKD-CPI outperforms existing state-of-the-art methods in inductive CPI prediction tasks. In particular, it achieves an average improvement of 4.94% in AUROC and 3.64% in AUPRC over the best-performing baseline across five benchmark datasets. AVAILABILITY AND IMPLEMENTATION: Our code and data are available at https://github.com/Hezy618/HKD-CPI.

MOTIVATION: Drug combinations are crucial for overcoming resistance in cancer therapy. Although deep learning has achieved strong performance in synergy prediction, existing models often treat cell-specific features and paired drugs as a static background and fail to capture how the specific cell-drug environment dynamically modulates drug representations, thereby hindering the modeling of environment-specific synergistic effects. RESULTS: We propose Env-Syn, a framework for modeling drug-drug-cell interactions through Environment-Conditioned Feature Modulation, which incorporates a Residual Feature-wise Linear Modulation (R-FiLM) module to perform precise affine transformations on drug representations conditioned on paired drugs and cellular environments. Benchmark evaluations show that Env-Syn consistently outperforms state-of-the-art methods. Notably, the model exhibits exceptional generalization performance in rigorous inductive scenarios. It maintains high predictive accuracy for unseen drugs with AUROC and AUPRC exceeding 0.81 in the Leave-drug-out setting and further demonstrates strong cross-dataset reliability by surpassing a recall of 0.7 on independent test set. Furthermore, among 15 novel predicted drug combinations, 8 are directly supported by literature evidence. These results demonstrate that Env-Syn is an effective computational tool for drug synergy discovery. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/AnQi-87/Env-Syn.

Lysine crotonylation (Kcr) is an important protein modification occurring after translation in biology, serving an essential function in a range of biological processes in both plants and animals, including the regulation of gene expression, the maintenance of cellular metabolic balance, and the enhancement of photosynthesis. Exploring the detection of Kcr sites is essential for uncovering their biological functions. Nonetheless, conventional experimental approaches for detection are often time-consuming, expensive, and hindered by various technical constraints, making the precise identification of Kcr sites a significant challenge. This study seeks to develop a computational approach for the rapid and accurate prediction of Kcr sites in plant non-histone proteins. We introduce a novel deep learning framework named DeepNhKcr, which integrates the protein language model (ESM2) with a bidirectional long short-term memory (BiLSTM) network. To address the challenge of data imbalance, the model replaces the conventional cross-entropy loss with the focal loss function. In addition, DeepNhKcr combines advanced deep learning approaches with traditional protein encoding strategies to enable effective feature extraction and integration. This method not only significantly boosts the accuracy of predicting Kcr sites in non-histone proteins of plants. but also provides interpretability, shedding light on the potential links between key sequence characteristics and their biological roles. DeepNhKcr delivers outstanding results, surpassing existing machine learning and deep learning models, and demonstrating excellent performance in both five-fold cross-validation and independent test experiments. Moreover, the model integrates interpretability analysis techniques to investigate the connections between important sequence features and their biological roles. DeepNhKcr acts as a powerful method for detecting Kcr sites in plant non-histone proteins and is anticipated to greatly advance future studies in plant Kcr site prediction.

Leveraging the wealth of biomedical data available, we can derive insights into the relationships between biological entities from various angles. This underscores the complexity and significance of developing a dynamic approach for integrating data from multiple sources, a critical endeavor in drug recommendation. In this study, we introduce an innovative deep learning approach termed "Multi-View Fusion Strategy with Self-Attention" (FusionMVSA), designed to predict associations between drugs and diseases. To effectively amalgamate data from diverse sources and extract representative features, we have developed a feature extraction mechanism that capitalizes on similarities. This mechanism computes self-attention across multiple perspectives using shared group parameters, thereby highlighting common characteristics. Simultaneously, we utilize biomedical similarities among multi-source data as guiding factors for calculating similarity, enabling the capture of more nuanced features. Subsequently, we integrate these features through a feature fusion process, where known associations between drugs and diseases act as guiding terms. This strategy allows us to uncover the complementary aspects of different viewpoints. Ultimately, we predict potential drug-disease associations using a multi-layer perceptron neural network. Our methodology has undergone rigorous testing through various cross-validation experiments and case studies. We are confident that FusionMVSA will prove to be a valuable tool in drug recommendation, offering new avenues for exploration and discovery in the quest to combat diseases.

Protein-ligand binding affinity prediction is critical for drug discovery, yet existing methods struggle to jointly model local atomic interactions and global contextual dependencies. To address this, we propose the Interpretable Dual-Branch Graph-Transformer framework for Protein-Ligand Affinity prediction (DBGT-PLA), a novel dual-branch architecture that integrates graph neural network (GNN) with a stability-enhanced Transformer equipped with learnable positional embeddings and a NaN-filtering mechanism that handles potential Not-a-Number (NaN) values arising from numerical instability or data preprocessing. We design a Gated Residual Learning (GRL) Fusion module that performs dimension-wise adaptive integration between local graph topology and global Transformer context. This mechanism enables multi-level feature coordination through a residual path, achieving biophysically consistent alignment between atomic-level interactions and global conformational dependencies. Furthermore, we introduce an edge-level Shapley attribution framework tailored to protein-ligand interaction graphs, quantifying contributions of chemical bonds (e.g., hydrophobic contacts) and non-covalent interactions. Experiments show DBGT-PLA reduces RMSE by 18.3% (from 1.522 to 1.244 on the Holdout Set 2019), outperforming state-of-the-art models. Crucially, our explainability module reveals that the ligand edges dominate affinity predictions, accounting for nearly 70%. This work not only advances predictive accuracy but also offers unprecedented, quantitative insights into interaction determinants, which can guide rational drug optimization.

Predicting drug-target interactions (DTI) is critical for advancing drug discovery. However, existing DTI approaches struggle with data imbalance and heterogeneous information. This study presents a novel framework called PDGCL-DTI, which leverages two graph contrastive learning frameworks in parallel to capture both local and global features from drug-target heterogeneous networks. First, PDGCL-DTI effectively handles data imbalance through the AdaL-GCL module, which dynamically adjusts the weights of minority class samples to mitigate the impact of the imbalance. Second, by combining local and global contrastive learning, it extracts features from both local node information and global structural information, improving its adaptability to complex heterogeneous networks. This dual strategy enables PDGCL-DTI to exhibit greater robustness and higher prediction accuracy when handling complex DTI data. Experimental results on the ChEMBL, DrugBank, and DAVIS datasets show that PDGCL-DTI outperforms existing DTI methods, achieving an average AUC of 0.958 and an average accuracy of 0.95 across the three datasets. Additionally, case studies demonstrate that PDGCL-DTI successfully predicts interactions between Enasidenib and GABA-AT, as well as Sorafenib and Caspase-3, underscoring its practical applicability in the visualization workflow on the ChEMBL dataset.

Designing new molecules with ideal properties is a critical task in drug discovery. In recent years, the accumulation of available molecular datasets has facilitated the widespread application of deep generative models in drug design. Nonetheless, a significant challenge remains in developing highperformance generative models that not only need to produce chemically valid molecular structures but also optimize the chemical properties of the generated molecules. In this study, we introduce TransFVAE, a graph Transformer-based flow Variational AutoEncoder tailored for molecular graph generation. Our approach employs VAE as the encoder and integrates a lightweight flow model as the decoder. The encoder is strategically designed to expedite the training process of the decoder, while the decoder reciprocally enhances the performance of the encoder. Unlike some existing models that only account for local node connections, our model leverages Transformer architecture in the encoder, ensuring comprehensive consideration of global information. This enables each atom to holistically interact with all other atoms, thereby enhancing molecular attribute constraint optimization in molecular optimization tasks. Validation of our model is conducted through three core tasks: molecule generation and reconstruction, latent space visualization, and molecular optimization. The results affirm the state-of-the-art performance of our model, underscoring its substantial potential in facilitating the generation of drug molecules endowed with desired properties. All source datasets and codes can be downloaded from: https://github.com/Biowust/TransFVAE.

Identifying synergistic drug combinations is crucial for improving cancer therapies. However, the combinatorial explosion of candidate drug pairs and the complexity of drug-cell interactions make exhaustive experimental validation infeasible. Existing deep learning approaches often rely solely on twodimensional molecular graphs or static cell line expression profiles, limiting their ability to capture spatial molecular conformations and dynamic cellular responses. To overcome these limitations, we propose ConGraSyn, a conformation enhanced graph attention framework for drug synergy prediction. For each drug, ConGraSyn integrates descriptor-based fingerprints with molecular graphs, where atom features encode interatomic distances through a scale attention mechanism. A gated fusion module adaptively combines fingerprint-level and graph-level embeddings into a unified drug representation. For cell lines, static protein-protein interaction-informed embeddings are augmented with drug-induced perturbations simulated from basal expression and drug embeddings. The resulting drug and cell features are concatenated and fed into a classifier to predict synergistic outcomes. Across benchmark datasets, ConGraSyn matches or exceeds representative deep learning baselines and consistently outperforms classical machine learning methods. Ablation and sensitivity analyses attribute the gains to its conformation-aware drug modeling and perturbation-informed cell representations. Leave-one-out validation, representation visualizations and case studies indicate robust generalization and biologically plausible novel synergies, supporting its utility for identifying effective drug combinations. The complete source code and datasets are publicly available at: https://github.com/HuazeLoong/ConGraSyn.

In real-world applications where knowledge systems continuously evolve with new relationships, current knowledge graph completion (KGC) methods face a fundamental limitation: their over-reliance on localized patterns and inability to capture structural semantic correlations lead to significant performance degradation when encountering unseen relations. This manifests particularly in their failure to effectively predict potential entity interactions for these novel relations. To bridge this gap, we propose BiRMet, a novel framework integrating bidirectional relational fusion with meta-learning. The framework innovates through relational graph structures that preserve semantic relationships, multi-head attention mechanisms modeling complex relational interactions, and bidirectional feature fusion enabling dynamic co-adaptation of entities and relations. When combined with meta-learning, these components collectively address the core challenge of generalizing to unseen relations. Experimental results across multiple benchmarks demonstrate consistent improvements over existing approaches in handling unseen relations. Furthermore, case studies on drug repurposing based on a biomedical knowledge graph further highlight the potential of our framework in accelerating real-world drug discovery. Codes are available at https://anonymous.4open.science/r/BiRMet-DE01

Spatial transcriptomics (STs) technology is a powerful technique that simultaneously preserves gene expression profiles and spatial information, enabling deeper exploration of tissue organization and function. However, many existing computational approaches often rely on labeled ST data and overlook the rich spatial information, resulting in limited representations and suboptimal clustering. In this paper, we propose ST-GCP, a self-supervised graph representation learning framework for ST data, which incorporates a structure-feature perturbation mechanism. First, ST-GCP applies feature-level random permutation of the gene expression matrix and random edge dropout in the spatial neighbor network, creating two complementary augmented graph views of ST data. ST-GCP then employs a two-layer graph convolutional network (GCN) encoder-decoder to extract spatial representations and reconstruct gene expression. Finally, a cosine-similarity-based contrastive objective aligns the view-specific representations, and the overall loss jointly optimizes reconstruction fidelity and contrastive consistency, thereby coupling graph topology with transcriptomic profiles in a shared low-dimensional space. Experimental results on multiple ST datasets demonstrate that ST-GCP can uncover biologically meaningful patterns, such as tumor heterogeneity, brain developmental architecture, and cellular developmental trajectories.

MOTIVATION: The classification task based on whole-slide images (WSIs) is a classic problem in computational pathology. Multiple instance learning (MIL) provides a robust framework for analyzing whole slide images with slide-level labels at gigapixel resolution. However, existing MIL models typically focus on modeling the relationships between instances while neglecting the variability across the channel dimensions of instances, which prevents the model from fully capturing critical information in the channel dimension. RESULTS: To address this issue, we propose a plug-and-play module called Multi-scale Channel Attention Block (MCAB), which models the interdependencies between channels by leveraging local features with different receptive fields. By alternately stacking four layers of Transformer and MCAB, we designed a channel attention-based MIL model (CAMIL) capable of simultaneously modeling both inter-instance relationships and intra-channel dependencies. To verify the performance of the proposed CAMIL in classification tasks, several comprehensive experiments were conducted across three datasets: Camelyon16, TCGA-NSCLC, and TCGA-RCC. Empirical results demonstrate that, whether the feature extractor is pretrained on natural images or on WSIs, our CAMIL surpasses current state-of-the-art MIL models across multiple evaluation metrics. AVAILABILITY AND IMPLEMENTATION: All implementation code is available at https://github.com/maojy0914/CAMIL.

The process of new drug development is complex, whereas drug-disease association (DDA) prediction aims to identify new therapeutic uses for existing medications. However, existing graph contrastive learning approaches typically rely on single-view contrastive learning, which struggle to fully capture drug-disease relationships. Subsequently, we introduce a novel multi-view contrastive learning framework, named CDPMF-DDA, which enhances the model's ability to capture drug-disease associations by incorporating diverse information representations from different views. First, we decompose the original drug-disease association matrix into drug and disease feature matrices, which are then used to reconstruct the drug-disease association network, as well as the drug-drug and disease-disease similarity networks. This process effectively reduces noise in the data, establishing a reliable foundation for the networks produced. Next, we generate multiple contrastive views from both the original and generated networks. These views effectively capture hidden feature associations, significantly enhancing the model's ability to represent complex relationships. Extensive cross-validation experiments on three standard datasets show that CDPMF-DDA achieves an average AUC of 0.9475 and an AUPR of 0.5009, outperforming existing models. Additionally, case studies on Alzheimer's disease and epilepsy further validate the model's effectiveness, demonstrating its high accuracy and robustness in drug-disease association prediction. Based on a multi-view contrastive learning framework, CDPMF-DDA is capable of integrating multi-source information and effectively capturing complex drug-disease associations, making it a powerful tool for drug repositioning and the discovery of new therapeutic strategies.

In recent years, deep learning achieves significant advancements in medical image segmentation. Research finds that integrating Transformers and CNNs effectively addresses the limitations of CNNs in managing long-distance dependencies and understanding global information.However, existing models typically employ a serial approach to combine Transformers and CNNs, which complicates the simultaneous processing of global and local information. To address this, our study proposes a parallel multi-path attention architecture, SWMA-UNET, that integrates Transformers and CNNs. This architecture deeply mines features through parallel strategies while capturing both local details and global context information, thereby enhancing the accuracy of medical image segmentation. Experimental results indicate that our method surpasses all previously reported methods in the literature on the Synapse, ACDC, ISIC 2018 and MoNuSeg datasets.

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.

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.

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.

Medical applications heavily rely on medical image segmentation for tasks such as disease detection, treatment planning, and surgical navigation. While CNNs excel at local feature extraction, they have limitations in capturing global features. Transformer-based models are effective in global feature extraction but struggle with local features. TransUnet combines CNN and Transformer but lacks sufficient global and local feature extraction due to its serial connection approach. TransFuse addresses this by designing parallel Transformer and CNN branches for global and local feature extraction. The self-attention of ViT, the core network of the Transformer branch, has a computational complexity that is directly correlated with the square of the image size, which means it cannot meet the need for multi-level information in complicated segmentation tasks. To overcome these limitations, we propose SR-Unet, a novel dual-branch medical image segmentation network. It merges Transformer and CNN branches in the encoder for optimal global and local feature extraction, utilizing the Swin Transformer as the Transformer branch backbone. Furthermore, we integrate CBAM(Convolutional Block Attention Module) in the decoder’s fusion block to fully merge global and local features and eliminate redundant and irrelevant information, thereby enhancing segmentation accuracy. Experimental results on the Synapse, CXML, and BUSI datasets demonstrate that SR-Unet outperforms TransFuse. It achieves higher DSC metrics by 3.47%, 0.16%, and 0.35%, and significantly better HD metrics by 41.21%, 6.98%, and 11.33%.

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.

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.

Class imbalance is one of the important challenges for machine learning because of it's learning to bias toward the majority classes. The oversampling method is a fundamental imbalance-learning technique with many real-world applications. However, when the small disjuncts problem occurs, how to effectively avoiding the negative oversampling results rather than using clusters previously, remains a challenging task. Thus, this study introduces a disjuncts-robust oversampling (DROS) method. The novel method shows that the data filling of new synthetic samples to the minority class areas in data space can be thought of as the searchlight illuminating with light cones to the restricted areas in real life. In the first step, DROS computes a series of light-cone structures that is first started from the inner minority class area, then passes through the boundary minority class area, last is stopped by the majority class area. In the second step, DROS generates new synthetic samples in those light-cone structures. Experiments considering both real-world and 2D emulational datasets demonstrate that our method outperforms the current state-of-the-art oversampling methods and suggest that our method is able to deal with the small disjuncts.

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).

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.

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).

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.