Background The spread of antibiotic resistance has become one of the most urgent threats to global health, which is estimated to cause 700,000 deaths each year globally. Its surrogates, antibiotic resistance genes (ARGs), are highly transmittable between food, water, animal, and human to mitigate the efficacy of antibiotics. Accurately identifying ARGs is thus an indispensable step to understanding the ecology, and transmission of ARGs between environmental and human-associated reservoirs. Unfortunately, the previous computational methods for identifying ARGs are mostly based on sequence alignment, which cannot identify novel ARGs, and their applications are limited by currently incomplete knowledge about ARGs. Results Here, we propose an end-to-end Hierarchical Multi-task Deep learning framework for ARG annotation (HMD-ARG). Taking raw sequence encoding as input, HMD-ARG can identify, without querying against existing sequence databases, multiple ARG properties simultaneously, including if the input protein sequence is an ARG, and if so, what antibiotic family it is resistant to, what resistant mechanism the ARG takes, and if the ARG is an intrinsic one or acquired one. In addition, if the predicted antibiotic family is beta-lactamase, HMD-ARG further predicts the subclass of beta-lactamase that the ARG is resistant to. Comprehensive experiments, including cross-fold validation, third-party dataset validation in human gut microbiota, wet-experimental functional validation, and structural investigation of predicted conserved sites, demonstrate not only the superior performance of our method over the state-of-art methods, but also the effectiveness and robustness of the proposed method. Conclusions We propose a hierarchical multi-task method, HMD-ARG, which is based on deep learning and can provide detailed annotations of ARGs from three important aspects: resistant antibiotic class, resistant mechanism, and gene mobility. We believe that HMD-ARG can serve as a powerful tool to identify antibiotic resistance genes and, therefore mitigate their global threat. Our method and the constructed database are available at http://www.cbrc.kaust.edu.sa/HMDARG/.
Fully exploring correlation among points in point clouds is essential for their feature modeling. This paper presents a novel end-to-end graph model, named Point2Node, to represent a given point cloud. Point2Node can dynamically explore correlation among all graph nodes from different levels, and adaptively aggregate the learned features. Specifically, first, to fully explore the spatial correlation among points for enhanced feature description, in a high-dimensional node graph, we dynamically integrate the node's correlation with self, local, and non-local nodes. Second, to more effectively integrate learned features, we design a data-aware gate mechanism to self-adaptively aggregate features at the channel level. Extensive experiments on various point cloud benchmarks demonstrate that our method outperforms the state-of-the-art.
We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8-mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.
Fully exploring correlation among points in point clouds is essential for their feature modeling. This paper presents a novel end-to-end graph model, named Point2Node, to represent a given point cloud. Point2Node can dynamically explore correlation among all graph nodes from different levels, and adaptively aggregate the learned features. Specifically, first, to fully explore the spatial correlation among points for enhanced feature description, in a high-dimensional node graph, we dynamically integrate the node's correlation with self, local, and non-local nodes. Second, to more effectively integrate learned features, we design a data-aware gate mechanism to self-adaptively aggregate features at the channel level. Extensive experiments on various point cloud benchmarks demonstrate that our method outperforms the state-ofthe-art.
Single-cell RNA-sequencing (scRNA-seq) has become a powerful tool to reveal the complex biological diversity and heterogeneity among cell populations. However, the technical noise and bias of the technology still have negative impacts on the downstream analysis. Here, we present a self-supervised Contrastive LEArning framework for scRNA-seq (CLEAR) profile representation and the downstream analysis. CLEAR overcomes the heterogeneity of the experimental data with a specifically designed representation learning task and thus can handle batch effects and dropout events. In the task, the deep learning model learns to pull together the representations of similar cells while pushing apart distinct cells, without manual labeling. It achieves superior performance on a broad range of fundamental tasks, including clustering, visualization, dropout correction, batch effect removal, and pseudo-time inference. The proposed method successfully identifies and illustrates inflammatory-related mechanisms in a COVID-19 disease study with 43,695 single cells from peripheral blood mononuclear cells. Further experiments to process a million-scale single-cell dataset demonstrate the scalability of CLEAR. This scalable method generates effective scRNA-seq data representation while eliminating technical noise, and it will serve as a general computational framework for single-cell data analysis.
Modern machine learning models towards various tasks with omic data analysis give rise to threats of privacy leakage of patients involved in those datasets. Despite the advances in different privacy technologies, existing methods tend to introduce too much noise, which hampers model accuracy and usefulness. Here, we built a secure and privacy-preserving machine learning (PPML) system by combining federated learning (FL), differential privacy (DP) and shuffling mechanism. We applied this system to analyze data from three sequencing technologies, and addressed the privacy concern in three major tasks of omic data, namely cancer classification with bulk RNA-seq, clustering with single-cell RNA-seq, and the integration of spatial gene expression and tumour morphology with spatial transcriptomics, under three representative deep learning models. We also examined privacy breaches in depth through privacy attack experiments and demonstrated that our PPML-Omics system could protect patients' privacy. In each of these applications, PPML-Omics was able to outperform state-of-the-art systems under the same level of privacy guarantee, demonstrating the versatility of the system in simultaneously balancing the privacy-preserving capability and utility in omic data analysis. Furthermore, we gave the theoretical proof of the privacy-preserving capability of PPML-Omics, suggesting the first mathematically guaranteed model with robust and generalizable empirical performance.
We present a novel self-supervised Contrastive LEArning framework for single-cell ribonucleic acid (RNA)-sequencing (CLEAR) data representation and the downstream analysis. Compared with current methods, CLEAR overcomes the heterogeneity of the experimental data with a specifically designed representation learning task and thus can handle batch effects and dropout events simultaneously. It achieves superior performance on a broad range of fundamental tasks, including clustering, visualization, dropout correction, batch effect removal, and pseudo-time inference. The proposed method successfully identifies and illustrates inflammatory-related mechanisms in a COVID-19 disease study with 43 695 single cells from peripheral blood mononuclear cells.
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