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Combination therapy is a promising strategy for confronting the complexity of cancer. However, experimental exploration of the vast space of potential drug combinations is costly and unfeasible. Therefore, computational methods for predicting drug synergy are much needed for narrowing down this space, especially when examining new cellular contexts. Here, we thus introduce CCSynergy, a flexible, context aware and integrative deep-learning framework that we have established to unleash the potential of the Chemical Checker extended drug bioactivity profiles for the purpose of drug synergy prediction. We have shown that CCSynergy enables predictions of superior accuracy, remarkable robustness and improved context generalizability as compared to the state-of-the-art methods in the field. Having established the potential of CCSynergy for generating experimentally validated predictions, we next exhaustively explored the untested drug combination space. This resulted in a compendium of potentially synergistic drug combinations on hundreds of cancer cell lines, which can guide future experimental screens.

The coronavirus disease of 2019 pandemic has catalyzed the rapid development of mRNA vaccines, whereas, how to optimize the mRNA sequence of exogenous gene such as severe acute respiratory syndrome coronavirus 2 spike to fit human cells remains a critical challenge. A new algorithm, iDRO (integrated deep-learning-based mRNA optimization), is developed to optimize multiple components of mRNA sequences based on given amino acid sequences of target protein. Considering the biological constraints, we divided iDRO into two steps: open reading frame (ORF) optimization and 5′ untranslated region (UTR) and 3′UTR generation. In ORF optimization, BiLSTM-CRF (bidirectional long-short-term memory with conditional random field) is employed to determine the codon for each amino acid. In UTR generation, RNA-Bart (bidirectional auto-regressive transformer) is proposed to output the corresponding UTR. The results show that the optimized sequences of exogenous genes acquired the pattern of human endogenous gene sequence. In experimental validation, the mRNA sequence optimized by our method, compared with conventional method, shows higher protein expression. To the best of our knowledge, this is the first study by introducing deep-learning methods to integrated mRNA sequence optimization, and these results may contribute to the development of mRNA therapeutics.

In recent years, the explosive growth of spatial technologies has enabled the characterization of spatial heterogeneity of tissue architectures. Compared to traditional sequencing, spatial transcriptomics reserves the spatial information of each captured location and provides novel insights into diverse spatially related biological contexts. Even though two spatial transcriptomics databases exist, they provide limited analytical information. Information such as spatial heterogeneity of genes and cells, cell-cell communication activities in space, and the cell type compositions in the microenvironment are critical clues to unveil the mechanism of tumorigenesis and embryo differentiation. Therefore, we constructed a new spatial transcriptomics database, named SPASCER (https://ccsm.uth.edu/SPASCER), designed to help understand the heterogeneity of tissue organizations, region-specific microenvironment, and intercellular interactions across tissue architectures at multiple levels. SPASCER contains datasets from 43 studies, including 1082 sub-datasets from 16 organ types across four species. scRNA-seq was integrated to deconvolve/map spatial transcriptomics, and processed with spatial cell-cell interaction, gene pattern and pathway enrichment analysis. Cell–cell interactions and gene regulation network of scRNA-seq from matched spatial transcriptomics were performed as well. The application of SPASCER will provide new insights into tissue architecture and a solid foundation for the mechanistic understanding of many biological processes in healthy and diseased tissues.

The distributed cryptocurrency networking is critical because the information delivered through it drives the mining consensus protocol and the rest of the operations. However, the cryptocurrency peer-to-peer (P2P) network remains vulnerable, and the existing security approaches are either ineffective or inefficient because of the permissionless requirement and the broadcasting overhead. We design a Lightweight and Identifier-Oblivious eNgine (LION) for the anomaly detection of the cryptocurrency networking. LION is not only effective in permissionless networking but is also lightweight and practical for the computation-intensive miners. We build LION for anomaly detection and use traffic analyses so that it minimally affects the mining rate and is substantially superior in its computational efficiency than the previous approaches based on machine learning. We implement a LION prototype on an active Bitcoin node to show that LION yields less than 1% of mining rate reduction subject to our prototype, in contrast to the state-of-the-art machine-learning approaches costing 12% or more depending on the algorithms subject to our prototype, while having detection accuracy of greater than 97% F1-score against the attack prototypes and real-world anomalies. LION therefore can be deployed on the existing miners without the need to introduce new entities in the cryptocurrency ecosystem.

Public Key Infrastructure (PKI) generates and distributes digital certificates to provide the root of trust for securing digital networking systems. To continue securing digital networking in the quantum era, PKI should transition to use quantum-resistant cryptographic algorithms. The cryptography community is developing quantum-resistant primitives/algorithms, studying, and analyzing them for cryptanalysis and improvements. National Institute of Standards and Technology (NIST) selected finalist algorithms for the post-quantum digital signature cipher standardization, which are Dilithium, Falcon, and Rainbow. We study and analyze the feasibility and the processing performance of these algorithms in memory/size and time/speed when used for PKI, including the key generation from the PKI end entities (e.g., a HTTPS/TLS server), the signing, and the certificate generation by the certificate authority within the PKI. The transition to post-quantum from the classical ciphers incur changes in the parameters in the PKI, for example, Rainbow I significantly increases the certificate size by 163 times when compared with RSA 3072. Nevertheless, we learn that the current X.509 supports the NIST post-quantum digital signature ciphers and that the ciphers can be modularly adapted for PKI. According to our empirical implementations-based study, the post-quantum ciphers can increase the certificate verification time cost compared to the current classicalmore »cipher and therefore the verification overheads require careful considerations when using the post-quantum-cipher-based certificates.« less