Encoding spatially resolved transcriptomics (SRT) data serves to identify the biological semantics of RNA expression within the tissue while preserving spatial characteristics. Depending on the analytical scenario, one may focus on different contextual structures of tissues. For instance, anatomical regions reveal consistent patterns by focusing on spatial homogeneity, while elucidating complex tumor micro-environments requires more expression heterogeneity. However, current spatial encoding methods lack consideration of the tissue context. Meanwhile, most developed SRT technologies are still limited in providing exact patterns of intact tissues due to limitations such as low resolution or missed measurements. Here, we propose STForte, a novel pairwise graph autoencoder-based approach with cross-reconstruction and adversarial distribution matching, to model the spatial homogeneity and expression heterogeneity of SRT data. STForte extracts interpretable latent encodings, enabling downstream analysis by accurately portraying various tissue contexts. Moreover, STForte allows spatial imputation using only spatial consistency to restore the biological patterns of unobserved locations or low-quality cells, thereby providing fine-grained views to enhance the SRT analysis. Extensive evaluations of datasets under different scenarios and SRT platforms demonstrate that STForte is a scalable and versatile tool for providing enhanced insights into spatial data analysis.

MOTIVATION: Identifying bacteriophages (phages) within metagenomic sequences is essential for understanding microbial community dynamics. Transformer-based foundation models have been successfully employed to address various biological challenges. However, these models are typically pre-trained with self-supervised tasks that do not consider label variance in the pre-training data. This presents a challenge for phage identification as pre-training on mixed bacterial and phage data may lead to information bias due to the imbalance between bacterial and phage samples. RESULTS: To overcome this limitation, we proposed a novel conditional BERT framework that incorporates label classes as special tokens during pre-training. Specifically, our conditional BERT model attaches labels directly during tokenization, introducing label constraints into the model's input. Additionally, we introduced a new fine-tuning scheme that enables the conditional BERT to be effectively utilized for classification tasks. This framework allows the BERT model to acquire label-specific contextual representations from mixed sequence data during pre-training and applies the conditional BERT as a classifier during fine-tuning, and we named the fine-tuned model as PharaCon. We evaluated PharaCon against several existing methods on both simulated sequence datasets and real metagenomic contig datasets. The results demonstrate PharaCon's effectiveness and efficiency in phage identification, highlighting the advantages of incorporating label information during both pre-training and fine-tuning. AVAILABILITY AND IMPLEMENTATION: The source code and associated data can be accessed at https://github.com/Celestial-Bai/PharaCon.

Cancer development is driven by an accumulation of a small number of driver genetic mutations that confer the selective growth advantage to the cell, while most passenger mutations do not contribute to tumor progression. The identification of these driver genes responsible for tumorigenesis is a crucial step in designing effective cancer treatments. Although many computational methods have been developed with this purpose, the majority of existing methods solely provided a single driver gene list for the entire cohort of patients, ignoring the high heterogeneity of driver events across patients. It remains challenging to identify the personalized driver genes. Here, we propose a novel method (PDRWH), which aims to prioritize the mutated genes of a single patient based on their impact on the abnormal expression of downstream genes across a group of patients who share the co-mutation genes and similar gene expression profiles. The wide experimental results on 16 cancer datasets from TCGA showed that PDRWH excels in identifying known general driver genes and tumor-specific drivers. In the comparative testing across five cancer types, PDRWH outperformed existing individual-level methods as well as cohort-level methods. Our results also demonstrated that PDRWH could identify both common and rare drivers. The personalized driver profiles could improve tumor stratification, providing new insights into understanding tumor heterogeneity and taking a further step toward personalized treatment. We also validated one of our predicted novel personalized driver genes on tumor cell proliferation by vitro cell-based assays, the promoting effect of the high expression of Low-density lipoprotein receptor-related protein 1 (LRP1) on tumor cell proliferation.

MicroRNA (miRNA)-target interaction (MTI) plays a substantial role in various cell activities, molecular regulations and physiological processes. Published biomedical literature is the carrier of high-confidence MTI knowledge. However, digging out this knowledge in an efficient manner from large-scale published articles remains challenging. To address this issue, we were motivated to construct a deep learning-based model. We applied the pre-trained language models to biomedical text to obtain the representation, and subsequently fed them into a deep neural network with gate mechanism layers and a fully connected layer for the extraction of MTI information sentences. Performances of the proposed models were evaluated using two datasets constructed on the basis of text data obtained from miRTarBase. The validation and test results revealed that incorporating both PubMedBERT and SciBERT for sentence level encoding with the long short-term memory (LSTM)-based deep neural network can yield an outstanding performance, with both F1 and accuracy being higher than 80% on validation data and test data. Additionally, the proposed deep learning method outperformed the following machine learning methods: random forest, support vector machine, logistic regression and bidirectional LSTM. This work would greatly facilitate studies on MTI analysis and regulations. It is anticipated that this work can assist in large-scale screening of miRNAs, thereby revealing their functional roles in various diseases, which is important for the development of highly specific drugs with fewer side effects. Source code and corpus are publicly available at https://github.com/qi29.

The emergence of multidrug-resistant bacteria is a critical global crisis that poses a serious threat to public health, particularly with the rise of multidrug-resistant Staphylococcus aureus. Accurate assessment of drug resistance is essential for appropriate treatment and prevention of transmission of these deadly pathogens. Early detection of drug resistance in patients is critical for providing timely treatment and reducing the spread of multidrug-resistant bacteria. This study aims to develop a novel risk assessment framework for S. aureus that can accurately determine the resistance to multiple antibiotics. The comprehensive 7-year study involved ˃20 000 isolates with susceptibility testing profiles of six antibiotics. By incorporating mass spectrometry and machine learning, the study was able to predict the susceptibility to four different antibiotics with high accuracy. To validate the accuracy of our models, we externally tested on an independent cohort and achieved impressive results with an area under the receiver operating characteristic curve of 0. 94, 0.90, 0.86 and 0.91, and an area under the precision-recall curve of 0.93, 0.87, 0.87 and 0.81, respectively, for oxacillin, clindamycin, erythromycin and trimethoprim-sulfamethoxazole. In addition, the framework evaluated the level of multidrug resistance of the isolates by using the predicted drug resistance probabilities, interpreting them in the context of a multidrug resistance risk score and analyzing the performance contribution of different sample groups. The results of this study provide an efficient method for early antibiotic decision-making and a better understanding of the multidrug resistance risk of S. aureus.

MOTIVATION: Antimicrobial peptides (AMPs) have the potential to inhibit multiple types of pathogens and to heal infections. Computational strategies can assist in characterizing novel AMPs from proteome or collections of synthetic sequences and discovering their functional abilities toward different microbial targets without intensive labor. RESULTS: Here, we present a deep learning-based method for computer-aided novel AMP discovery that utilizes the transformer neural network architecture with knowledge from natural language processing to extract peptide sequence information. We implemented the method for two AMP-related tasks: the first is to discriminate AMPs from other peptides, and the second task is identifying AMPs functional activities related to seven different targets (gram-negative bacteria, gram-positive bacteria, fungi, viruses, cancer cells, parasites and mammalian cell inhibition), which is a multi-label problem. In addition, asymmetric loss was adopted to resolve the intrinsic imbalance of dataset, particularly for the multi-label scenarios. The evaluation showed that our proposed scheme achieves the best performance for the first task (96.85% balanced accuracy) and has a more unbiased prediction for the second task (79.83% balanced accuracy averaged across all functional activities) when compared with that of strategies without imbalanced learning or deep learning. AVAILABILITY AND IMPLEMENTATION: The source code and data of this study are available at https://github.com/BiOmicsLab/TransImbAMP. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

As the current worldwide outbreaks of the SARS-CoV-2, it is urgently needed to develop effective therapeutic agents for inhibiting the pathogens or treating the related diseases. Antimicrobial peptides (AMP) with functional activity against coronavirus could be a considerable solution, yet there is no research for identifying anti-coronavirus (anti-CoV) peptides with the computational approach. In this study, we first investigated the physiochemical and compositional properties of the collected anti-CoV peptides by comparing against three other negative sets: antivirus peptides without anti-CoV function (antivirus), regular AMP without antivirus functions (non-AVP) and peptides without antimicrobial functions (non-AMP). Then, we established classifiers for identifying anti-CoV peptides between different negative sets based on random forest. Imbalanced learning strategies were adopted due to the severe class-imbalance within the datasets. The geometric mean of the sensitivity and specificity (GMean) under the identification from antivirus, non-AVP and non-AMP reaches 83.07%, 85.51% and 98.82%, respectively. Then, to pursue identifying anti-CoV peptides from broad-spectrum peptides, we designed a double-stages classifier based on the collected datasets. In the first stage, the classifier characterizes AMPs from regular peptides. It achieves an area under the receiver operating curve (AUCROC) value of 97.31%. The second stage is to identify the anti-CoV peptides between the combined negatives of other AMPs. Here, the GMean of evaluation on the independent test set is 79.42%. The proposed approach is considered as an applicable scheme for assisting the development of novel anti-CoV peptides. The datasets and source codes used in this study are available at https://github.com/poncey/PreAntiCoV.

Antiviral peptide (AVP) is a kind of antimicrobial peptide (AMP) that has the potential ability to fight against virus infection. Machine learning-based prediction with a computational biology approach can facilitate the development of the novel therapeutic agents. In this study, we proposed a double-stage classification scheme, named AVPIden, for predicting the AVPs and their functional activities against different viruses. The first stage is to distinguish the AVP from a broad-spectrum peptide collection, including not only the regular peptides (non-AMP) but also the AMPs without antiviral functions (non-AVP). The second stage is responsible for characterizing one or more virus families or species that the AVP targets. Imbalanced learning is utilized to improve the performance of prediction. The AVPIden uses multiple descriptors to precisely demonstrate the peptide properties and adopts explainable machine learning strategies based on Shapley value to exploit how the descriptors impact the antiviral activities. Finally, the evaluation performance of the proposed model suggests its ability to predict the antivirus activities and their potential functions against six virus families (Coronaviridae, Retroviridae, Herpesviridae, Paramyxoviridae, Orthomyxoviridae, Flaviviridae) and eight kinds of virus (FIV, HCV, HIV, HPIV3, HSV1, INFVA, RSV, SARS-CoV). The AVPIden gives an option for reinforcing the development of AVPs with the computer-aided method and has been deployed at http://awi.cuhk.edu.cn/AVPIden/.