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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. [ABSTRACT FROM AUTHOR]

Metagenomics involves the study of genetic material obtained directly from communities of microorganisms living in natural environments. The field of metagenomics has provided valuable insights into the structure, diversity and ecology of microbial communities. Once an environmental sample is sequenced and processed, metagenomic binning clusters the sequences into bins representing different taxonomic groups such as species, genera, or higher levels. Several computational tools have been developed to automate the process of metagenomic binning. These tools have enabled the recovery of novel draft genomes of microorganisms allowing us to study their behaviors and functions within microbial communities. This review classifies and analyzes different approaches of metagenomic binning and different refinement, visualization, and evaluation techniques used by these methods. Furthermore, the review highlights the current challenges and areas of improvement present within the field of research. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing (scRNA-seq) enables the exploration of biological heterogeneity among different cell types within tissues at a resolution. Inferring cell types within tissues is foundational for downstream research. Most existing methods for cell type inference based on scRNA-seq data primarily utilize highly variable genes (HVGs) with higher expression levels as clustering features, overlooking the contribution of HVGs with lower expression levels. To address this, we have designed a novel cell type inference method for scRNA-seq data, termed scLEGA. scLEGA employs a novel zero-inflated negative binomial (ZINB) loss function that fully considers the contribution of genes with lower expression levels and combines two distinct scRNA-seq clustering strategies through a multi-head attention mechanism. It utilizes a low-expression optimized denoising autoencoder, based on the novel ZINB model, to extract low-dimensional features and handle dropout events, and a GCN-based graph autoencoder (GAE) that leverages neighbor information to guide dimensionality reduction. The iterative fusion of denoising and topological embedding in scLEGA facilitates the acquisition of cluster-friendly cell representations in the hidden embedding, where similar cells are brought closer together. Compared to 12 state-of-the-art cell type inference methods on 15 scRNA-seq datasets, scLEGA demonstrates superior performance in clustering accuracy, scalability, and stability. Our scLEGA model codes are freely available at https://github.com/Masonze/scLEGA-main. [ABSTRACT FROM AUTHOR]

Histone modifications, known as histone marks, are pivotal in regulating gene expression within cells. The vast array of potential combinations of histone marks presents a considerable challenge in decoding the regulatory mechanisms solely through biological experimental approaches. To overcome this challenge, we have developed a method called CatLearning. It utilizes a modified convolutional neural network architecture with a specialized adaptation Residual Network to quantitatively interpret histone marks and predict gene expression. This architecture integrates long-range histone information up to 500Kb and learns chromatin interaction features without 3D information. By using only one histone mark, CatLearning achieves a high level of accuracy. Furthermore, CatLearning predicts gene expression by simulating changes in histone modifications at enhancers and throughout the genome. These findings help comprehend the architecture of histone marks and develop diagnostic and therapeutic targets for diseases with epigenetic changes. [ABSTRACT FROM AUTHOR]

Deciphering the intricate relationships between transcription factors (TFs), enhancers, and genes through the inference of enhancer-driven gene regulatory networks (eGRNs) is crucial in understanding gene regulatory programs in a complex biological system. This study introduces STREAM, a novel method that leverages a Steiner forest problem model, a hybrid biclustering pipeline, and submodular optimization to infer eGRNs from jointly profiled single-cell transcriptome and chromatin accessibility data. Compared to existing methods, STREAM demonstrates enhanced performance in terms of TF recovery, TF–enhancer linkage prediction, and enhancer–gene relation discovery. Application of STREAM to an Alzheimer's disease dataset and a diffuse small lymphocytic lymphoma dataset reveals its ability to identify TF-enhancer–gene relations associated with pseudotime, as well as key TF-enhancer–gene relations and TF cooperation underlying tumor cells. [ABSTRACT FROM AUTHOR]

Recent advances in single-cell technologies enable the rapid growth of multi-omics data. Cell type annotation is one common task in analyzing single-cell data. It is a challenge that some cell types in the testing set are not present in the training set (i.e. unknown cell types). Most scATAC-seq cell type annotation methods generally assign each cell in the testing set to one known type in the training set but neglect unknown cell types. Here, we present OVAAnno, an automatic cell types annotation method which utilizes open-set domain adaptation to detect unknown cell types in scATAC-seq data. Comprehensive experiments show that OVAAnno successfully identifies known and unknown cell types. Further experiments demonstrate that OVAAnno also performs well on scRNA-seq data. Our codes are available online at https://github.com/lisaber/OVAAnno/tree/master. [ABSTRACT FROM AUTHOR]

The development of omics technologies has driven a profound expansion in the scale of biological data and the increased complexity in internal dimensions, prompting the utilization of machine learning (ML) as a powerful toolkit for extracting knowledge and understanding underlying biological patterns. Kidney disease represents one of the major growing global health threats with intricate pathogenic mechanisms and a lack of precise molecular pathology-based therapeutic modalities. Accordingly, there is a need for advanced high-throughput approaches to capture implicit molecular features and complement current experiments and statistics. This review aims to delineate strategies for integrating multi-omics data with appropriate ML methods, highlighting key clinical translational scenarios, including predicting disease progression risks to improve medical decision-making, comprehensively understanding disease molecular mechanisms, and practical applications of image recognition in renal digital pathology. Examining the benefits and challenges of current integration efforts is expected to shed light on the complexity of kidney disease and advance clinical practice. [ABSTRACT FROM AUTHOR]

Constructing accurate gene regulatory network s (GRNs), which reflect the dynamic governing process between genes, is critical to understanding the diverse cellular process and unveiling the complexities in biological systems. With the development of computer sciences, computational-based approaches have been applied to the GRNs inference task. However, current methodologies face challenges in effectively utilizing existing topological information and prior knowledge of gene regulatory relationships, hindering the comprehensive understanding and accurate reconstruction of GRNs. In response, we propose a novel graph neural network (GNN)-based Multi-Task Learning framework for GRN reconstruction, namely MTLGRN. Specifically, we first encode the gene promoter sequences and the gene biological features and concatenate the corresponding feature representations. Then, we construct a multi-task learning framework including GRN reconstruction , Gene knockout predict , and Gene expression matrix reconstruction. With joint training, MTLGRN can optimize the gene latent representations by integrating gene knockout information, promoter characteristics, and other biological attributes. Extensive experimental results demonstrate superior performance compared with state-of-the-art baselines on the GRN reconstruction task, efficiently leveraging biological knowledge and comprehensively understanding the gene regulatory relationships. MTLGRN also pioneered attempts to simulate gene knockouts on bulk data by incorporating gene knockout information. [ABSTRACT FROM AUTHOR]

Protein–protein interactions (PPIs) are important for many biological processes, but predicting them from sequence data remains challenging. Existing deep learning models often cannot generalize to proteins not present in the training set and do not provide uncertainty estimates for their predictions. To address these limitations, we present TUnA, a Transformer-based uncertainty-aware model for PPI prediction. TUnA uses ESM-2 embeddings with Transformer encoders and incorporates a Spectral-normalized Neural Gaussian Process. TUnA achieves state-of-the-art performance and, importantly, evaluates uncertainty for unseen sequences. We demonstrate that TUnA's uncertainty estimates can effectively identify the most reliable predictions, significantly reducing false positives. This capability is crucial in bridging the gap between computational predictions and experimental validation. [ABSTRACT FROM AUTHOR]

PROteolysis TArgeting Chimeras (PROTACs) has recently emerged as a promising technology. However, the design of rational PROTACs, especially the linker component, remains challenging due to the absence of structure–activity relationships and experimental data. Leveraging the structural characteristics of PROTACs, fragment-based drug design (FBDD) provides a feasible approach for PROTAC research. Concurrently, artificial intelligence–generated content has attracted considerable attention, with diffusion models and Transformers emerging as indispensable tools in this field. In response, we present a new diffusion model, DiffPROTACs, harnessing the power of Transformers to learn and generate new PROTAC linkers based on given ligands. To introduce the essential inductive biases required for molecular generation, we propose the O(3) equivariant graph Transformer module, which augments Transformers with graph neural networks (GNNs), using Transformers to update nodes and GNNs to update the coordinates of PROTAC atoms. DiffPROTACs effectively competes with existing models and achieves comparable performance on two traditional FBDD datasets, ZINC and GEOM. To differentiate the molecular characteristics between PROTACs and traditional small molecules, we fine-tuned the model on our self-built PROTACs dataset, achieving a 93.86% validity rate for generated PROTACs. Additionally, we provide a generated PROTAC database for further research, which can be accessed at https://bailab.siais.shanghaitech.edu.cn/service/DiffPROTACs-generated.tgz. The corresponding code is available at https://github.com/Fenglei104/DiffPROTACs and the server is at https://bailab.siais.shanghaitech.edu.cn/services/diffprotacs. [ABSTRACT FROM AUTHOR]

A biochemical pathway consists of a series of interconnected biochemical reactions to accomplish specific life activities. The participating reactants and resultant products of a pathway, including gene fragments, proteins, and small molecules, coalesce to form a complex reaction network. Biochemical pathways play a critical role in the biochemical domain as they can reveal the flow of biochemical reactions in living organisms, making them essential for understanding life processes. Existing studies of biochemical pathway networks are mainly based on experimentation and pathway database analysis methods, which are plagued by substantial cost constraints. Inspired by the success of representation learning approaches in biomedicine, we develop the biochemical pathway prediction (BPP) platform, which is an automatic BPP platform to identify potential links or attributes within biochemical pathway networks. Our BPP platform incorporates a variety of representation learning models, including the latest hypergraph neural networks technology to model biochemical reactions in pathways. In particular, BPP contains the latest biochemical pathway-based datasets and enables the prediction of potential participants or products of biochemical reactions in biochemical pathways. Additionally, BPP is equipped with an SHAP explainer to explain the predicted results and to calculate the contributions of each participating element. We conduct extensive experiments on our collected biochemical pathway dataset to benchmark the effectiveness of all models available on BPP. Furthermore, our detailed case studies based on the chronological pattern of our dataset demonstrate the effectiveness of our platform. Our BPP web portal, source code and datasets are freely accessible at https://github.com/Glasgow-AI4BioMed/BPP. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) serve as a crucial tool for identifying genetic factors associated with specific traits. However, ethical constraints prevent the direct exchange of genetic information, prompting the need for privacy preservation solutions. To address these issues, earlier works are based on cryptographic mechanisms such as homomorphic encryption, secure multi-party computing, and differential privacy. Very recently, federated learning has emerged as a promising solution for enabling secure and collaborative GWAS computations. This work provides an extensive overview of existing methods for GWAS privacy preserving, with the main focus on collaborative and distributed approaches. This survey provides a comprehensive analysis of the challenges faced by existing methods, their limitations, and insights into designing efficient solutions. [ABSTRACT FROM AUTHOR]

Large language models (LLMs) are sophisticated AI-driven models trained on vast sources of natural language data. They are adept at generating responses that closely mimic human conversational patterns. One of the most notable examples is OpenAI's ChatGPT, which has been extensively used across diverse sectors. Despite their flexibility, a significant challenge arises as most users must transmit their data to the servers of companies operating these models. Utilizing ChatGPT or similar models online may inadvertently expose sensitive information to the risk of data breaches. Therefore, implementing LLMs that are open source and smaller in scale within a secure local network becomes a crucial step for organizations where ensuring data privacy and protection has the highest priority, such as regulatory agencies. As a feasibility evaluation, we implemented a series of open-source LLMs within a regulatory agency's local network and assessed their performance on specific tasks involving extracting relevant clinical pharmacology information from regulatory drug labels. Our research shows that some models work well in the context of few- or zero-shot learning, achieving performance comparable, or even better than, neural network models that needed thousands of training samples. One of the models was selected to address a real-world issue of finding intrinsic factors that affect drugs' clinical exposure without any training or fine-tuning. In a dataset of over 700 000 sentences, the model showed a 78.5% accuracy rate. Our work pointed to the possibility of implementing open-source LLMs within a secure local network and using these models to perform various natural language processing tasks when large numbers of training examples are unavailable. [ABSTRACT FROM AUTHOR]

A large amount of clinical evidence began to mount, showing that circular ribonucleic acids (RNAs; circRNAs) perform a very important function in complex diseases by participating in transcription and translation regulation of microRNA (miRNA) target genes. However, with strict high-throughput techniques based on traditional biological experiments and the conditions and environment, the association between circRNA and miRNA can be discovered to be labor-intensive, expensive, time-consuming, and inefficient. In this paper, we proposed a novel computational model based on Word2vec, Structural Deep Network Embedding (SDNE), Convolutional Neural Network and Deep Neural Network, which predicts the potential circRNA-miRNA associations, called Word2vec, SDNE, Convolutional Neural Network and Deep Neural Network (WSCD). Specifically, the WSCD model extracts attribute feature and behaviour feature by word embedding and graph embedding algorithm, respectively, and ultimately feed them into a feature fusion model constructed by combining Convolutional Neural Network and Deep Neural Network to deduce potential circRNA-miRNA interactions. The proposed method is proved on dataset and obtained a prediction accuracy and an area under the receiver operating characteristic curve of 81.61% and 0.8898, respectively, which is shown to have much higher accuracy than the state-of-the-art models and classifier models in prediction. In addition, 23 miRNA-related circular RNAs (circRNAs) from the top 30 were confirmed in relevant experiences. In these works, all results represent that WSCD would be a helpful supplementary reliable method for predicting potential miRNA-circRNA associations compared to wet laboratory experiments. [ABSTRACT FROM AUTHOR]

Single-cell sequencing technologies are widely used to discover the evolutionary relationships and the differences in cells. Since dropout events may frustrate the analysis, many imputation approaches for single-cell RNA-seq data have appeared in previous attempts. However, previous imputation attempts usually suffer from the over-smooth problem, which may bring limited improvement or negative effect for the downstream analysis of single-cell RNA-seq data. To solve this difficulty, we propose a novel two-stage diffusion-denoising method called SCDD for large-scale single-cell RNA-seq imputation in this paper. We introduce the diffusion i.e. a direct imputation strategy using the expression of similar cells for potential dropout sites, to perform the initial imputation at first. After the diffusion, a joint model integrated with graph convolutional neural network and contractive autoencoder is developed to generate superposition states of similar cells, from which we restore the original states and remove the noise introduced by the diffusion. The final experimental results indicate that SCDD could effectively suppress the over-smooth problem and remarkably improve the effect of single-cell RNA-seq downstream analysis, including clustering and trajectory analysis. [ABSTRACT FROM AUTHOR]

The X-ray diffraction (XRD) technique based on crystallography is the main experimental method to analyze the three-dimensional structure of proteins. The production process of protein crystals on which the XRD technique relies has undergone multiple experimental steps, which requires a lot of manpower and material resources. In addition, studies have shown that not all proteins can form crystals under experimental conditions, and the success rate of the final crystallization of proteins is only <10%. Although some protein crystallization predictors have been developed, not many tools capable of predicting multi-stage protein crystallization propensity are available and the accuracy of these tools is not satisfactory. In this paper, we propose a novel deep learning framework, named SADeepcry, for predicting protein crystallization propensity. The framework can be used to estimate the three steps (protein material production, purification and crystallization) in protein crystallization experiments and the success rate of the final protein crystallization. SADeepcry uses the optimized self-attention and auto-encoder modules to extract sequence, structure and physicochemical features from the proteins. Compared with other state-of-the-art protein crystallization propensity prediction models, SADeepcry can obtain more complex global spatial long-distance dependence of protein sequence information. Our computational results show that SADeepcry has increased Matthews correlation coefficient and area under the curve, by 100.3% and 13.4%, respectively, over the DCFCrystal method on the benchmark dataset. The codes of SADeepcry are available at https://github.com/zhc940702/SADeepcry. [ABSTRACT FROM AUTHOR]

Deoxyribonucleic acid (DNA)-based data storage is a promising new storage technology which has the advantage of high storage capacity and long storage time compared with traditional storage media. However, the synthesis and sequencing process of DNA can randomly generate many types of errors, which makes it more difficult to cluster DNA sequences to recover DNA information. Currently, the available DNA clustering algorithms are targeted at DNA sequences in the biological domain, which not only cannot adapt to the characteristics of sequences in DNA storage, but also tend to be unacceptably time-consuming for billions of DNA sequences in DNA storage. In this paper, we propose an efficient DNA clustering method termed Clover for DNA storage with linear computational complexity and low memory. Clover avoids the computation of the Levenshtein distance by using a tree structure for interval-specific retrieval. We argue through theoretical proofs that Clover has standard linear computational complexity, low space complexity, etc. Experiments show that our method can cluster 10 million DNA sequences into 50 000 classes in 10 s and meet an accuracy rate of over 99%. Furthermore, we have successfully completed an unprecedented clustering of 10 billion DNA data on a single home computer and the time consumption still satisfies the linear relationship. Clover is freely available at https://github.com/Guanjinqu/Clover. [ABSTRACT FROM AUTHOR]

In recent years, a number of computational approaches have been proposed to effectively integrate multiple heterogeneous biological networks, and have shown impressive performance for inferring gene function. However, the previous methods do not fully represent the critical neighborhood relationship between genes during the feature learning process. Furthermore, it is difficult to accurately estimate the contributions of different views for multi-view integration. In this paper, we propose MGEGFP, a multi-view graph embedding method based on adaptive estimation with Graph Convolutional Network (GCN), to learn high-quality gene representations among multiple interaction networks for function prediction. First, we design a dual-channel GCN encoder to disentangle the view-specific information and the consensus pattern across diverse networks. By the aid of disentangled representations, we develop a multi-gate module to adaptively estimate the contributions of different views during each reconstruction process and make full use of the multiplexity advantages, where a diversity preservation constraint is designed to prevent the over-fitting problem. To validate the effectiveness of our model, we conduct experiments on networks from the STRING database for both yeast and human datasets, and compare the performance with seven state-of-the-art methods in five evaluation metrics. Moreover, the ablation study manifests the important contribution of the designed dual-channel encoder, multi-gate module and the diversity preservation constraint in MGEGFP. The experimental results confirm the superiority of our proposed method and suggest that MGEGFP can be a useful tool for gene function prediction. [ABSTRACT FROM AUTHOR]

CRISPR-Cas system is an adaptive immune system widely found in most bacteria and archaea to defend against exogenous gene invasion. One of the most critical steps in the study of exploring and classifying novel CRISPR-Cas systems and their functional diversity is the identification of Cas proteins in CRISPR-Cas systems. The discovery of novel Cas proteins has also laid the foundation for technologies such as CRISPR-Cas-based gene editing and gene therapy. Currently, accurate and efficient screening of Cas proteins from metagenomic sequences and proteomic sequences remains a challenge. For Cas proteins with low sequence conservation, existing tools for Cas protein identification based on homology cannot guarantee identification accuracy and efficiency. In this paper, we have developed a novel stacking-based ensemble learning framework for Cas protein identification, called CRISPRCasStack. In particular, we applied the SHAP (SHapley Additive exPlanations) method to analyze the features used in CRISPRCasStack. Sufficient experimental validation and independent testing have demonstrated that CRISPRCasStack can address the accuracy deficiencies and inefficiencies of the existing state-of-the-art tools. We also provide a toolkit to accurately identify and analyze potential Cas proteins, Cas operons, CRISPR arrays and CRISPR-Cas locus in prokaryotic sequences. The CRISPRCasStack toolkit is available at https://github.com/yrjia1015/CRISPRCasStack. [ABSTRACT FROM AUTHOR]

Measuring the semantic similarity between Gene Ontology (GO) terms is a fundamental step in numerous functional bioinformatics applications. To fully exploit the metadata of GO terms, word embedding-based methods have been proposed recently to map GO terms to low-dimensional feature vectors. However, these representation methods commonly overlook the key information hidden in the whole GO structure and the relationship between GO terms. In this paper, we propose a novel representation model for GO terms, named GT2Vec, which jointly considers the GO graph structure obtained by graph contrastive learning and the semantic description of GO terms based on BERT encoders. Our method is evaluated on a protein similarity task on a collection of benchmark datasets. The experimental results demonstrate the effectiveness of using a joint encoding graph structure and textual node descriptors to learn vector representations for GO terms. [ABSTRACT FROM AUTHOR]

Multi-drug combinations for the treatment of complex diseases are gradually becoming an important treatment, and this type of treatment can take advantage of the synergistic effects among drugs. However, drug–drug interactions (DDIs) are not just all beneficial. Accurate and rapid identifications of the DDIs are essential to enhance the effectiveness of combination therapy and avoid unintended side effects. Traditional DDIs prediction methods use only drug sequence information or drug graph information, which ignores information about the position of atoms and edges in the spatial structure. In this paper, we propose Molormer, a method based on a lightweight attention mechanism for DDIs prediction. Molormer takes the two-dimension (2D) structures of drugs as input and encodes the molecular graph with spatial information. Besides, Molormer uses lightweight-based attention mechanism and self-attention distilling to process spatially the encoded molecular graph, which not only retains the multi-headed attention mechanism but also reduces the computational and storage costs. Finally, we use the Siamese network architecture to serve as the architecture of Molormer, which can make full use of the limited data to train the model for better performance and also limit the differences to some extent between networks dealing with drug features. Experiments show that our proposed method outperforms state-of-the-art methods in Accuracy, Precision, Recall and F1 on multi-label DDIs dataset. In the case study section, we used Molormer to make predictions of new interactions for the drugs Aliskiren, Selexipag and Vorapaxar and validated parts of the predictions. Code and models are available at https://github.com/IsXudongZhang/Molormer. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 pandemic has alerted people of the threat caused by viruses. Vaccine is the most effective way to prevent the disease from spreading. The interaction between antibodies and antigens will clear the infectious organisms from the host. Identifying B-cell epitopes is critical in vaccine design, development of disease diagnostics and antibody production. However, traditional experimental methods to determine epitopes are time-consuming and expensive, and the predictive performance using the existing in silico methods is not satisfactory. This paper develops a general framework to predict variable-length linear B-cell epitopes specific for human-adapted viruses with machine learning approaches based on Protvec representation of peptides and physicochemical properties of amino acids. QR decomposition is incorporated during the embedding process that enables our models to handle variable-length sequences. Experimental results on large immune epitope datasets validate that our proposed model's performance is superior to the state-of-the-art methods in terms of AUROC (0.827) and AUPR (0.831) on the testing set. Moreover, sequence analysis also provides the results of the viral category for the corresponding predicted epitopes with high precision. Therefore, this framework is shown to reliably identify linear B-cell epitopes of human-adapted viruses given protein sequences and could provide assistance for potential future pandemics and epidemics. [ABSTRACT FROM AUTHOR]

Motivation Digital pathological analysis is run as the main examination used for cancer diagnosis. Recently, deep learning-driven feature extraction from pathology images is able to detect genetic variations and tumor environment, but few studies focus on differential gene expression in tumor cells. Results In this paper, we propose a self-supervised contrastive learning framework, HistCode, to infer differential gene expression from whole slide images (WSIs). We leveraged contrastive learning on large-scale unannotated WSIs to derive slide-level histopathological features in latent space, and then transfer it to tumor diagnosis and prediction of differentially expressed cancer driver genes. Our experiments showed that our method outperformed other state-of-the-art models in tumor diagnosis tasks, and also effectively predicted differential gene expression. Interestingly, we found the genes with higher fold change can be more precisely predicted. To intuitively illustrate the ability to extract informative features from pathological images, we spatially visualized the WSIs colored by the attention scores of image tiles. We found that the tumor and necrosis areas were highly consistent with the annotations of experienced pathologists. Moreover, the spatial heatmap generated by lymphocyte-specific gene expression patterns was also consistent with the manually labeled WSIs. [ABSTRACT FROM AUTHOR]

Circular RNA (circRNA) is closely involved in physiological and pathological processes of many diseases. Discovering the associations between circRNAs and diseases is of great significance. Due to the high-cost to verify the circRNA-disease associations by wet-lab experiments, computational approaches for predicting the associations become a promising research direction. In this paper, we propose a method, MDGF-MCEC, based on multi-view dual attention graph convolution network (GCN) with cooperative ensemble learning to predict circRNA-disease associations. First, MDGF-MCEC constructs two disease relation graphs and two circRNA relation graphs based on different similarities. Then, the relation graphs are fed into a multi-view GCN for representation learning. In order to learn high discriminative features, a dual-attention mechanism is introduced to adjust the contribution weights, at both channel level and spatial level, of different features. Based on the learned embedding features of diseases and circRNAs, nine different feature combinations between diseases and circRNAs are treated as new multi-view data. Finally, we construct a multi-view cooperative ensemble classifier to predict the associations between circRNAs and diseases. Experiments conducted on the CircR2Disease database demonstrate that the proposed MDGF-MCEC model achieves a high area under curve of 0.9744 and outperforms the state-of-the-art methods. Promising results are also obtained from experiments on the circ2Disease and circRNADisease databases. Furthermore, the predicted associated circRNAs for hepatocellular carcinoma and gastric cancer are supported by the literature. The code and dataset of this study are available at https://github.com/ABard0/MDGF-MCEC. [ABSTRACT FROM AUTHOR]

Structural variations (SVs) play important roles in human genetic diversity; deletions and insertions are two common types of SVs that have been proven to be associated with genetic diseases. Hence, accurately detecting and genotyping SVs is significant for disease research. Despite the fact that long-read sequencing technologies have improved the field of SV detection and genotyping, there are still some challenges that prevent satisfactory results from being obtained. In this paper, we propose MAMnet, a fast and scalable SV detection and genotyping method based on long reads and a combination of convolutional neural network and long short-term network. MAMnet uses a deep neural network to implement sensitive SV detection with a novel prediction strategy. On real long-read sequencing datasets, we demonstrate that MAMnet outperforms Sniffles, SVIM, cuteSV and PBSV in terms of their F1 scores while achieving better scaling performance. The source code is available from https://github.com/micahvista/MAMnet. [ABSTRACT FROM AUTHOR]

The development of single-cell RNA-sequencing (scRNA-seq) technologies has offered insights into complex biological systems at the single-cell resolution. In particular, these techniques facilitate the identifications of genes showing cell-type-specific differential expressions (DE). In this paper, we introduce MARBLES, a novel statistical model for cross-condition DE gene detection from scRNA-seq data. MARBLES employs a Markov Random Field model to borrow information across similar cell types and utilizes cell-type-specific pseudobulk count to account for sample-level variability. Our simulation results showed that MARBLES is more powerful than existing methods to detect DE genes with an appropriate control of false positive rate. Applications of MARBLES to real data identified novel disease-related DE genes and biological pathways from both a single-cell lipopolysaccharide mouse dataset with 24 381 cells and 11 076 genes and a Parkinson's disease human data set with 76 212 cells and 15 891 genes. Overall, MARBLES is a powerful tool to identify cell-type-specific DE genes across conditions from scRNA-seq data. [ABSTRACT FROM AUTHOR]

The association between the compositions of microbial communities and various host phenotypes is an important research topic. Microbiome association research addresses multiple domains, such as human disease and diet. Statistical methods for testing microbiome–phenotype associations have been studied recently to determine their ability to assess longitudinal microbiome data. However, existing methods fail to detect sparse association signals in longitudinal microbiome data. In this paper, we developed a novel method, namely aGEEMIHC, which is a data-driven adaptive microbiome higher criticism analysis based on generalized estimating equations to detect sparse microbial association signals from longitudinal microbiome data. aGEEMiHC adopts generalized estimating equations framework that fully considers the correlation among different observations from the same subject in longitudinal data. To be robust to diverse correlation structures for longitudinal data, aGEEMiHC integrates multiple microbiome higher criticism analyses based on generalized estimating equations with different working correlation structures. Extensive simulation experiments demonstrate that aGEEMiHC can control the type I error correctly and achieve superior performance according to a statistical power comparison. We also applied it to longitudinal microbiome data with various types of host phenotypes to demonstrate the stability of our method. aGEEMiHC is also utilized for real longitudinal microbiome data, and we found a significant association between the gut microbiome and Crohn's disease. In addition, our method ranks the significant factors associated with the host phenotype to provide potential biomarkers. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has infected hundreds of millions of people and killed millions of them. As an RNA virus, COVID-19 is more susceptible to variation than other viruses. Many problems involved in this epidemic have made biosafety and biosecurity (hereafter collectively referred to as 'biosafety') a popular and timely topic globally. Biosafety research covers a broad and diverse range of topics, and it is important to quickly identify hotspots and trends in biosafety research through big data analysis. However, the data-driven literature on biosafety research discovery is quite scant. We developed a novel topic model based on l atent D irichlet a llocation, a ffinity p ropagation clustering and the P age R ank algorithm (LDAPR) to extract knowledge from biosafety research publications from 2011 to 2020. Then, we conducted hotspot and trend analysis with LDAPR and carried out further studies, including annual hot topic extraction, a 10-year keyword evolution trend analysis, topic map construction, hot region discovery and fine-grained correlation analysis of interdisciplinary research topic trends. These analyses revealed valuable information that can guide epidemic prevention work: (1) the research enthusiasm over a certain infectious disease not only is related to its epidemic characteristics but also is affected by the progress of research on other diseases, and (2) infectious diseases are not only strongly related to their corresponding microorganisms but also potentially related to other specific microorganisms. The detailed experimental results and our code are available at https://github.com/KEAML-JLU/Biosafety-analysis. [ABSTRACT FROM AUTHOR]

With the development of high-throughput technologies, the accumulation of large amounts of multidimensional genomic data provides an excellent opportunity to study the multilevel biological regulatory relationships in cancer. Based on the hypothesis of competitive endogenous ribonucleic acid (RNA) (ceRNA) network, lncRNAs can eliminate the inhibition of microRNAs (miRNAs) on their target genes by binding to intracellular miRNA sites so as to improve the expression level of these target genes. However, previous studies on cancer expression mechanism are mostly based on individual or two-dimensional data, and lack of integration and analysis of various RNA-seq data, making it difficult to verify the complex biological relationships involved. To explore RNA expression patterns and potential molecular mechanisms of cancer, a network-regularized sparse orthogonal-regularized joint non-negative matrix factorization (NSOJNMF) algorithm is proposed, which combines the interaction relations among RNA-seq data in the way of network regularization and effectively prevents multicollinearity through sparse constraints and orthogonal regularization constraints to generate good modular sparse solutions. NSOJNMF algorithm is performed on the datasets of liver cancer and colon cancer, then ceRNA co-modules of them are recognized. The enrichment analysis of these modules shows that >90% of them are closely related to the occurrence and development of cancer. In addition, the ceRNA networks constructed by the ceRNA co-modules not only accurately mine the known correlations of the three RNA molecules but also further discover their potential biological associations, which may contribute to the exploration of the competitive relationships among multiple RNAs and the molecular mechanisms affecting tumor development. [ABSTRACT FROM AUTHOR]

Medical Dialogue Information Extraction (MDIE) is a promising task for modern medical care systems, which greatly facilitates the development of many real-world applications such as electronic medical record generation, automatic disease diagnosis, etc. Recent methods have firstly achieved considerable performance in Chinese MDIE but still suffer from some inherent limitations, such as poor exploitation of the inter-dependencies in multiple utterances, weak discrimination of the hard samples. In this paper, we propose a contrastive multi-utterance inference (CMUI) method to address these issues. Specifically, we first use a type-aware encoder to provide an efficient encode mechanism toward different categories. Subsequently, we introduce a selective attention mechanism to explicitly capture the dependencies among utterances, which thus constructs a multi-utterance inference. Finally, a supervised contrastive learning approach is integrated into our framework to improve the recognition ability for the hard samples. Extensive experiments show that our model achieves state-of-the-art performance on a public benchmark Chinese-based dataset and delivers significant performance gain on MDIE as compared with baselines. Specifically, we outperform the state-of-the-art results in F1-score by 2.27%, 0.55% in Recall and 3.61% in Precision (The codes that support the findings of this study are openly available in CMUI at https://github.com/jc4357/CMUI.). [ABSTRACT FROM AUTHOR]

Protein-DNA and protein-RNA interactions are involved in many biological activities. In the post-genome era, accurate identification of DNA- and RNA-binding residues in protein sequences is of great significance for studying protein functions and promoting new drug design and development. Therefore, some sequence-based computational methods have been proposed for identifying DNA- and RNA-binding residues. However, they failed to fully utilize the functional properties of residues, leading to limited prediction performance. In this paper, a sequence-based method iDRNA-ITF was proposed to incorporate the functional properties in residue representation by using an induction and transfer framework. The properties of nucleic acid-binding residues were induced by the nucleic acid-binding residue feature extraction network, and then transferred into the feature integration modules of the DNA-binding residue prediction network and the RNA-binding residue prediction network for the final prediction. Experimental results on four test sets demonstrate that iDRNA-ITF achieves the state-of-the-art performance, outperforming the other existing sequence-based methods. The webserver of iDRNA-ITF is freely available at http://bliulab.net/iDRNA-ITF. [ABSTRACT FROM AUTHOR]

In recent work, researchers have paid considerable attention to the estimation of causal effects in observational studies with a large number of covariates, which makes the unconfoundedness assumption plausible. In this paper, we review propensity score (PS) methods developed in high-dimensional settings and broadly group them into model-based methods that extend models for prediction to causal inference and balance-based methods that combine covariate balancing constraints. We conducted systematic simulation experiments to evaluate these two types of methods, and studied whether the use of balancing constraints further improved estimation performance. Our comparison methods were post-double-selection (PDS), double-index PS (DiPS), outcome-adaptive LASSO (OAL), group LASSO and doubly robust estimation (GLiDeR), high-dimensional covariate balancing PS (hdCBPS), regularized calibrated estimators (RCAL) and approximate residual balancing method (balanceHD). For the four model-based methods, simulation studies showed that GLiDeR was the most stable approach, with high estimation accuracy and precision, followed by PDS, OAL and DiPS. For balance-based methods, hdCBPS performed similarly to GLiDeR in terms of accuracy, and outperformed balanceHD and RCAL. These findings imply that PS methods do not benefit appreciably from covariate balancing constraints in high-dimensional settings. In conclusion, we recommend the preferential use of GLiDeR and hdCBPS approaches for estimating causal effects in high-dimensional settings; however, further studies on the construction of valid confidence intervals are required. [ABSTRACT FROM AUTHOR]

Computational prediction of multiple-type drug–drug interaction (DDI) helps reduce unexpected side effects in poly-drug treatments. Although existing computational approaches achieve inspiring results, they ignore to study which local structures of drugs cause DDIs, and their interpretability is still weak. In this paper, by supposing that the interactions between two given drugs are caused by their local chemical structures (substructures) and their DDI types are determined by the linkages between different substructure sets, we design a novel Substructure-aware Tensor Neural Network model for DDI prediction (STNN-DDI). The proposed model learns a 3-D tensor of |$\langle $|   substructure, substructure, interaction type   |$\rangle $| triplets, which characterizes a substructure–substructure interaction (SSI) space. According to a list of predefined substructures with specific chemical meanings, the mapping of drugs into this SSI space enables STNN-DDI to perform the multiple-type DDI prediction in both transductive and inductive scenarios in a unified form with an explicable manner. The comparison with deep learning-based state-of-the-art baselines demonstrates the superiority of STNN-DDI with the significant improvement of AUC, AUPR, Accuracy and Precision. More importantly, case studies illustrate its interpretability by both revealing an important substructure pair across drugs regarding a DDI type of interest and uncovering interaction type-specific substructure pairs in a given DDI. In summary, STNN-DDI provides an effective approach to predicting DDIs as well as explaining the interaction mechanisms among drugs. Source code is freely available at https://github.com/zsy-9/STNN-DDI. [ABSTRACT FROM AUTHOR]

Motivation Interaction between transcription factor (TF) and its target genes establishes the knowledge foundation for biological researches in transcriptional regulation, the number of which is, however, still limited by biological techniques. Existing computational methods relevant to the prediction of TF-target interactions are mostly proposed for predicting binding sites, rather than directly predicting the interactions. To this end, we propose here a graph attention-based autoencoder model to predict TF-target gene interactions using the information of the known TF-target gene interaction network combined with two sequential and chemical gene characters, considering that the unobserved interactions between transcription factors and target genes can be predicted by learning the pattern of the known ones. To the best of our knowledge, the proposed model is the first attempt to solve this problem by learning patterns from the known TF-target gene interaction network. Results In this paper, we formulate the prediction task of TF-target gene interactions as a link prediction problem on a complex knowledge graph and propose a deep learning model called GraphTGI, which is composed of a graph attention-based encoder and a bilinear decoder. We evaluated the prediction performance of the proposed method on a real dataset, and the experimental results show that the proposed model yields outstanding performance with an average AUC value of 0.8864 +/- 0.0057 in the 5-fold cross-validation. It is anticipated that the GraphTGI model can effectively and efficiently predict TF-target gene interactions on a large scale. Availability Python code and the datasets used in our studies are made available at https://github.com/YanghanWu/GraphTGI [ABSTRACT FROM AUTHOR]

It is tough to detect unexpected drug–drug interactions (DDIs) in poly-drug treatments because of high costs and clinical limitations. Computational approaches, such as deep learning-based approaches, are promising to screen potential DDIs among numerous drug pairs. Nevertheless, existing approaches neglect the asymmetric roles of two drugs in interaction. Such an asymmetry is crucial to poly-drug treatments since it determines drug priority in co-prescription. This paper designs a directed graph attention network (DGAT-DDI) to predict asymmetric DDIs. First, its encoder learns the embeddings of the source role, the target role and the self-roles of a drug. The source role embedding represents how a drug influences other drugs in DDIs. In contrast, the target role embedding represents how it is influenced by others. The self-role embedding encodes its chemical structure in a role-specific manner. Besides, two role-specific items, aggressiveness and impressionability, capture how the number of interaction partners of a drug affects its interaction tendency. Furthermore, the predictor of DGAT-DDI discriminates direction-specific interactions by the combination between two proximities and the above two role-specific items. The proximities measure the similarity between source/target embeddings and self-role embeddings. In the designated experiments, the comparison with state-of-the-art deep learning models demonstrates the superiority of DGAT-DDI across a direction-specific predicting task and a direction-blinded predicting task. An ablation study reveals how well each component of DGAT-DDI contributes to its ability. Moreover, a case study of finding novel DDIs confirms its practical ability, where 7 out of the top 10 candidates are validated in DrugBank. [ABSTRACT FROM AUTHOR]

The identification of the protein fold class is a challenging problem in structural biology. Recent computational methods for fold prediction leverage deep learning techniques to extract protein fold-representative embeddings mainly using evolutionary information in the form of multiple sequence alignment (MSA) as input source. In contrast, protein language models (LM) have reshaped the field thanks to their ability to learn efficient protein representations (protein-LM embeddings) from purely sequential information in a self-supervised manner. In this paper, we analyze a framework for protein fold prediction using pre-trained protein-LM embeddings as input to several fine-tuning neural network models, which are supervisedly trained with fold labels. In particular, we compare the performance of six protein-LM embeddings: the long short-term memory-based UniRep and SeqVec, and the transformer-based ESM-1b, ESM-MSA, ProtBERT and ProtT5; as well as three neural networks: Multi-Layer Perceptron, ResCNN-BGRU (RBG) and Light-Attention (LAT). We separately evaluated the pairwise fold recognition (PFR) and direct fold classification (DFC) tasks on well-known benchmark datasets. The results indicate that the combination of transformer-based embeddings, particularly those obtained at amino acid level, with the RBG and LAT fine-tuning models performs remarkably well in both tasks. To further increase prediction accuracy, we propose several ensemble strategies for PFR and DFC, which provide a significant performance boost over the current state-of-the-art results. All this suggests that moving from traditional protein representations to protein-LM embeddings is a very promising approach to protein fold-related tasks. [ABSTRACT FROM AUTHOR]

Predicting protein properties from amino acid sequences is an important problem in biology and pharmacology. Protein–protein interactions among SARS-CoV-2 spike protein, human receptors and antibodies are key determinants of the potency of this virus and its ability to evade the human immune response. As a rapidly evolving virus, SARS-CoV-2 has already developed into many variants with considerable variation in virulence among these variants. Utilizing the proteomic data of SARS-CoV-2 to predict its viral characteristics will, therefore, greatly aid in disease control and prevention. In this paper, we review and compare recent successful prediction methods based on long short-term memory (LSTM), transformer, convolutional neural network (CNN) and a similarity-based topological regression (TR) model and offer recommendations about appropriate predictive methodology depending on the similarity between training and test datasets. We compare the effectiveness of these models in predicting the binding affinity and expression of SARS-CoV-2 spike protein sequences. We also explore how effective these predictive methods are when trained on laboratory-created data and are tasked with predicting the binding affinity of the in-the-wild SARS-CoV-2 spike protein sequences obtained from the GISAID datasets. We observe that TR is a better method when the sample size is small and test protein sequences are sufficiently similar to the training sequence. However, when the training sample size is sufficiently large and prediction requires extrapolation, LSTM embedding and CNN-based predictive model show superior performance. [ABSTRACT FROM AUTHOR]

Predicting differentially expressed genes (DEGs) from epigenetics signal data is the key to understand how epigenetics controls cell functional heterogeneity by gene regulation. This knowledge can help developing 'epigenetics drugs' for complex diseases like cancers. Most of existing machine learning-based methods suffer defects in prediction accuracy, interpretability or training speed. To address these problems, in this paper, we propose a M ultiple S elf- A ttention model for predicting DEGs on Epi genetic data (Epi-MSA). Epi-MSA first uses convolutional neural networks for neighborhood bins information embedding, and then employs multiple self-attention encoders on different input epigenetics factors data to learn which locations of genes are important for predicting DEGs. Next it trains a soft attention module to pick out which epigenetics factors are significant. The attention mechanism makes the model interpretable, and the pure matrix operation of self-attention enables the model to be parallel calculated and speeds up the training. Experiments on datasets from the Roadmap Epigenome Project and BluePrint Data Analysis Portal (BDAP) show that the performance of Epi-MSA is better than existing competitive methods, and Epi-MSA also has a smaller standard deviation, which shows that Epi-MSA is effective and stable. In addition, Epi-MSA has a good interpretability, this is confirmed by referring its attention weight matrix with existing biological knowledge. [ABSTRACT FROM AUTHOR]

With the advances in sequencing technologies, a huge amount of biological data is extracted nowadays. Analyzing this amount of data is beyond the ability of human beings, creating a splendid opportunity for machine learning methods to grow. The methods, however, are practical only when the sequences are converted into feature vectors. Many tools target this task including iLearnPlus, a Python-based tool which supports a rich set of features. In this paper, we propose a holistic tool that extracts features from biological sequences (i.e. DNA, RNA and Protein). These features are the inputs to machine learning models that predict properties, structures or functions of the input sequences. Our tool not only supports all features in iLearnPlus but also 30 additional features which exist in the literature. Moreover, our tool is based on R language which makes an alternative for bioinformaticians to transform sequences into feature vectors. We have compared the conversion time of our tool with that of iLearnPlus: we transform the sequences much faster. We convert small nucleotides by a median of 2.8X faster, while we outperform iLearnPlus by a median of 6.3X for large sequences. Finally, in amino acids, our tool achieves a median speedup of 23.9X. [ABSTRACT FROM AUTHOR]

Synthetic lethality (SL) occurs between two genes when the inactivation of either gene alone has no effect on cell survival but the inactivation of both genes results in cell death. SL-based therapy has become one of the most promising targeted cancer therapies in the last decade as PARP inhibitors achieve great success in the clinic. The key point to exploiting SL-based cancer therapy is the identification of robust SL pairs. Although many wet-lab-based methods have been developed to screen SL pairs, known SL pairs are less than 0.1% of all potential pairs due to large number of human gene combinations. Computational prediction methods complement wet-lab-based methods to effectively reduce the search space of SL pairs. In this paper, we review the recent applications of computational methods and commonly used databases for SL prediction. First, we introduce the concept of SL and its screening methods. Second, various SL-related data resources are summarized. Then, computational methods including statistical-based methods, network-based methods, classical machine learning methods and deep learning methods for SL prediction are summarized. In particular, we elaborate on the negative sampling methods applied in these models. Next, representative tools for SL prediction are introduced. Finally, the challenges and future work for SL prediction are discussed. [ABSTRACT FROM AUTHOR]

In recent years, with the rapid development of techniques in bioinformatics and life science, a considerable quantity of biomedical data has been accumulated, based on which researchers have developed various computational approaches to discover potential associations between human microbes, drugs and diseases. This paper provides a comprehensive overview of recent advances in prediction of potential correlations between microbes, drugs and diseases from biological data to computational models. Firstly, we introduced the widely used datasets relevant to the identification of potential relationships between microbes, drugs and diseases in detail. And then, we divided a series of a lot of representative computing models into five major categories including network, matrix factorization, matrix completion, regularization and artificial neural network for in-depth discussion and comparison. Finally, we analysed possible challenges and opportunities in this research area, and at the same time we outlined some suggestions for further improvement of predictive performances as well. [ABSTRACT FROM AUTHOR]

There are a large number of unannotated proteins with unknown functions in rice, which are difficult to be verified by biological experiments. Therefore, computational method is one of the mainstream methods for rice proteins function prediction. Two representative rice proteins, indica protein and japonica protein, are selected as the experimental dataset. In this paper, two feature extraction methods (the residue couple model method and the pseudo amino acid composition method) and the Principal Component Analysis method are combined to design protein descriptive features. Moreover, based on the state-of-the-art MIML algorithm EnMIMLNN, a novel MIML learning framework MK-EnMIMLNN is proposed. And the MK-EnMIMLNN algorithm is designed by learning multiple kernel fusion function neural network. The experimental results show that the hybrid feature extraction method is better than the single feature extraction method. More importantly, the MK-EnMIMLNN algorithm is superior to most classic MIML learning algorithms, which proves the effectiveness of the MK-EnMIMLNN algorithm in rice proteins function prediction. [ABSTRACT FROM AUTHOR]

While the technologies of ribonucleic acid-sequence (RNA-seq) and transcript assembly analysis have continued to improve, a novel topology of RNA transcript was uncovered in the last decade and is called circular RNA (circRNA). Recently, researchers have revealed that they compete with messenger RNA (mRNA) and long noncoding for combining with microRNA in gene regulation. Therefore, circRNA was assumed to be associated with complex disease and discovering the relationship between them would contribute to medical research. However, the work of identifying the association between circRNA and disease in vitro takes a long time and usually without direction. During these years, more and more associations were verified by experiments. Hence, we proposed a computational method named identifying circRNA–disease association based on graph representation learning (iGRLCDA) for the prediction of the potential association of circRNA and disease, which utilized a deep learning model of graph convolution network (GCN) and graph factorization (GF). In detail, iGRLCDA first derived the hidden feature of known associations between circRNA and disease using the Gaussian interaction profile (GIP) kernel combined with disease semantic information to form a numeric descriptor. After that, it further used the deep learning model of GCN and GF to extract hidden features from the descriptor. Finally, the random forest classifier is introduced to identify the potential circRNA–disease association. The five-fold cross-validation of iGRLCDA shows strong competitiveness in comparison with other excellent prediction models at the gold standard data and achieved an average area under the receiver operating characteristic curve of 0.9289 and an area under the precision-recall curve of 0.9377. On reviewing the prediction results from the relevant literature, 22 of the top 30 predicted circRNA–disease associations were noted in recent published papers. These exceptional results make us believe that iGRLCDA can provide reliable circRNA–disease associations for medical research and reduce the blindness of wet-lab experiments. [ABSTRACT FROM AUTHOR]

DNA N6-methyladenine (6mA) is produced by the N6 position of the adenine being methylated, which occurs at the molecular level, and is involved in numerous vital biological processes in the rice genome. Given the shortcomings of biological experiments, researchers have developed many computational methods to predict 6mA sites and achieved good performance. However, the existing methods do not consider the occurrence mechanism of 6mA to extract features from the molecular structure. In this paper, a novel deep learning method is proposed by devising DNA molecular graph feature and residual block structure for 6mA sites prediction in rice, named MGF6mARice. Firstly, the DNA sequence is changed into a simplified molecular input line entry system (SMILES) format, which reflects chemical molecular structure. Secondly, for the molecular structure data, we construct the DNA molecular graph feature based on the principle of graph convolutional network. Then, the residual block is designed to extract higher level, distinguishable features from molecular graph features. Finally, the prediction module is used to obtain the result of whether it is a 6mA site. By means of 10-fold cross-validation, MGF6mARice outperforms the state-of-the-art approaches. Multiple experiments have shown that the molecular graph feature and residual block can promote the performance of MGF6mARice in 6mA prediction. To the best of our knowledge, it is the first time to derive a feature of DNA sequence by considering the chemical molecular structure. We hope that MGF6mARice will be helpful for researchers to analyze 6mA sites in rice. [ABSTRACT FROM AUTHOR]

Integrated modelling of biological systems is becoming a necessity for constructing models containing the major biochemical processes of such systems in order to obtain a holistic understanding of their dynamics and to elucidate emergent behaviours. Hybrid modelling methods are crucial to achieve integrated modelling of biological systems. This paper reviews currently popular hybrid modelling methods, developed for systems biology, mainly revealing why they are proposed, how they are formed from single modelling formalisms and how to simulate them. By doing this, we identify future research requirements regarding hybrid approaches for further promoting integrated modelling of biological systems. [ABSTRACT FROM AUTHOR]

Drug resistance is a major threat to the global health and a significant concern throughout the clinical treatment of diseases and drug development. The mutation in proteins that is related to drug binding is a common cause for adaptive drug resistance. Therefore, quantitative estimations of how mutations would affect the interaction between a drug and the target protein would be of vital significance for the drug development and the clinical practice. Computational methods that rely on molecular dynamics simulations, Rosetta protocols, as well as machine learning methods have been proven to be capable of predicting ligand affinity changes upon protein mutation. However, the severely limited sample size and heavy noise induced overfitting and generalization issues have impeded wide adoption of machine learning for studying drug resistance. In this paper, we propose a robust machine learning method, termed SPLDExtraTrees, which can accurately predict ligand binding affinity changes upon protein mutation and identify resistance-causing mutations. Especially, the proposed method ranks training data following a specific scheme that starts with easy-to-learn samples and gradually incorporates harder and diverse samples into the training, and then iterates between sample weight recalculations and model updates. In addition, we calculate additional physics-based structural features to provide the machine learning model with the valuable domain knowledge on proteins for these data-limited predictive tasks. The experiments substantiate the capability of the proposed method for predicting kinase inhibitor resistance under three scenarios and achieve predictive accuracy comparable with that of molecular dynamics and Rosetta methods with much less computational costs. [ABSTRACT FROM AUTHOR]

Single-particle cryo-electron microscopy (cryo-EM) has become one of the mainstream technologies in the field of structural biology to determine the three-dimensional (3D) structures of biological macromolecules. Heterogeneous cryo-EM projection image classification is an effective way to discover conformational heterogeneity of biological macromolecules in different functional states. However, due to the low signal-to-noise ratio of the projection images, the classification of heterogeneous cryo-EM projection images is a very challenging task. In this paper, two novel distance measures between projection images integrating the reliability of common lines, pixel intensity and class averages are designed, and then a two-stage spectral clustering algorithm based on the two distance measures is proposed for heterogeneous cryo-EM projection image classification. In the first stage, the novel distance measure integrating common lines and pixel intensities of projection images is used to obtain preliminary classification results through spectral clustering. In the second stage, another novel distance measure integrating the first novel distance measure and class averages generated from each group of projection images is used to obtain the final classification results through spectral clustering. The proposed two-stage spectral clustering algorithm is applied on a simulated and a real cryo-EM dataset for heterogeneous reconstruction. Results show that the two novel distance measures can be used to improve the classification performance of spectral clustering, and using the proposed two-stage spectral clustering algorithm can achieve higher classification and reconstruction accuracy than using RELION and XMIPP. [ABSTRACT FROM AUTHOR]

Ribonucleic acid (RNA) is a pivotal nucleic acid that plays a crucial role in regulating many biological activities. Recently, one study utilized a machine learning algorithm to automatically classify RNA structural events generated by a Mycobacterium smegmatis porin A nanopore trap. Although it can achieve desirable classification results, compared with deep learning (DL) methods, this classic machine learning requires domain knowledge to manually extract features, which is sophisticated, labor-intensive and time-consuming. Meanwhile, the generated original RNA structural events are not strictly equal in length, which is incompatible with the input requirements of DL models. To alleviate this issue, we propose a sequence-to-sequence (S2S) module that transforms the unequal length sequence (UELS) to the equal length sequence. Furthermore, to automatically extract features from the RNA structural events, we propose a sequence-to-sequence neural network based on DL. In addition, we add an attention mechanism to capture vital information for classification, such as dwell time and blockage amplitude. Through quantitative and qualitative analysis, the experimental results have achieved about a 2% performance increase (accuracy) compared to the previous method. The proposed method can also be applied to other nanopore platforms, such as the famous Oxford nanopore. It is worth noting that the proposed method is not only aimed at pursuing state-of-the-art performance but also provides an overall idea to process nanopore data with UELS. [ABSTRACT FROM AUTHOR]

This is a correction to: Zhou Yao, Wenjing Zhang, Peng Song, Yuxue Hu, Jianxiao Liu, DeepFormer: a hybrid network based on convolutional neural network and flow-attention mechanism for identifying the function of DNA sequences, Briefings in Bioinformatics, Volume 24, Issue 2, March 2023, bbad095, https://doi.org/10.1093/bib/bbad095.In the originally published version of this manuscript the first affiliation for author Zhou Yao was inadvertently omitted from the online version of the paper. This has now been corrected online. [Extracted from the article]

Structural information for chemical compounds is often described by pictorial images in most scientific documents, which cannot be easily understood and manipulated by computers. This dilemma makes optical chemical structure recognition (OCSR) an essential tool for automatically mining knowledge from an enormous amount of literature. However, existing OCSR methods fall far short of our expectations for realistic requirements due to their poor recovery accuracy. In this paper, we developed a deep neural network model named ABC-Net (Atom and Bond Center Network) to predict graph structures directly. Based on the divide-and-conquer principle, we propose to model an atom or a bond as a single point in the center. In this way, we can leverage a fully convolutional neural network (CNN) to generate a series of heat-maps to identify these points and predict relevant properties, such as atom types, atom charges, bond types and other properties. Thus, the molecular structure can be recovered by assembling the detected atoms and bonds. Our approach integrates all the detection and property prediction tasks into a single fully CNN, which is scalable and capable of processing molecular images quite efficiently. Experimental results demonstrate that our method could achieve a significant improvement in recognition performance compared with publicly available tools. The proposed method could be considered as a promising solution to OCSR problems and a starting point for the acquisition of molecular information in the literature. [ABSTRACT FROM AUTHOR]