Bacterial defense systems exhibit synergistic anti-phage activity.

Bacterial defense against phage predation involves diverse defense systems acting individually and concurrently, yet their interactions remain poorly understood. We investigated >100 defense systems in 42,925 bacterial genomes and identified numerous instances of their non-random co-occurrence and negative association. For several pairs of defense systems significantly co-occurring in Escherichia coli strains, we demonstrate synergistic anti-phage activity. Notably, Zorya II synergizes with Druantia III and ietAS defense systems, while tmn exhibits synergy with co-occurring systems Gabija, Septu I, and PrrC. For Gabija, tmn co-opts the sensory switch ATPase domain, enhancing anti-phage activity. Some defense system pairs that are negatively associated in E. coli show synergy and significantly co-occur in other taxa, demonstrating that bacterial immune repertoires are largely shaped by selection for resistance against host-specific phages rather than negative epistasis. Collectively, these findings demonstrate compatibility and synergy between defense systems, allowing bacteria to adopt flexible strategies for phage defense.

Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans.

Chemokine-driven leukocyte recruitment is a key component of the immune response and of various diseases. Therapeutically targeting the chemokine system in inflammatory disease has been unsuccessful, which has been attributed to redundancy. We investigated why chemokines instead have specific, specialized functions, as demonstrated by multiple studies. We analyzed the expression of genes encoding chemokines and their receptors across species, tissues, and diseases. This analysis revealed complex expression patterns such that genes encoding multiple chemokines that mediated recruitment of the same leukocyte type were expressed in the same context, such as the genes encoding the CXCR3 ligands CXCL9, CXCL10, and CXCL11. Through biophysical approaches, we showed that these chemokines differentially interacted with extracellular matrix glycosaminoglycans (ECM GAGs), which was enhanced by sulfation of specific GAGs. Last, in vivo approaches demonstrated that GAG binding was critical for the CXCL9-dependent recruitment of specific T cell subsets but not of others, irrespective of CXCR3 expression. Our data demonstrate that interactions with ECM GAGs regulated whether chemokines were presented on cell surfaces or remained more soluble, thereby affecting chemokine availability and ensuring specificity of chemokine action. Our findings provide a mechanistic understanding of chemokine-mediated immune cell recruitment and identify strategies to target specific chemokines during inflammatory disease.

Advances in RIPK1 kinase inhibitors.

Programmed necrosis is a new modulated cell death mode with necrotizing morphological characteristics. Receptor interacting protein 1 (RIPK1) is a critical mediator of the programmed necrosis pathway that is involved in stroke, myocardial infarction, fatal systemic inflammatory response syndrome, Alzheimer's disease, and malignancy. At present, the reported inhibitors are divided into four categories. The first category is the type I ATP-competitive kinase inhibitors that targets the area occupied by the ATP adenylate ring; The second category is type Ⅱ ATP competitive kinase inhibitors targeting the DLG-out conformation of RIPK1; The third category is type Ⅲ kinase inhibitors that compete for binding to allosteric sites near ATP pockets; The last category is others. This paper reviews the structure, biological function, and recent research progress of receptor interaction protein-1 kinase inhibitors.

Horizontal Gene Transfer as a Source of Conflict and Cooperation in Prokaryotes.

Horizontal gene transfer (HGT) is one of the most important processes in prokaryote evolution. The sharing of DNA can spread neutral or beneficial genes, as well as genetic parasites across populations and communities, creating a large proportion of the variability acted on by natural selection. Here, we highlight the role of HGT in enhancing the opportunities for conflict and cooperation within and between prokaryote genomes. We discuss how horizontally acquired genes can cooperate or conflict both with each other and with a recipient genome, resulting in signature patterns of gene co-occurrence, avoidance, and dependence. We then describe how interactions involving horizontally transferred genes may influence cooperation and conflict at higher levels (populations, communities, and symbioses). Finally, we consider the benefits and drawbacks of HGT for prokaryotes and its fundamental role in understanding conflict and cooperation from the gene-gene to the microbiome level.

Eukaryote Genes Are More Likely than Prokaryote Genes to Be Composites.

The formation of new genes by combining parts of existing genes is an important evolutionary process. Remodelled genes, which we call composites, have been investigated in many species, however, their distribution across all of life is still unknown. We set out to examine the extent to which genomes from cells and mobile genetic elements contain composite genes. We identify composite genes as those that show partial homology to at least two unrelated component genes. In order to identify composite and component genes, we constructed sequence similarity networks (SSNs) of more than one million genes from all three domains of life, as well as viruses and plasmids. We identified non-transitive triplets of nodes in this network and explored the homology relationships in these triplets to see if the middle nodes were indeed composite genes. In total, we identified 221,043 (18.57%) composites genes, which were distributed across all genomic and functional categories. In particular, the presence of composite genes is statistically more likely in eukaryotes than prokaryotes.