Holmes, C. D. | Search bioRxiv

bioRxiv2025

AquIRE reveals multiple mechanisms of clinically induced RNA damage and the conservation and dynamics of glycoRNAs

RNA is subject to many modifications, from small chemical changes such as methylation through to conjugation of biomolecules such as glycans. As well as these endogenously written modifications, RNA is also exposed to damage induced by its environment. Certain clinical compounds are known to drive covalent modifications of RNA with a growing appreciation for how these affect function. To understand the regulation of these modifications we need a reliable, sensitive and rapid methodology for their quantification. Thus, we developed AquIRE and applied it to the analysis of drug-induced RNA damage, showing this to be widespread with intricate temporal dynamics. Using the same methodology we identify RNA:protein crosslinking and the rewriting of the epitranscriptome as a consequence of clinical RNA damage. We also demonstrate how liquid-liquid phase separation increases RNA damage and expand the horizons of the glycoRNA world across the kingdoms of life and into cell-free glycoRNA.

molecular biology↗

bioRxiv2025

Compositional architecture: Orthogonal neural codes for task context and spatial memory in prefrontal cortex

The prefrontal cortex (PFC) is crucial for maintaining working memory across diverse cognitive tasks, yet how it adapts to varying task demands remains unclear. Compositional theories propose that cognitive processes in neural network rely on shared components that can be reused to support different behaviors. However, previous studies have suggested that working memory components are task specific, challenging this framework. Here, we revisit this question using a population-based approach. We recorded neural activity in macaque monkeys performing two spatial working memory tasks with opposing goals: one requiring movement toward previously presented spatial locations (look task) and the other requiring avoidance of those locations (no-look task). Despite differences in task demands, we found that spatial memory representations were largely conserved at the population level, with a common low-dimensional neural subspace encoding memory across both tasks. In parallel, task identity was encoded in an orthogonal subspace, providing a stable and independent representation of contextual information. These results provide neural evidence for a compositional model of working memory, where representational geometry enables the efficient and flexible reuse of mnemonic codes across behavioral contexts while maintaining an independent representation of context.

neuroscience↗