ASOptimizer: Optimizing antisense oligonucleotides through deep learning for IDO1 gene regulation.

Recent studies have highlighted the effectiveness of using antisense oligonucleotides (ASOs) for cellular RNA regulation, including targets that are considered undruggable; however, manually designing optimal ASO sequences can be labor intensive and time consuming, which potentially limits their broader application. To address this challenge, we introduce a platform, the ASOptimizer, a deep-learning-based framework that efficiently designs ASOs at a low cost. This platform not only selects the most efficient mRNA target sites but also optimizes the chemical modifications for enhanced performance. Indoleamine 2,3-dioxygenase 1 (IDO1) promotes cancer survival by depleting tryptophan and producing kynurenine, leading to immunosuppression through the aryl-hydrocarbon receptor (Ahr) pathway within the tumor microenvironment. We used ASOptimizer to identify ASOs that target IDO1 mRNA as potential cancer therapeutics. Our methodology consists of two stages: sequence engineering and chemical engineering. During the sequence-engineering stage, we optimized and predicted ASO sequences that could target IDO1 mRNA efficiently. In the chemical-engineering stage, we further refined these ASOs to enhance their inhibitory activity while reducing their potential cytotoxicity. In conclusion, our research demonstrates the potential of ASOptimizer for identifying ASOs with improved efficacy and safety.

Molecular characterization and environmental impact of newly isolated lytic phage SLAM_phiST1N3 in the Cornellvirus genus for biocontrol of a multidrug-resistant Salmonella Typhimurium in the swine industry chain.

Salmonella Typhimurium is a highly lethal pathogenic bacterium in weaned piglets, causing significant treatment costs and economic losses in the swine industry. Additionally, due to its ability to induce zoonotic diseases, resulting in harm to humans through the transmission of the pathogen from pork, it presents a serious public health issue. Bacteriophages (phages), viruses that infect specific bacterial strains, have been proposed as an alternative to antibiotics for controlling pathogenic bacteria. In this study, we isolated SLAM_phiST1N3, a phage infecting a multidrug-resistant (MDR) S. Typhimurium wild-type strain isolated from diseased pigs. First, comparative genomics and phylogenetic analysis revealed that SLAM_phiST1N3 belongs to the Cornellvirus genus. Moreover, utilizing a novel classification approach introduced in this study, SLAM_phiST1N3 was classified at the species level. Host range experiments demonstrated that SLAM_phiST1N3 did not infect other pathogenic bacteria or probiotics derived from pigs or other livestock. While complete eradication of Salmonella was not achievable in the liquid inhibition assay, surprisingly, we succeeded in largely eliminating Salmonella in the FIMM analysis, a gut simulation system using weaned piglet feces. Furthermore, using the C. elegans model, we showcased the potential of SLAM_phiST1N3 to prevent S. Typhimurium infection in living organisms. In addition, it was confirmed that bacterial control could be achieved when phage was applied to Salmonella-contaminated pork. pH and temperature stability experiments demonstrated that SLAM_phiST1N3 can endure swine industry processes and digestive conditions. In conclusion, SLAM_phiST1N3 demonstrates potential environmental impact as a substance for Salmonella prevention across various aspects of the swine industry chain.

Polystyrene microplastics biodegradation by gut bacterial Enterobacter hormaechei from mealworms under anaerobic conditions: Anaerobic oxidation and depolymerization.

Synthetic plastic is used throughout daily life and industry, threatening organisms with microplastic pollution. Polystyrene is a major plastic polymer and also widely found sources of plastic wastes and microplastics. Here, we report that Enterobacter hormaechei LG3 (CP118279.1), a facultative anaerobic bacterial strain isolated from the gut of Tenebrio molitor larvae (mealworms) can oxidize and depolymerize polystyrene under anaerobic conditions. LG3 performed biodegradation while forming a biofilm on the plastic surface. PS biodegradation was characterized by analyses of surface oxidation, change in morphology and molecular weights, and production of biodegraded derivative. The biodegradation performance by LG3 was compared with PS biodegradation by Bacillus amyloliquefaciens SCGB1 under both anaerobic and aerobic conditions. In addition, through nanopore sequencing technology, we identified degradative enzymes, including thiol peroxidase (tpx), alkyl hydroperoxide reductase C (ahpC) and bacterioferritin comigratory protein (bcp). Along with the upregulation of degradative enzymes for biodegradation, changes in lipid A and biofilm-associated proteins were also observed after the cells were incubated with polystyrene microplastics. Our results provide evidence for anaerobic biodegradation by polystyrene-degrading bacteria and show alterations in gene expression patterns after polystyrene microplastics treatment in the opportunistic pathogen Enterobacter hormaechei.