Spatial transcriptomics technologies produce rich multimodal data, including gene expression profiles, spatial coordinates, and histological images, offering unprecedented opportunities to characterize tissue organization. However, effectively integrating these heterogeneous modalities remains challenging due to the complex molecular and morphological interplay. To address this, we propose PCMF-RC, a novel Prototype-Calibrated Multimodal Fusion framework with Relational Consistency, designed for accurate spatial domain identification. Our approach first partitions high-resolution histopathological images into patches centered on spatial transcriptomics spots and extracts spatially aware visual features using a pre-trained visual state space model. We then obtain modality-specific latent embeddings where we separately encode gene expression and image features via graph convolutional networks. To improve semantic consistency, a cross-view prototype matching module that aligns cluster prototypes across modalities is introduced to mitigate prototype shift. We further design a relational consistency contrastive learning module to effectively enforce alignment of spatial relational structures, reducing distributional discrepancies and enhancing robustness. Extensive experiments on multiple spatial transcriptomics datasets demonstrate that PCMF-RC outperforms existing methods in spatial domain delineation, offering a robust and generalizable solution for multimodal spatial omics integration.

The functional study of proteins is a critical task in modern biology, playing a pivotal role in understanding the mechanisms of pathogenesis, developing new drugs, and discovering novel drug targets. However, existing computational models for subcellular localization face significant challenges, such as reliance on known Gene Ontology (GO) annotation databases or overlooking the relationship between GO annotations and subcellular localization. To address these issues, we propose DeepMTC, an end-to-end deep learning-based multi-task collaborative training model. DeepMTC integrates the interrelationship between subcellular localization and the functional annotation of proteins, leveraging multi-task collaborative training to eliminate dependence on known GO databases. This strategy gives DeepMTC a distinct advantage in predicting newly discovered proteins without prior functional annotations. First, DeepMTC leverages pre-trained language model with high accuracy to obtain the 3D structure and sequence features of proteins. Additionally, it employs a graph transformer module to encode protein sequence features, addressing the problem of long-range dependencies in graph neural networks. Finally, DeepMTC uses a functional cross-attention mechanism to efficiently combine upstream learned functional features to perform the subcellular localization task. The experimental results demonstrate that DeepMTC outperforms state-of-the-art models in both protein function prediction and subcellular localization. Moreover, interpretability experiments revealed that DeepMTC can accurately identify the key residues and functional domains of proteins, confirming its superior performance. The code and dataset of DeepMTC are freely available at https://github.com/ghli16/DeepMTC.

BACKGROUND: Conducting traditional wet experiments to guide drug development is an expensive, time-consuming and risky process. Analyzing drug function and repositioning plays a key role in identifying new therapeutic potential of approved drugs and discovering therapeutic approaches for untreated diseases. Exploring drug-disease associations has far-reaching implications for identifying disease pathogenesis and treatment. However, reliable detection of drug-disease relationships via traditional methods is costly and slow. Therefore, investigations into computational methods for predicting drug-disease associations are currently needed. RESULTS: This paper presents a novel drug-disease association prediction method, RAFGAE. First, RAFGAE integrates known associations between diseases and drugs into a bipartite network. Second, RAFGAE designs the Re_GAT framework, which includes multilayer graph attention networks (GATs) and two residual networks. The multilayer GATs are utilized for learning the node embeddings, which is achieved by aggregating information from multihop neighbors. The two residual networks are used to alleviate the deep network oversmoothing problem, and an attention mechanism is introduced to combine the node embeddings from different attention layers. Third, two graph autoencoders (GAEs) with collaborative training are constructed to simulate label propagation to predict potential associations. On this basis, free multiscale adversarial training (FMAT) is introduced. FMAT enhances node feature quality through small gradient adversarial perturbation iterations, improving the prediction performance. Finally, tenfold cross-validations on two benchmark datasets show that RAFGAE outperforms current methods. In addition, case studies have confirmed that RAFGAE can detect novel drug-disease associations. CONCLUSIONS: The comprehensive experimental results validate the utility and accuracy of RAFGAE. We believe that this method may serve as an excellent predictor for identifying unobserved disease-drug associations.

BACKGROUND: There is a growing body of evidence from biological experiments suggesting that microRNAs (miRNAs) play a significant regulatory role in both diverse cellular activities and pathological processes. Exploring miRNA-disease associations not only can decipher pathogenic mechanisms but also provide treatment solutions for diseases. As it is inefficient to identify undiscovered relationships between diseases and miRNAs using biotechnology, an explosion of computational methods have been advanced. However, the prediction accuracy of existing models is hampered by the sparsity of known association network and single-category feature, which is hard to model the complicated relationships between diseases and miRNAs. RESULTS: In this study, we advance a new computational framework (GATMDA) to discover unknown miRNA-disease associations based on graph attention network with multi-source information, which effectively fuses linear and non-linear features. In our method, the linear features of diseases and miRNAs are constructed by disease-lncRNA correlation profiles and miRNA-lncRNA correlation profiles, respectively. Then, the graph attention network is employed to extract the non-linear features of diseases and miRNAs by aggregating information of each neighbor with different weights. Finally, the random forest algorithm is applied to infer the disease-miRNA correlation pairs through fusing linear and non-linear features of diseases and miRNAs. As a result, GATMDA achieves impressive performance: an average AUC of 0.9566 with five-fold cross validation, which is superior to other previous models. In addition, case studies conducted on breast cancer, colon cancer and lymphoma indicate that 50, 50 and 48 out of the top fifty prioritized candidates are verified by biological experiments. CONCLUSIONS: The extensive experimental results justify the accuracy and utility of GATMDA and we could anticipate that it may regard as a utility tool for identifying unobserved disease-miRNA relationships.

For the past several years, semantic segmentation method based on deep learning, especially Unet, have achieved tremendous success in medical image processing. The U-shaped topology of Unet can well solve image segmentation tasks. However, due to the limitation of traditional convolution operations, Unet cannot realize global semantic information interaction. To address this problem, this paper proposes RT-Unet, which combines the advantages of Transformer and Residual network for accurate medical segmentation. In RT-Unet, the Residual block is taken as the image feature extraction layer to alleviate the problem of gradient degradation and obtain more effective features. Meanwhile, Skip-Transformer is proposed, which takes Multi-head Self-Attention as the main algorithm framework, instead of the original Skip-Connection layer in Unet to avoid the influence of shallow features on the network's performance. Besides, we add attention module at the decoder to reduce semantic differences. According to the experiments on MoNuSeg data set and ISBI_2018cell data set, RT-Unet achieves better segmentation performance than other deep learning-based algorithms. In addition, a series of further ablation experiments were conducted on Residual network and Skip-Transformer, which verified the effectiveness and efficiency of the proposed methods in this paper.

Currently, deep learning has become more and more mature in the field of medical image segmentation. Through using the computer, the deep learning models established can completely help doctors to perform medical image segmentation. Most of the current deep learning models are based on Unet. The U-shaped structure and the skip connection layer of Unet can effectively achieve precise image segmentation. However, for complicated images, the network structure of Unet is not sufficient enough. In response to this problem, some scholars have designed Unet++ by adding a denser skip connection layer to U-Net. Compared to U-Net, Unet++ is more effective in dealing with complex images, but it has drawbacks in many aspects, and there is still a large loss of eigenvalues in the skip connection and up-sampling processes. To address these issues, this paper uses the channel and attention mechanism to improve the Unet++ model to obtain better image segmentation efficiency and accuracy. Meanwhile, based on Unet++, this paper designs a new model called CA-Unet++. The proposed model uses the channel module and the attention module to solve the eigenvalues loses in the long-distance skip connection process and the up-sampling process, respectively. The experimental results and data analysis shows that our proposed CA-Unet++ can achieve better performance in medical computed tomography scan image segmentation.

Due to the complex structure of cytopathological images, data loss and low transmission efficiency may occur in the transmission of cytopathological images by common data stream transmission methods. To ensure the stable transmission of the data stream of the cytopathology image storage system and maintain the safe operation of the cytopathology image storage system, a safe transmission method of the data stream of the cytopathology image storage system was designed. The security threats faced by the data flow of the cytopathology image storage system were analyzed from the aspects of information network and control network, and the risk indexes of data flow and attack loss were constructed. The security risk indexes were quantified by the general vulnerability scoring system, and the data flow security transmission model of the cytopathology image storage system was constructed. Different transmission nodes and cytopathological image storage system devices were set as attack graph nodes to collect and configure data and optimize data flow transmission path. Deploy the network node equilibrium state, control the time slot window interval equilibrium, output transmission delay allocation, and ensure the confidentiality and integrity of the data stream transmission of the cytopathological image storage system. The simulation results show that the proposed method has a higher transmission efficiency of about 11.76 Mb/s. It is highly practical and can realize the safe transmission of data stream in the cytopathological image storage system.

Combinatorial drug therapy is a promising way for treating cancers, which can reduce drug side effects and improve drug efficacy. However, due to the large-scale combinatorial space, it is difficult to quickly and effectively identify novel synergistic drug combinations for further implementing combinatorial drug therapy. The computational method of fusing multi-source knowledge is a time- and cost-efficient strategy to infer synergistic drug combinations for testing. However, for the existing computational methods of inferring synergistic drug combinations, it still remains a challenging to effectively combine multi-source information to achieve the desired results. Hence, in this study, we developed a novel Inference method of Synergistic Drug Combinations based on Symmetric Meta-Path (ISDCSMP), which can systematically and accurately prioritize synergistic drug combinations in a novel drug-target heterogeneous network integrating multi-source information. In the experiment, ISDCSMP outperformed the state-of-the-art methods in terms of AUC and precision on the benchmark dataset in five-fold cross validation. Moreover, we further illustrated performances of different ways for obtaining the combination coefficients, and analyzed the influences of the maximum meta-path length. The performances of various single meta-paths were described in five-fold cross validation. Finally, we confirmed the practical usefulness of ISDCSMP with the predicted novel synergistic drug combinations. The source code of ISDCSMP is available at https://github.com/KDDing/ISDCSMP.

BACKGROUND: As regulators of gene expression, microRNAs (miRNAs) are increasingly recognized as critical biomarkers of human diseases. Till now, a series of computational methods have been proposed to predict new miRNA-disease associations based on similarity measurements. Different categories of features in miRNAs are applied in these methods for miRNA-miRNA similarity calculation. Benchmarking tests on these miRNA similarity measures are warranted to assess their effectiveness and robustness. RESULTS: In this study, 5 categories of features, i.e. miRNA sequences, miRNA expression profiles in cell-lines, miRNA expression profiles in tissues, gene ontology (GO) annotations of miRNA target genes and Medical Subject Heading (MeSH) terms of miRNA-associated diseases, are collected and similarity values between miRNAs are quantified based on these feature spaces, respectively. We systematically compare the 5 similarities from multi-statistical views. Furthermore, we adopt a rule-based inference method to test their performance on miRNA-disease association predictions with the similarity measurements. Comprehensive comparison is made based on leave-one-out cross-validations and a case study. Experimental results demonstrate that the similarity measurement using MeSH terms performs best among the 5 measurements. It should be noted that the other 4 measurements can also achieve reliable prediction performance. The best-performed similarity measurement is used for new miRNA-disease association predictions and the inferred results are released for further biomedical screening. CONCLUSIONS: Our study suggests that all the 5 features, even though some are restricted by data availability, are useful information for inferring novel miRNA-disease associations. However, biased prediction results might be produced in GO- and MeSH-based similarity measurements due to incomplete feature spaces. Similarity fusion may help produce more reliable prediction results. We expect that future studies will provide more detailed information into the 5 feature spaces and widen our understanding about disease pathogenesis.

Long non-coding RNAs (lncRNAs) have been shown to be involved in multiple biological processes and play critical roles in tumorigenesis. Numerous lncRNAs have been discovered in diverse species, but the functions of most lncRNAs still remain unclear. Meanwhile, their expression patterns and regulation mechanisms are also far from being fully understood. With the advances of high-throughput technologies, the increasing availability of genomic data creates opportunities for deciphering the molecular mechanism and underlying pathogenesis of human diseases. Here, we develop an integrative framework called JONMF to identify lncRNA-mRNA co-expression modules based on the sample-matched lncRNA and mRNA expression profiles. We formulate the module detection task as an optimization problem with joint orthogonal non-negative matrix factorization that could effectively prevent multicollinearity and produce a good modularity interpretation. The constructed lncRNA-mRNA co-expression network and the gene-gene interaction network are used as the network-regularized constraints to improve the module accuracy, while the sparsity constraints are simultaneously utilized to achieve modular sparse solutions. We applied JONMF to human ovarian cancer dataset and the experiment results demonstrate that the proposed method can effectively discover biologically functional co-expression modules, which may provide insights into the function of lncRNAs and molecular mechanism of human diseases.

BACKGROUND: Non-coding RNAs (ncRNAs) are emerging as key regulators and play critical roles in a wide range of tumorigenesis. Recent studies have suggested that long non-coding RNAs (lncRNAs) could interact with microRNAs (miRNAs) and indirectly regulate miRNA targets through competing interactions. Therefore, uncovering the competing endogenous RNA (ceRNA) regulatory mechanism of lncRNAs, miRNAs and mRNAs in post-transcriptional level will aid in deciphering the underlying pathogenesis of human polygenic diseases and may unveil new diagnostic and therapeutic opportunities. However, the functional roles of vast majority of cancer specific ncRNAs and their combinational regulation patterns are still insufficiently understood. RESULTS: Here we develop an integrative framework called CeModule to discover lncRNA, miRNA and mRNA-associated regulatory modules. We fully utilize the matched expression profiles of lncRNAs, miRNAs and mRNAs and establish a model based on joint orthogonality non-negative matrix factorization for identifying modules. Meanwhile, we impose the experimentally verified miRNA-lncRNA interactions, the validated miRNA-mRNA interactions and the weighted gene-gene network into this framework to improve the module accuracy through the network-based penalties. The sparse regularizations are also used to help this model obtain modular sparse solutions. Finally, an iterative multiplicative updating algorithm is adopted to solve the optimization problem. CONCLUSIONS: We applied CeModule to two cancer datasets including ovarian cancer (OV) and uterine corpus endometrial carcinoma (UCEC) obtained from TCGA. The modular analysis indicated that the identified modules involving lncRNAs, miRNAs and mRNAs are significantly associated and functionally enriched in cancer-related biological processes and pathways, which may provide new insights into the complex regulatory mechanism of human diseases at the system level.