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Abstract Widespread manganese-sensing transcriptional riboswitches effect the dependable gene regulation needed for bacterial manganese homeostasis in changing environments. Riboswitches – like most structured RNAs – are believed to fold co-transcriptionally, subject to both ligand binding and transcription events; yet how these processes are orchestrated for robust regulation is poorly understood. Through a combination of single-molecule and bulk approaches, we discover how a single Mn²⁺ion and the transcribing RNA polymerase (RNAP), paused immediately downstream by a DNA template sequence, are coordinated by the bridging switch helix P1.1 in the representativeLactococcus lactisriboswitch. This coordination achieves a heretofore-overlooked semi-docked global conformation of the nascent RNA, P1.1 base pair stabilization, transcription factor NusA ejection, and RNAP pause extension, thereby enforcing transcription readthrough. Our work demonstrates how a central, adaptable RNA helix functions analogous to a molecular fulcrum of a first-class lever system to integrate disparate signals for finely balanced gene expression control. 

Synopsis In this future-spanning perspective, we examine how an agent-based model could be used to define general rules for interactions across biological systems and evolutionary time. To date, there have been a number of attempts to simulate the emergence of ecological communities using agent-based models of individuals that have evolving traits. Here we speculate whether it is possible to use this computational modeling to simulate self-organizing systems and, importantly, to decipher universal principles that govern biological interactions. This perspective is a thought exercise, meant to extrapolate from current knowledge to how we may make Jupiter-shot leaps to further advance the biosciences in the 21st century.