Shaer Tamar, E. | bioRxiv Science

bioRxiv2025

Tissue-level division of labor is coordinated across organs through universal programs and context-specific adaptations

Fibroblasts, macrophages, and endothelial cells are common to most mammalian tissues, where they support homeostasis, repair, and immune regulation. Yet how they coordinate their functions across diverse tissue environments remains unclear. Here, we analyze single-cell RNA sequencing data from 14 human tissues using Pareto optimality framework and identify 16 archetypes - specialized transcriptional programs representing functional tradeoffs. These include universal archetypes shared across tissues and tissue-specific archetypes shaped by local context. We find that tissues align along a continuous axis of archetype distributions, from metabolically active to barrier organs, reflecting coordinated functional adaptation. Using ligand-receptor enrichment mapping, we reveal task-specific crosstalk across cell types, suggesting that intercellular communication underlies supportive division of labor. Applying this analysis to mouse tissues, we find similar patterns, indicating evolutionary conserved tradeoffs. These findings provide a framework for understanding how division of labor is coordinated in health and how its dysregulation may contribute to disease.

systems biology↗

bioRxiv2019

Escape mutations circumvent a tradeoff between resistance to beta-lactams and a beta-lactamase inhibitor

Beta-lactamase inhibitors are increasingly used to counteract microbial resistance to beta-lactam antibiotics mediated by beta-lactamase enzymes. These inhibitors compete with the beta-lactam drug for the same binding site of the beta-lactamase, thereby generating an inherent evolutionary tradeoff: enzyme mutations that increase its activity against the beta-lactam drug also increase its susceptibility towards the inhibitor. It is unclear how common and accessible are mutants that escape this adaptive tradeoff. Here, systematically constructing and phenotyping a deep mutant library of the ampC beta-lactamase gene of Escherichia coli, we identified escape mutations, which even in the presence of the enzyme inhibitor allow growth at beta-lactam concentrations far exceeding the native inhibitory levels of the wildtype strain. Importantly, while such escape mutations appear for combinations of avibactam with some beta-lactam drugs, for other drugs escape phenotypes are completely restricted. Amplicon sequencing of the selected mutant pool identified these escape mutations and showed that they are rare and drug specific. For the combination of avibactam with aztreonam, an escape phenotype was conferred via multiple substitutions in a single conserved amino acid (Tyr 150). In contrast, a different set of mutations showed an escape phenotype for cefepime, and no escape mutants appeared for piperacillin. The differential adaptive potential of ampC to combinations of avibactam and different beta-lactam drugs can help guide drug treatments that are more resilient to evolution of resistance.

microbiology↗