Briefings in bioinformatics最新文献

Decoding DNA methylation sites through nanopore sequencing has emerged as a cutting-edge technology in the field of DNA methylation research, as it enables direct sequencing of native DNA molecules without the need for prior enzymatic or chemical treatments. During nanopore sequencing, methylation modifications on DNA bases cause changes in electrical current intensity. Therefore, constructing deep neural network models to decode the electrical signals of nanopore sequencing has become a crucial step in methylation site identification. In this study, we utilized nanopore sequencing data containing diverse DNA methylation types and motif sequence diversity. We proposed a feature encoding method based on current signal clustering and leveraged the powerful attention mechanism in the Transformer framework to construct the PoreFormer model for identifying DNA methylation sites in nanopore sequencing. The model demonstrated excellent performance under conditions of multi-class methylation and motif sequence diversity, offering new insights into related research fields.

Medication recommendation is a crucial application of artificial intelligence in healthcare. Current methodologies mostly depend on patient-level longitudinal representation, which utilizes the entirety of historical electronic health records for making predictions. However, they tend to overlook a few key elements: (1) The need to analyze the impact of past medications on previous conditions. (2) Similarity in patient visits is more common than similarity in the complete medical histories of patients. (3) It is difficult to accurately represent patient-level longitudinal data due to the varying numbers of visits. To our knowledge, current models face difficulties in dealing with initial patient visits (i.e. in cold-start scenarios) which are common in clinical practice. This paper introduces DrugDoctor, an innovative drug recommendation model crafted to emulate the decision-making mechanics of human doctors. Unlike previous methods, DrugDoctor explores the visit-level relationship between prescriptions and diseases while considering the impact of past prescriptions on the patient's condition to provide more accurate recommendations. We design a plug-and-play block to effectively capture drug substructure-aware disease information and effectiveness-aware medication information, employing cross-attention and multi-head self-attention mechanisms. Furthermore, DrugDoctor adopts a fundamentally new visit-level training strategy, aligning more closely with the practices of doctors. Extensive experiments conducted on the MIMIC-III and MIMIC-IV datasets demonstrate that DrugDoctor outperforms 10 other state-of-the-art methods in terms of Jaccard, F1-score, and PRAUC. Moreover, DrugDoctor exhibits strong robustness in handling patients with varying numbers of visits and effectively tackles "cold-start" issues in medication combination recommendations.

Messenger RNA (mRNA) vaccines represent a groundbreaking advancement in immunology and public health, particularly highlighted by their role in combating the COVID-19 pandemic. Optimizing mRNA-based antigen expression is a crucial focus in this emerging industry. We have developed a bioinformatics tool named AntigenBoost to address the challenge posed by destabilizing dipeptides that hinder ribosomal translation. AntigenBoost identifies these dipeptides within specific antigens and provides a range of potential amino acid substitution strategies using a two-dimensional scoring system. Through a combination of bioinformatics analysis and experimental validation, we significantly enhanced the in vitro expression of mRNA-derived Respiratory Syncytial Virus fusion glycoprotein and Influenza A Hemagglutinin antigen. Notably, a single amino acid substitution improved the immune response in mice, underscoring the effectiveness of AntigenBoost in mRNA vaccine design.

Multiscale models provide a unique tool for analyzing complex processes that study events occurring at different scales across space and time. In the context of biological systems, such models can simulate mechanisms happening at the intracellular level such as signaling, and at the extracellular level where cells communicate and coordinate with other cells. These models aim to understand the impact of genetic or environmental deregulation observed in complex diseases, describe the interplay between a pathological tissue and the immune system, and suggest strategies to revert the diseased phenotypes. The construction of these multiscale models remains a very complex task, including the choice of the components to consider, the level of details of the processes to simulate, or the fitting of the parameters to the data. One additional difficulty is the expert knowledge needed to program these models in languages such as C++ or Python, which may discourage the participation of non-experts. Simplifying this process through structured description formalisms-coupled with a graphical interface-is crucial in making modeling more accessible to the broader scientific community, as well as streamlining the process for advanced users. This article introduces three examples of multiscale models which rely on the framework PhysiBoSS, an add-on of PhysiCell that includes intracellular descriptions as continuous time Boolean models to the agent-based approach. The article demonstrates how to construct these models more easily, relying on PhysiCell Studio, the PhysiCell Graphical User Interface. A step-by-step tutorial is provided as Supplementary Material and all models are provided at https://physiboss.github.io/tutorial/.

The evolution of lung adenocarcinoma is accompanied by a multitude of gene mutations and dysfunctions, rendering its phenotypic state and evolutionary direction highly complex. To interpret the evolution of lung adenocarcinoma, various methods have been developed to elucidate the molecular pathogenesis and functional evolution processes. However, most of these methods are constrained by the absence of cancerous temporal information, and the challenges of heterogeneous characteristics. To handle these problems, in this study, a patient quasi-potential landscape method was proposed to estimate the cancerous time of phenotypic states' emergence during the evolutionary process. Subsequently, a total of 39 different oncogenetic paths were identified based on cancerous time and mutations, reflecting the molecular pathogenesis of the evolutionary process of lung adenocarcinoma. To interpret the evolution patterns of lung adenocarcinoma, three oncogenetic graphs were obtained as the common evolutionary patterns by merging the oncogenetic paths. Moreover, patients were evenly re-divided into early, middle, and late evolutionary stages according to cancerous time, and a feasible framework was developed to construct the functional evolution network of lung adenocarcinoma. A total of six significant functional evolution processes were identified from the functional evolution network based on the pathway enrichment analysis, which plays critical roles in understanding the development of lung adenocarcinoma.

The recent development of artificial intelligence (AI) technology, especially the advance of deep neural network (DNN) technology, has revolutionized many fields. While DNN plays a central role in modern AI technology, it has rarely been used in genetic data analysis due to analytical and computational challenges brought by high-dimensional genetic data and an increasing number of samples. To facilitate the use of AI in genetic data analysis, we developed a C++ package, AIGen, based on two newly developed neural networks (i.e. kernel neural networks and functional neural networks) that are capable of modeling complex genotype-phenotype relationships (e.g. interactions) while providing robust performance against high-dimensional genetic data. Moreover, computationally efficient algorithms (e.g. a minimum norm quadratic unbiased estimation approach and batch training) are implemented in the package to accelerate the computation, making them computationally efficient for analyzing large-scale datasets with thousands or even millions of samples. By applying AIGen to the UK Biobank dataset, we demonstrate that it can efficiently analyze large-scale genetic data, attain improved accuracy, and maintain robust performance. Availability: AIGen is developed in C++ and its source code, along with reference libraries, is publicly accessible on GitHub at https://github.com/TingtHou/AIGen.

Mass spectrometry (MS)-based proteomics has become instrumental in comprehensively investigating complex biological systems. Data-independent acquisition (DIA)-MS, utilizing hybrid spectral library search strategies, allows for the simultaneous quantification of thousands of proteins, showing promise in enhancing protein identification and quantification precision. However, low-quality profiles can considerably undermine quantitative precision, resulting in inaccurate protein quantification. To tackle this challenge, we introduced STAVER, a novel algorithm that leverages standardized benchmark datasets to reduce non-biological variation in large-scale DIA-MS analyses. By eliminating unwanted noise in MS signals, STAVER significantly improved protein quantification precision, especially in hybrid spectral library searches. Moreover, we validated STAVER's robustness and applicability across multiple large-scale DIA datasets, demonstrating significantly enhanced precision and reproducibility of protein quantification. STAVER offers an innovative and effective approach for enhancing the quality of large-scale DIA proteomic data, facilitating cross-platform and cross-laboratory comparative analyses. This advancement significantly enhances the consistency and reliability of findings in clinical research. The complete package is available at https://github.com/Ran485/STAVER.

Inflammatory responses may lead to tissue or organ damage, and proinflammatory peptides (PIPs) are signaling peptides that can induce such responses. Many diseases have been redefined as inflammatory diseases. To identify PIPs more efficiently, we expanded the dataset and designed an ensemble learning model with manually encoded features. Specifically, we adopted a more comprehensive feature encoding method and considered the actual impact of certain features to filter them. Identification and prediction of PIPs were performed using an ensemble learning model based on five different classifiers. The results show that the model's sensitivity, specificity, accuracy, and Matthews correlation coefficient are all higher than those of the state-of-the-art models. We named this model MultiFeatVotPIP, and both the model and the data can be accessed publicly at https://github.com/ChaoruiYan019/MultiFeatVotPIP. Additionally, we have developed a user-friendly web interface for users, which can be accessed at http://www.bioai-lab.com/MultiFeatVotPIP.

The spatial reconstruction of single-cell RNA sequencing (scRNA-seq) data into spatial transcriptomics (ST) is a rapidly evolving field that addresses the significant challenge of aligning gene expression profiles to their spatial origins within tissues. This task is complicated by the inherent batch effects and the need for precise gene expression characterization to accurately reflect spatial information. To address these challenges, we developed SELF-Former, a transformer-based framework that utilizes multi-scale structures to learn gene representations, while designing spatial correlation constraints for the reconstruction of corresponding ST data. SELF-Former excels in recovering the spatial information of ST data and effectively mitigates batch effects between scRNA-seq and ST data. A novel aspect of SELF-Former is the introduction of a gene filtration module, which significantly enhances the spatial reconstruction task by selecting genes that are crucial for accurate spatial positioning and reconstruction. The superior performance and effectiveness of SELF-Former's modules have been validated across four benchmark datasets, establishing it as a robust and effective method for spatial reconstruction tasks. SELF-Former demonstrates its capability to extract meaningful gene expression information from scRNA-seq data and accurately map it to the spatial context of real ST data. Our method represents a significant advancement in the field, offering a reliable approach for spatial reconstruction.

The transcriptional regulatory network (TRN) is a graph framework that helps understand the complex transcriptional regulation mechanisms in the transcription process. Identifying the phenotype-specific transcription regulators is vital to reveal the functional roles of transcription elements in associating the specific phenotypes. Although many methods have been developed towards detecting the phenotype-specific transcription elements based on the static TRN in the past decade, most of them are not satisfactory for elucidating the phenotype-related functional roles of transcription regulators in multiple levels, as the dynamic characteristics of transcription regulators are usually ignored in static models. In this study, we introduce a novel framework called DTGN to identify the phenotype-specific transcription factors (TFs) and pathways by constructing dynamic TRNs. We first design a graph autoencoder model to integrate the phenotype-oriented time-series gene expression data and static TRN to learn the temporal representations of genes. Then, based on the learned temporal representations of genes, we develop a statistical method to construct a series of dynamic TRNs associated with the development of specific phenotypes. Finally, we identify the phenotype-specific TFs and pathways from the constructed dynamic TRNs. Results from multiple phenotypic datasets show that the proposed DTGN framework outperforms most existing methods in identifying phenotype-specific TFs and pathways. Our framework offers a new approach to exploring the functional roles of transcription regulators that associate with specific phenotypes in a dynamic model.