Single-cell RNA-sequencing (scRNA-Seq) is widely used to reveal the heterogeneity and dynamics of tissues, organisms, and complex diseases, but its analyses still suffer from multiple grand challenges, including the sequencing sparsity and complex differential patterns in gene expression. We introduce the scGNN (single-cell graph neural network) to provide a hypothesis-free deep learning framework for scRNA-Seq analyses. This framework formulates and aggregates cell–cell relationships with graph neural networks and models heterogeneous gene expression patterns using a left-truncated mixture Gaussian model. scGNN integrates three iterative multi-modal autoencoders and outperforms existing tools for gene imputation and cell clustering on four benchmark scRNA-Seq datasets. In an Alzheimer’s disease study with 13,214 single nuclei from postmortem brain tissues, scGNN successfully illustrated disease-related neural development and the differential mechanism. scGNN provides an effective representation of gene expression and cell–cell relationships. It is also a powerful framework that can be applied to general scRNA-Seq analyses.

No abstract

Motivation Mitochondria are an essential organelle in most eukaryotes. They not only play an important role in energy metabolism but also take part in many critical cytopathological processes. Abnormal mitochondria can trigger a series of human diseases, such as Parkinson's disease, multifactor disorder and Type-II diabetes. Protein submitochondrial localization enables the understanding of protein function in studying disease pathogenesis and drug design. Results We proposed a new method, SubMito-XGBoost, for protein submitochondrial localization prediction. Three steps are included: (i) the g-gap dipeptide composition (g-gap DC), pseudo-amino acid composition (PseAAC), auto-correlation function (ACF) and Bi-gram position-specific scoring matrix (Bi-gram PSSM) are employed to extract protein sequence features, (ii) Synthetic Minority Oversampling Technique (SMOTE) is used to balance samples, and the ReliefF algorithm is applied for feature selection and (iii) the obtained feature vectors are fed into XGBoost to predict protein submitochondrial locations. SubMito-XGBoost has obtained satisfactory prediction results by the leave-one-out-cross-validation (LOOCV) compared with existing methods. The prediction accuracies of the SubMito-XGBoost method on the two training datasets M317 and M983 were 97.7% and 98.9%, which are 2.8–12.5% and 3.8–9.9% higher than other methods, respectively. The prediction accuracy of the independent test set M495 was 94.8%, which is significantly better than the existing studies. The proposed method also achieves satisfactory predictive performance on plant and non-plant protein submitochondrial datasets. SubMito-XGBoost also plays an important role in new drug design for the treatment of related diseases. Availability and implementation The source codes and data are publicly available at https://github.com/QUST-AIBBDRC/SubMito-XGBoost/. Supplementary information Supplementary data are available at Bioinformatics online.

Motivation The prediction of protein–protein interaction (PPI) sites is a key to mutation design, catalytic reaction and the reconstruction of PPI networks. It is a challenging task considering the significant abundant sequences and the imbalance issue in samples. Results A new ensemble learning-based method, Ensemble Learning of synthetic minority oversampling technique (SMOTE) for Unbalancing samples and RF algorithm (EL-SMURF), was proposed for PPI sites prediction in this study. The sequence profile feature and the residue evolution rates were combined for feature extraction of neighboring residues using a sliding window, and the SMOTE was applied to oversample interface residues in the feature space for the imbalance problem. The Multi-dimensional Scaling feature selection method was implemented to reduce feature redundancy and subset selection. Finally, the Random Forest classifiers were applied to build the ensemble learning model, and the optimal feature vectors were inserted into EL-SMURF to predict PPI sites. The performance validation of EL-SMURF on two independent validation datasets showed 77.1% and 77.7% accuracy, which were 6.2–15.7% and 6.1–18.9% higher than the other existing tools, respectively. Availability and implementation The source codes and data used in this study are publicly available at http://github.com/QUST-AIBBDRC/EL-SMURF/. Supplementary information Supplementary data are available at Bioinformatics online.

Appropriate ways to measure the similarity between single-cell RNA-sequencing (scRNA-seq) data are ubiquitous in bioinformatics, but using single clustering or classification methods to process scRNA-seq data is generally difficult. This has led to the emergence of integrated methods and tools that aim to automatically process specific problems associated with scRNA-seq data. These approaches have attracted a lot of interest in bioinformatics and related fields. In this paper, we systematically review the integrated methods and tools, highlighting the pros and cons of each approach. We not only pay particular attention to clustering and classification methods but also discuss methods that have emerged recently as powerful alternatives, including nonlinear and linear methods and descending dimension methods. Finally, we focus on clustering and classification methods for scRNA-seq data, in particular, integrated methods, and provide a comprehensive description of scRNA-seq data and download URLs.

Motivation The biclustering of large-scale gene expression data holds promising potential for detecting condition-specific functional gene modules (i.e. biclusters). However, existing methods do not adequately address a comprehensive detection of all significant bicluster structures and have limited power when applied to expression data generated by RNA-Sequencing (RNA-Seq), especially single-cell RNA-Seq (scRNA-Seq) data, where massive zero and low expression values are observed. Results We present a new biclustering algorithm, QUalitative BIClustering algorithm Version 2 (QUBIC2), which is empowered by: (i) a novel left-truncated mixture of Gaussian model for an accurate assessment of multimodality in zero-enriched expression data, (ii) a fast and efficient dropouts-saving expansion strategy for functional gene modules optimization using information divergency and (iii) a rigorous statistical test for the significance of all the identified biclusters in any organism, including those without substantial functional annotations. QUBIC2 demonstrated considerably improved performance in detecting biclusters compared to other five widely used algorithms on various benchmark datasets from E.coli, Human and simulated data. QUBIC2 also showcased robust and superior performance on gene expression data generated by microarray, bulk RNA-Seq and scRNA-Seq. Availability and implementation The source code of QUBIC2 is freely available at https://github.com/OSU-BMBL/QUBIC2. Contact czhang87@iu.edu or qin.ma@osumc.edu Supplementary information Supplementary data are available at Bioinformatics online.

Sex bias exists in the development and progression of non-reproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8 + T cell-dependent anti-tumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7 /TCF1 + progenitor exhausted CD8 + T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8 + T cells and a pertinent contribution from AR as a direct transcriptional trans-activator of Tcf7 /TCF1. The T cell intrinsic function of AR in promoting CD8 + T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8 + T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

Together with various hosts and environments, ubiquitous microbes interact closely with each other forming an intertwined system or community. Of interest, shifts of the relationships between microbes and their hosts or environments are associated with critical diseases and ecological changes. While advances in high-throughput Omics technologies offer a great opportunity for understanding the structures and functions of microbiome, it is still challenging to analyse and interpret the omics data. Specifically, the heterogeneity and diversity of microbial communities, compounded with the large size of the datasets, impose a tremendous challenge to mechanistically elucidate the complex communities. Fortunately, network analyses provide an efficient way to tackle this problem, and several network approaches have been proposed to improve this understanding recently. Here, we systemically illustrate these network theories that have been used in biological and biomedical research. Then, we review existing network modelling methods of microbial studies at multiple layers from metagenomics to metabolomics and further to multi-omics. Lastly, we discuss the limitations of present studies and provide a perspective for further directions in support of the understanding of microbial communities.