Pakpoor, J. | Search bioRxiv

bioRxiv2023

A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires an understanding of how cellular networks change following therapy. We describe a therapeutic atlas for Crohns disease (CD) and ulcerative colitis (UC) following anti-tumour necrosis factor (TNF) therapy. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies from 38 patients and three controls, revealing disease- and therapy-specific differences. A systems-biology analysis identified distinct spatially-resolved cellular microenvironments: granuloma signatures in CD and interferon (IFN)-response signatures localising to T-cell aggregates and epithelial damage in CD and UC. Longitudinal comparisons demonstrated that disease progression in non-responders associated with myeloid and stromal cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas informs drug positioning across IMIDs, and suggests a rationale for the use of janus kinase (JAK) inhibition following anti-TNF resistance.

immunology↗

bioRxiv2021

De novo motor learning of a bimanual control task over multiple days of practice

Although much research on motor learning has focused on how we adapt our movements to maintain performance in the face of imposed perturbations, in many cases we must learn new skills from scratch, or de novo. In comparison to adaptation, relatively little is known about de novo learning. In part, this is because learning a new skill can involve many challenges, including learning to recognize new patterns of sensory input and generate new patterns of motor output. However, even with familiar sensory cues and well-practiced movements, the problem of quickly selecting the appropriate actions in response to the current state is challenging. Here, we devised a bimanual hand-to-cursor mapping which isolates this control problem. We find that participants initially struggled to control the cursor under this bimanual mapping, despite explicit knowledge of the mapping. Performance improved steadily over multiple days of practice, however. Participants exhibited no aftereffects when reverting to a veridical cursor, confirming that participants learned the new task de novo, rather than through adaptation. Corrective responses to mid-movement perturbations of the target were initially weak, but with practice, participants gradually became able to respond rapidly and robustly to these perturbations. After four days of practice, participants behavior under the bimanual mapping almost matched performance with a veridically mapped cursor. However, there remained a small but persistent difference in performance level. Our findings illustrate the dynamics and limitations of learning a novel controller and introduce a promising paradigm for tractably investigating this aspect of motor skill learning.

neuroscience↗