Drug repositioning allows for the identification of potential alternative therapeutic uses for existing drugs, thereby accelerating the drug development process. In this field, there are numerous methods that utilize deep learning techniques for Drug−Disease Association (DDA) prediction. However, capturing complex features of biological entities and graph nodes still presents challenges. To tackle these challenges, we proposed a Dual-Branch Graph (DBG) representation learning approach for DDA (DBG-DDA). Specifically, we integrate features obtained from graph learning algorithms based on random walks and convolutions for subsequent classification operations. Firstly, we construct a drug−Protein−Disease Heterogeneous Information Network (HIN). Then, we employ the Meta-path Aggregation HIN method (MAHIN) based on meta-path to extract high-level features from the graph network, followed by utilizing the graph attention network for graph transformer structure algorithm to extract low-level features, and fuse the features by applying nonlinear transformations followed by summation. Finally, the fused features are inputted into a classifier to predict DDAs. A series of experimental results demonstrate that DBG-DDA outperforms several state-of-the-art DDA prediction methods on multiple public databases, providing effective predictions for discovering new drug indications and novel therapeutic approaches for diseases. Overall, the results indicate that DBG-DDA offers a promising direction in drug repositioning. Our code is available at https://github.com/guanzhenghua/DBG-DDA.

The perpetual molecular arms race between bacteriophages and their prokaryotic hosts revolves around nucleotide-derived signaling molecules that serve as pivotal regulators of offensive and defensive strategies. This review integrates contemporary advances elucidating how cyclic nucleotide monophosphates (cNMPs), bacterial second messengers (c-di-GMP, c-di-AMP, (p)ppGpp), and nucleotide-activated antiviral defense systems (CBASS, Thoeris, Pycsar, Kongming) coordinate phage-bacteria interactions through sophisticated molecular surveillance networks. We systematically analyze phage counteradaptation mechanisms that hijack nucleotide-mediated signaling pathways for replicative advantage and immune suppression, contrasted with bacterial counterstrategies employing nucleotide dynamics in restriction mechanisms and abortive infection systems. The review further examines cutting-edge biotechnological applications capitalizing on these molecular interactions, including precision phage therapeutics, engineered phage platforms, functional phage biodesign, and phage-mediated microbiome modulation. By synthesizing structural insights into nucleotide-based defense architectures with emerging phage resistance paradigms, we identify critical knowledge gaps regarding signal transduction specificity, evolutionary trade-offs in defense systems, and spatiotemporal regulation of nucleotide networks during lytic/lysogenic cycles. This comprehensive analysis provides a conceptual framework for advancing phage engineering and antimicrobial development in the post-antibiotic era.

The human body is colonized by a diverse community of microorganisms that are crucial for human health, while microbiota homeostasis is modulated by both environmental and host-derived cues. Specific microbial species form surface-attached microcolonies surrounded by their self-generated extracellular polymeric substances called biofilms. These complex assemblies may protect commensal bacteria, serving as a barrier against pathogenic microorganisms as well as hostile conditions, thus creating structuralized microbial communities for complex microbial interactions. However, biofilms formed by pathogenic bacteria will lead to invasion and perturbance of microbiota homeostasis, potentially leading to dysbiosis and diseases. In this review, we provide an in-depth analysis of the multiple-species biofilms on microbiota homeostasis within the human body. We describe the nature of biofilms in various anatomical regions, emphasizing their protective role against pathogenic invasions and their potential roles in causing disease under certain conditions. We also explore the microbial interactions between biofilms and microbial communities, emphasizing the significant potential of biofilms to alter the structure and composition of microbial assemblages. Finally, we suggest the directions for future biofilm research to enhance our understanding of the pathogenesis of diseases related to microbial dysbiosis and human health.

As pathogenic fungi increasingly threaten public health, particularly in immunocompromised populations, understanding the mechanisms behind fungal drug resistance has become critical. This review focuses on the pivotal role of mitochondria in this process. Evidence indicates that mitochondria are essential not only for cellular energy metabolism and responses to oxidative stress but also for significantly influencing the expression and activity of drug efflux pumps, which facilitate the expulsion of antifungal agents. Moreover, the intricate roles of mitochondria in iron homoeostasis and calcium signalling are closely linked to the development of drug resistance in fungi. By elucidating these mechanisms, we can identify potential therapeutic targets and pave the way for more effective strategies to combat resistant fungal infections.

Pseudomonas aeruginosa is one of the leading nosocomial pathogens that causes both severe acute and chronic infections. The strong capacity of P. aeruginosa to form biofilms can dramatically increase its antibiotic resistance and lead to treatment failure. The biofilm resident bacterial cells display distinct gene expression profiles and phenotypes compared to their free-living counterparts. Elucidating the genetic determinants of biofilm formation is crucial for the development of antibiofilm drugs. In this study, a high-throughput transposon-insertion site sequencing (Tn-seq) approach was employed to identify novel P. aeruginosa biofilm genetic determinants. When analyzing the novel biofilm regulatory genes, we found that the cell division factor ZapE (PA4438) controls the P. aeruginosa pqs quorum sensing system. The ∆zapE mutant lost fitness against the wild-type PAO1 strain in biofilms and its production of 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) had been reduced. Further biochemical analysis showed that ZapE interacts with PqsH, which encodes the synthase that converts 2-heptyl-4-quinolone (HHQ) to PQS. In addition, site-directed mutagenesis of the ATPase active site of ZapE (K72A) abolished the positive regulation of ZapE on PQS signaling. As ZapE is highly conserved among the Pseudomonas group, our study suggests that it is a potential drug target for the control of Pseudomonas infections.