Contrastive learning for enhancing feature extraction in anticancer peptides.

Cancer, recognized as a primary cause of death worldwide, has profound health implications and incurs a substantial social burden. Numerous efforts have been made to develop cancer treatments, among which anticancer peptides (ACPs) are garnering recognition for their potential applications. While ACP screening is time-consuming and costly, in silico prediction tools provide a way to overcome these challenges. Herein, we present a deep learning model designed to screen ACPs using peptide sequences only. A contrastive learning technique was applied to enhance model performance, yielding better results than a model trained solely on binary classification loss. Furthermore, two independent encoders were employed as a replacement for data augmentation, a technique commonly used in contrastive learning. Our model achieved superior performance on five of six benchmark datasets against previous state-of-the-art models. As prediction tools advance, the potential in peptide-based cancer therapeutics increases, promising a brighter future for oncology research and patient care.

Accurately deciphering spatial domains for spatially resolved transcriptomics with stCluster.

Spatial transcriptomics provides valuable insights into gene expression within the native tissue context, effectively merging molecular data with spatial information to uncover intricate cellular relationships and tissue organizations. In this context, deciphering cellular spatial domains becomes essential for revealing complex cellular dynamics and tissue structures. However, current methods encounter challenges in seamlessly integrating gene expression data with spatial information, resulting in less informative representations of spots and suboptimal accuracy in spatial domain identification. We introduce stCluster, a novel method that integrates graph contrastive learning with multi-task learning to refine informative representations for spatial transcriptomic data, consequently improving spatial domain identification. stCluster first leverages graph contrastive learning technology to obtain discriminative representations capable of recognizing spatially coherent patterns. Through jointly optimizing multiple tasks, stCluster further fine-tunes the representations to be able to capture complex relationships between gene expression and spatial organization. Benchmarked against six state-of-the-art methods, the experimental results reveal its proficiency in accurately identifying complex spatial domains across various datasets and platforms, spanning tissue, organ, and embryo levels. Moreover, stCluster can effectively denoise the spatial gene expression patterns and enhance the spatial trajectory inference. The source code of stCluster is freely available at https://github.com/hannshu/stCluster.

scCRT: a contrastive-based dimensionality reduction model for scRNA-seq trajectory inference.

Trajectory inference is a crucial task in single-cell RNA-sequencing downstream analysis, which can reveal the dynamic processes of biological development, including cell differentiation. Dimensionality reduction is an important step in the trajectory inference process. However, most existing trajectory methods rely on cell features derived from traditional dimensionality reduction methods, such as principal component analysis and uniform manifold approximation and projection. These methods are not specifically designed for trajectory inference and fail to fully leverage prior information from upstream analysis, limiting their performance. Here, we introduce scCRT, a novel dimensionality reduction model for trajectory inference. In order to utilize prior information to learn accurate cells representation, scCRT integrates two feature learning components: a cell-level pairwise module and a cluster-level contrastive module. The cell-level module focuses on learning accurate cell representations in a reduced-dimensionality space while maintaining the cell-cell positional relationships in the original space. The cluster-level contrastive module uses prior cell state information to aggregate similar cells, preventing excessive dispersion in the low-dimensional space. Experimental findings from 54 real and 81 synthetic datasets, totaling 135 datasets, highlighted the superior performance of scCRT compared with commonly used trajectory inference methods. Additionally, an ablation study revealed that both cell-level and cluster-level modules enhance the model's ability to learn accurate cell features, facilitating cell lineage inference. The source code of scCRT is available at https://github.com/yuchen21-web/scCRT-for-scRNA-seq.

CELA-MFP: a contrast-enhanced and label-adaptive framework for multi-functional therapeutic peptides prediction.

Functional peptides play crucial roles in various biological processes and hold significant potential in many fields such as drug discovery and biotechnology. Accurately predicting the functions of peptides is essential for understanding their diverse effects and designing peptide-based therapeutics. Here, we propose CELA-MFP, a deep learning framework that incorporates feature Contrastive Enhancement and Label Adaptation for predicting Multi-Functional therapeutic Peptides. CELA-MFP utilizes a protein language model (pLM) to extract features from peptide sequences, which are then fed into a Transformer decoder for function prediction, effectively modeling correlations between different functions. To enhance the representation of each peptide sequence, contrastive learning is employed during training. Experimental results demonstrate that CELA-MFP outperforms state-of-the-art methods on most evaluation metrics for two widely used datasets, MFBP and MFTP. The interpretability of CELA-MFP is demonstrated by visualizing attention patterns in pLM and Transformer decoder. Finally, a user-friendly online server for predicting multi-functional peptides is established as the implementation of the proposed CELA-MFP and can be freely accessed at http://dreamai.cmii.online/CELA-MFP.

TCR clustering by contrastive learning on antigen specificity.

Effective clustering of T-cell receptor (TCR) sequences could be used to predict their antigen-specificities. TCRs with highly dissimilar sequences can bind to the same antigen, thus making their clustering into a common antigen group a central challenge. Here, we develop TouCAN, a method that relies on contrastive learning and pretrained protein language models to perform TCR sequence clustering and antigen-specificity predictions. Following training, TouCAN demonstrates the ability to cluster highly dissimilar TCRs into common antigen groups. Additionally, TouCAN demonstrates TCR clustering performance and antigen-specificity predictions comparable to other leading methods in the field.

Heterogeneous biomedical entity representation learning for gene-disease association prediction.

Understanding the genetic basis of disease is a fundamental aspect of medical research, as genes are the classic units of heredity and play a crucial role in biological function. Identifying associations between genes and diseases is critical for diagnosis, prevention, prognosis, and drug development. Genes that encode proteins with similar sequences are often implicated in related diseases, as proteins causing identical or similar diseases tend to show limited variation in their sequences. Predicting gene-disease association (GDA) requires time-consuming and expensive experiments on a large number of potential candidate genes. Although methods have been proposed to predict associations between genes and diseases using traditional machine learning algorithms and graph neural networks, these approaches struggle to capture the deep semantic information within the genes and diseases and are dependent on training data. To alleviate this issue, we propose a novel GDA prediction model named FusionGDA, which utilizes a pre-training phase with a fusion module to enrich the gene and disease semantic representations encoded by pre-trained language models. Multi-modal representations are generated by the fusion module, which includes rich semantic information about two heterogeneous biomedical entities: protein sequences and disease descriptions. Subsequently, the pooling aggregation strategy is adopted to compress the dimensions of the multi-modal representation. In addition, FusionGDA employs a pre-training phase leveraging a contrastive learning loss to extract potential gene and disease features by training on a large public GDA dataset. To rigorously evaluate the effectiveness of the FusionGDA model, we conduct comprehensive experiments on five datasets and compare our proposed model with five competitive baseline models on the DisGeNet-Eval dataset. Notably, our case study further demonstrates the ability of FusionGDA to discover hidden associations effectively. The complete code and datasets of our experiments are available at https://github.com/ZhaohanM/FusionGDA.

Spatially contrastive variational autoencoder for deciphering tissue heterogeneity from spatially resolved transcriptomics.

Recent advances in spatially resolved transcriptomics (SRT) have brought ever-increasing opportunities to characterize expression landscape in the context of tissue spatiality. Nevertheless, there still exist multiple challenges to accurately detect spatial functional regions in tissue. Here, we present a novel contrastive learning framework, SPAtially Contrastive variational AutoEncoder (SpaCAE), which contrasts transcriptomic signals of each spot and its spatial neighbors to achieve fine-grained tissue structures detection. By employing a graph embedding variational autoencoder and incorporating a deep contrastive strategy, SpaCAE achieves a balance between spatial local information and global information of expression, enabling effective learning of representations with spatial constraints. Particularly, SpaCAE provides a graph deconvolutional decoder to address the smoothing effect of local spatial structure on expression's self-supervised learning, an aspect often overlooked by current graph neural networks. We demonstrated that SpaCAE could achieve effective performance on SRT data generated from multiple technologies for spatial domains identification and data denoising, making it a remarkable tool to obtain novel insights from SRT studies.

SGCLDGA: unveiling drug-gene associations through simple graph contrastive learning.

Drug repurposing offers a viable strategy for discovering new drugs and therapeutic targets through the analysis of drug-gene interactions. However, traditional experimental methods are plagued by their costliness and inefficiency. Despite graph convolutional network (GCN)-based models' state-of-the-art performance in prediction, their reliance on supervised learning makes them vulnerable to data sparsity, a common challenge in drug discovery, further complicating model development. In this study, we propose SGCLDGA, a novel computational model leveraging graph neural networks and contrastive learning to predict unknown drug-gene associations. SGCLDGA employs GCNs to extract vector representations of drugs and genes from the original bipartite graph. Subsequently, singular value decomposition (SVD) is employed to enhance the graph and generate multiple views. The model performs contrastive learning across these views, optimizing vector representations through a contrastive loss function to better distinguish positive and negative samples. The final step involves utilizing inner product calculations to determine association scores between drugs and genes. Experimental results on the DGIdb4.0 dataset demonstrate SGCLDGA's superior performance compared with six state-of-the-art methods. Ablation studies and case analyses validate the significance of contrastive learning and SVD, highlighting SGCLDGA's potential in discovering new drug-gene associations. The code and dataset for SGCLDGA are freely available at https://github.com/one-melon/SGCLDGA.

Deeply integrating latent consistent representations in high-noise multi-omics data for cancer subtyping.

Cancer is a complex and high-mortality disease regulated by multiple factors. Accurate cancer subtyping is crucial for formulating personalized treatment plans and improving patient survival rates. The underlying mechanisms that drive cancer progression can be comprehensively understood by analyzing multi-omics data. However, the high noise levels in omics data often pose challenges in capturing consistent representations and adequately integrating their information. This paper proposed a novel variational autoencoder-based deep learning model, named Deeply Integrating Latent Consistent Representations (DILCR). Firstly, multiple independent variational autoencoders and contrastive loss functions were designed to separate noise from omics data and capture latent consistent representations. Subsequently, an Attention Deep Integration Network was proposed to integrate consistent representations across different omics levels effectively. Additionally, we introduced the Improved Deep Embedded Clustering algorithm to make integrated variable clustering friendly. The effectiveness of DILCR was evaluated using 10 typical cancer datasets from The Cancer Genome Atlas and compared with 14 state-of-the-art integration methods. The results demonstrated that DILCR effectively captures the consistent representations in omics data and outperforms other integration methods in cancer subtyping. In the Kidney Renal Clear Cell Carcinoma case study, cancer subtypes were identified by DILCR with significant biological significance and interpretability.

MS-BACL: enhancing metabolic stability prediction through bond graph augmentation and contrastive learning.

MOTIVATION: Accurately predicting molecular metabolic stability is of great significance to drug research and development, ensuring drug safety and effectiveness. Existing deep learning methods, especially graph neural networks, can reveal the molecular structure of drugs and thus efficiently predict the metabolic stability of molecules. However, most of these methods focus on the message passing between adjacent atoms in the molecular graph, ignoring the relationship between bonds. This makes it difficult for these methods to estimate accurate molecular representations, thereby being limited in molecular metabolic stability prediction tasks. RESULTS: We propose the MS-BACL model based on bond graph augmentation technology and contrastive learning strategy, which can efficiently and reliably predict the metabolic stability of molecules. To our knowledge, this is the first time that bond-to-bond relationships in molecular graph structures have been considered in the task of metabolic stability prediction. We build a bond graph based on 'atom-bond-atom', and the model can simultaneously capture the information of atoms and bonds during the message propagation process. This enhances the model's ability to reveal the internal structure of the molecule, thereby improving the structural representation of the molecule. Furthermore, we perform contrastive learning training based on the molecular graph and its bond graph to learn the final molecular representation. Multiple sets of experimental results on public datasets show that the proposed MS-BACL model outperforms the state-of-the-art model. AVAILABILITY AND IMPLEMENTATION: The code and data are publicly available at https://github.com/taowang11/MS.

A two-stage computational framework for identifying antiviral peptides and their functional types based on contrastive learning and multi-feature fusion strategy.

Antiviral peptides (AVPs) have shown potential in inhibiting viral attachment, preventing viral fusion with host cells and disrupting viral replication due to their unique action mechanisms. They have now become a broad-spectrum, promising antiviral therapy. However, identifying effective AVPs is traditionally slow and costly. This study proposed a new two-stage computational framework for AVP identification. The first stage identifies AVPs from a wide range of peptides, and the second stage recognizes AVPs targeting specific families or viruses. This method integrates contrastive learning and multi-feature fusion strategy, focusing on sequence information and peptide characteristics, significantly enhancing predictive ability and interpretability. The evaluation results of the model show excellent performance, with accuracy of 0.9240 and Matthews correlation coefficient (MCC) score of 0.8482 on the non-AVP independent dataset, and accuracy of 0.9934 and MCC score of 0.9869 on the non-AMP independent dataset. Furthermore, our model can predict antiviral activities of AVPs against six key viral families (Coronaviridae, Retroviridae, Herpesviridae, Paramyxoviridae, Orthomyxoviridae, Flaviviridae) and eight viruses (FIV, HCV, HIV, HPIV3, HSV1, INFVA, RSV, SARS-CoV). Finally, to facilitate user accessibility, we built a user-friendly web interface deployed at https://awi.cuhk.edu.cn/∼dbAMP/AVP/.

A multi-view graph contrastive learning framework for deciphering spatially resolved transcriptomics data.

Spatially resolved transcriptomics data are being used in a revolutionary way to decipher the spatial pattern of gene expression and the spatial architecture of cell types. Much work has been done to exploit the genomic spatial architectures of cells. Such work is based on the common assumption that gene expression profiles of spatially adjacent spots are more similar than those of more distant spots. However, related work might not consider the nonlocal spatial co-expression dependency, which can better characterize the tissue architectures. Therefore, we propose MuCoST, a Multi-view graph Contrastive learning framework for deciphering complex Spatially resolved Transcriptomic architectures with dual scale structural dependency. To achieve this, we employ spot dependency augmentation by fusing gene expression correlation and spatial location proximity, thereby enabling MuCoST to model both nonlocal spatial co-expression dependency and spatially adjacent dependency. We benchmark MuCoST on four datasets, and we compare it with other state-of-the-art spatial domain identification methods. We demonstrate that MuCoST achieves the highest accuracy on spatial domain identification from various datasets. In particular, MuCoST accurately deciphers subtle biological textures and elaborates the variation of spatially functional patterns.

Contrastive learning in protein language space predicts interactions between drugs and protein targets.

Sequence-based prediction of drug-target interactions has the potential to accelerate drug discovery by complementing experimental screens. Such computational prediction needs to be generalizable and scalable while remaining sensitive to subtle variations in the inputs. However, current computational techniques fail to simultaneously meet these goals, often sacrificing performance of one to achieve the others. We develop a deep learning model, ConPLex, successfully leveraging the advances in pretrained protein language models ("PLex") and employing a protein-anchored contrastive coembedding ("Con") to outperform state-of-the-art approaches. ConPLex achieves high accuracy, broad adaptivity to unseen data, and specificity against decoy compounds. It makes predictions of binding based on the distance between learned representations, enabling predictions at the scale of massive compound libraries and the human proteome. Experimental testing of 19 kinase-drug interaction predictions validated 12 interactions, including four with subnanomolar affinity, plus a strongly binding EPHB1 inhibitor (KD = 1.3 nM). Furthermore, ConPLex embeddings are interpretable, which enables us to visualize the drug-target embedding space and use embeddings to characterize the function of human cell-surface proteins. We anticipate that ConPLex will facilitate efficient drug discovery by making highly sensitive in silico drug screening feasible at the genome scale. ConPLex is available open source at https://ConPLex.csail.mit.edu.

NMDA-driven dendritic modulation enables multitask representation learning in hierarchical sensory processing pathways.

While sensory representations in the brain depend on context, it remains unclear how such modulations are implemented at the biophysical level, and how processing layers further in the hierarchy can extract useful features for each possible contextual state. Here, we demonstrate that dendritic N-Methyl-D-Aspartate spikes can, within physiological constraints, implement contextual modulation of feedforward processing. Such neuron-specific modulations exploit prior knowledge, encoded in stable feedforward weights, to achieve transfer learning across contexts. In a network of biophysically realistic neuron models with context-independent feedforward weights, we show that modulatory inputs to dendritic branches can solve linearly nonseparable learning problems with a Hebbian, error-modulated learning rule. We also demonstrate that local prediction of whether representations originate either from different inputs, or from different contextual modulations of the same input, results in representation learning of hierarchical feedforward weights across processing layers that accommodate a multitude of contexts.

ConSpaS: a contrastive learning framework for identifying spatial domains by integrating local and global similarities.

Spatial transcriptomics is a rapidly growing field that aims to comprehensively characterize tissue organization and architecture at single-cell or sub-cellular resolution using spatial information. Such techniques provide a solid foundation for the mechanistic understanding of many biological processes in both health and disease that cannot be obtained using traditional technologies. Several methods have been proposed to decipher the spatial context of spots in tissue using spatial information. However, when spatial information and gene expression profiles are integrated, most methods only consider the local similarity of spatial information. As they do not consider the global semantic structure, spatial domain identification methods encounter poor or over-smoothed clusters. We developed ConSpaS, a novel node representation learning framework that precisely deciphers spatial domains by integrating local and global similarities based on graph autoencoder (GAE) and contrastive learning (CL). The GAE effectively integrates spatial information using local similarity and gene expression profiles, thereby ensuring that cluster assignment is spatially continuous. To improve the characterization of the global similarity of gene expression data, we adopt CL to consider the global semantic information. We propose an augmentation-free mechanism to construct global positive samples and use a semi-easy sampling strategy to define negative samples. We validated ConSpaS on multiple tissue types and technology platforms by comparing it with existing typical methods. The experimental results confirmed that ConSpaS effectively improved the identification accuracy of spatial domains with biologically meaningful spatial patterns, and denoised gene expression data while maintaining the spatial expression pattern. Furthermore, our proposed method better depicted the spatial trajectory by integrating local and global similarities.

Subtype-DCC: decoupled contrastive clustering method for cancer subtype identification based on multi-omics data.

Due to the high heterogeneity and complexity of cancers, patients with different cancer subtypes often have distinct groups of genomic and clinical characteristics. Therefore, the discovery and identification of cancer subtypes are crucial to cancer diagnosis, prognosis and treatment. Recent technological advances have accelerated the increasing availability of multi-omics data for cancer subtyping. To take advantage of the complementary information from multi-omics data, it is necessary to develop computational models that can represent and integrate different layers of data into a single framework. Here, we propose a decoupled contrastive clustering method (Subtype-DCC) based on multi-omics data integration for clustering to identify cancer subtypes. The idea of contrastive learning is introduced into deep clustering based on deep neural networks to learn clustering-friendly representations. Experimental results demonstrate the superior performance of the proposed Subtype-DCC model in identifying cancer subtypes over the currently available state-of-the-art clustering methods. The strength of Subtype-DCC is also supported by the survival and clinical analysis.

MSGCL: inferring miRNA-disease associations based on multi-view self-supervised graph structure contrastive learning.

Potential miRNA-disease associations (MDA) play an important role in the discovery of complex human disease etiology. Therefore, MDA prediction is an attractive research topic in the field of biomedical machine learning. Recently, several models have been proposed for this task, but their performance limited by over-reliance on relevant network information with noisy graph structure connections. However, the application of self-supervised graph structure learning to MDA tasks remains unexplored. Our study is the first to use multi-view self-supervised contrastive learning (MSGCL) for MDA prediction. Specifically, we generated a learner view without association labels of miRNAs and diseases as input, and utilized the known association network to generate an anchor view that provides guiding signals for the learner view. The graph structure was optimized by designing a contrastive loss to maximize the consistency between the anchor and learner views. Our model is similar to a pre-trained model that continuously optimizes upstream tasks for high-quality association graph topology, thereby enhancing the latent representation of association predictions. The experimental results show that our proposed method outperforms state-of-the-art methods by 2.79$\%$ and 3.20$\%$ in area under the receiver operating characteristic curve (AUC) and area under the precision/recall curve (AUPR), respectively.

Zero-shot-capable identification of phage-host relationships with whole-genome sequence representation by contrastive learning.

Accurately identifying phage-host relationships from their genome sequences is still challenging, especially for those phages and hosts with less homologous sequences. In this work, focusing on identifying the phage-host relationships at the species and genus level, we propose a contrastive learning based approach to learn whole-genome sequence embeddings that can take account of phage-host interactions (PHIs). Contrastive learning is used to make phages infecting the same hosts close to each other in the new representation space. Specifically, we rephrase whole-genome sequences with frequency chaos game representation (FCGR) and learn latent embeddings that 'encapsulate' phages and host relationships through contrastive learning. The contrastive learning method works well on the imbalanced dataset. Based on the learned embeddings, a proposed pipeline named CL4PHI can predict known hosts and unseen hosts in training. We compare our method with two recently proposed state-of-the-art learning-based methods on their benchmark datasets. The experiment results demonstrate that the proposed method using contrastive learning improves the prediction accuracy on known hosts and demonstrates a zero-shot prediction capability on unseen hosts. In terms of potential applications, the rapid pace of genome sequencing across different species has resulted in a vast amount of whole-genome sequencing data that require efficient computational methods for identifying phage-host interactions. The proposed approach is expected to address this need by efficiently processing whole-genome sequences of phages and prokaryotic hosts and capturing features related to phage-host relationships for genome sequence representation. This approach can be used to accelerate the discovery of phage-host interactions and aid in the development of phage-based therapies for infectious diseases.

Prediction of multi-relational drug-gene interaction via Dynamic hyperGraph Contrastive Learning.

Drug-gene interaction prediction occupies a crucial position in various areas of drug discovery, such as drug repurposing, lead discovery and off-target detection. Previous studies show good performance, but they are limited to exploring the binding interactions and ignoring the other interaction relationships. Graph neural networks have emerged as promising approaches owing to their powerful capability of modeling correlations under drug-gene bipartite graphs. Despite the widespread adoption of graph neural network-based methods, many of them experience performance degradation in situations where high-quality and sufficient training data are unavailable. Unfortunately, in practical drug discovery scenarios, interaction data are often sparse and noisy, which may lead to unsatisfactory results. To undertake the above challenges, we propose a novel Dynamic hyperGraph Contrastive Learning (DGCL) framework that exploits local and global relationships between drugs and genes. Specifically, graph convolutions are adopted to extract explicit local relations among drugs and genes. Meanwhile, the cooperation of dynamic hypergraph structure learning and hypergraph message passing enables the model to aggregate information in a global region. With flexible global-level messages, a self-augmented contrastive learning component is designed to constrain hypergraph structure learning and enhance the discrimination of drug/gene representations. Experiments conducted on three datasets show that DGCL is superior to eight state-of-the-art methods and notably gains a 7.6% performance improvement on the DGIdb dataset. Further analyses verify the robustness of DGCL for alleviating data sparsity and over-smoothing issues.

Self-supervised learning with chemistry-aware fragmentation for effective molecular property prediction.

Molecular property prediction (MPP) is a crucial and fundamental task for AI-aided drug discovery (AIDD). Recent studies have shown great promise of applying self-supervised learning (SSL) to producing molecular representations to cope with the widely-concerned data scarcity problem in AIDD. As some specific substructures of molecules play important roles in determining molecular properties, molecular representations learned by deep learning models are expected to attach more importance to such substructures implicitly or explicitly to achieve better predictive performance. However, few SSL pre-trained models for MPP in the literature have ever focused on such substructures. To challenge this situation, this paper presents a Chemistry-Aware Fragmentation for Effective MPP (CAFE-MPP in short) under the self-supervised contrastive learning framework. First, a novel fragment-based molecular graph (FMG) is designed to represent the topological relationship between chemistry-aware substructures that constitute a molecule. Then, with well-designed hard negative pairs, a is pre-trained on fragment-level by contrastive learning to extract representations for the nodes in FMGs. Finally, a Graphormer model is leveraged to produce molecular representations for MPP based on the embeddings of fragments. Experiments on 11 benchmark datasets show that the proposed CAFE-MPP method achieves state-of-the-art performance on 7 of the 11 datasets and the second-best performance on 3 datasets, compared with six remarkable self-supervised methods. Further investigations also demonstrate that CAFE-MPP can learn to embed molecules into representations implicitly containing the information of fragments highly correlated to molecular properties, and can alleviate the over-smoothing problem of graph neural networks.