Biology subjects

O'Sullivan, M. J.

Publications and source records attributed to O'Sullivan, M. J..

4 recordsLinked to original sources

bioRxiv2023

White matter microstructure is associated with the precision of visual working memory

Visual working memory is critical for goal-directed behaviour as it maintains continuity between previous and current visual input. Functional neuroimaging studies have shown that visual working memory relies on communication between distributed brain regions, which implies an important role for long-range white matter connections in visual working memory performance. Here, we characterised the relationship between the microstructure of white matter association tracts and the precision of visual working memory representations. To that purpose, we devised a delayed estimation task which required participants to reproduce visual features along a continuous scale. A sample of 80 healthy adults performed the task and underwent diffusion-weighted MRI. We applied mixture distribution modelling to quantify the precision of working memory representations and guess rates, both of which contribute to observed responses. Latent components of tract-specific microstructural indices were identified by principal component analysis. Higher working memory precision was associated with lower bulk diffusion across ten tracts of interest and higher directionality of diffusion in a group of frontoparietal-occipital tracts. Importantly, there was no association between guess rates and any of the structural components. Our findings suggest that microstructural properties of white matter tracts connecting posterior and frontal brain regions mediate, in a functionally specific manner, the precision of visual working memory.

neuroscience↗

bioRxiv2022

In airway epithelium, basal stem cells and their stress fibers remodel during the unjamming transition

Under homeostatic conditions, epithelial cells remain non-migratory. However, during embryonic developmental and pathological processes, they become migratory. The mechanism underlying the transition between non-migratory and migratory epithelial cells is a fundamental question of cellular biology. In well-differentiated primary human bronchial epithelial cell layers, non-migratory epithelial cells become migratory through an unjamming transition (UJT). We have previously identified the hallmarks of UJT: apical cell elongation and collective cellular migration. These indicate that UJT is driven by intercellular force modulation, but the nature of these forces in pseudostratified epithelia is unknown. Here, we identify structural characteristics of basal stem cells that are indicative of force generation. During the UJT, basal stem cells elongate and enlarge, and their stress fibers lengthen and align. These morphological changes in basal stem cells correspond to the previously defined hallmarks of the UJT. Moreover, basal cell elongation and stress fiber lengthening precedes apical cell elongation. Together, these structural changes in basal stem cells suggest that in pseudostratified airway epithelium, basal stem cells may be the origin of the traction forces through stress fiber modeling during the UJT. Summary StatementOur image analysis of pseudostratified airway epithelium reveals basal stem cells as the likely source of traction forces driving collective cellular migration during an unjamming transition.

cell biology↗

bioRxiv2019

Splicing-sensitive fusion transcripts associated with key tumor characteristics occur at high frequency in neuroblastoma

The paucity of recurrent mutations has hampered efforts to understand and treat neuroblastoma. Alternative splicing and splicing-dependent RNA-fusions represent mechanisms able to increase the gene product repertoire but their role in neuroblastoma remains largely unexplored. Through analysis of RNA-sequenced neuroblastoma we here show that elevated expression of splicing factors is a strong predictor of poor clinical outcome. Furthermore, we identified >900 primarily intrachromosomal fusions containing canonical splicing sites. Fusions included transcripts from well-known oncogenes, were enriched for proximal genes and in chromosomal regions commonly gained or lost in neuroblastoma. As a proof-of-principle that these fusions can generate altered gene products, we characterized a ZNF451-BAG2 fusion, generating a truncated BAG2-protein which inhibited retinoic acid-induced differentiation. Spliceosome inhibition impeded neuroblastoma fusion expression, induced apoptosis and inhibited xenograft tumor growth. Our findings elucidate a splicing-dependent mechanism producing altered gene products in neuroblastoma and suggest that the spliceosome is a tractable therapeutical target.

cancer biology↗

bioRxiv2019

The unjamming transition is distinct from the epithelial-to-mesenchymal transition.

Every organ surface and body cavity is lined by a confluent collective of epithelial cells. In homeostatic circumstances the epithelial collective remains effectively solid-like and sedentary. But during morphogenesis, remodeling or repair, as well as during malignant invasion or metastasis, the epithelial collective becomes fluid-like and migratory1-4. This conversion from sedentary to migratory behavior has traditionally been understood as a manifestation of the epithelial-to-mesenchymal transition (EMT) or the partial EMT (pEMT)5-8. However, in certain contexts this conversion has been attributed to the recently discovered unjamming transition (UJT), in which epithelial cells move collectively and cooperatively9-11. UJT and pEMT share certain aspects of collective cellular migration, but the extent to which these processes are distinct, overlapping or perhaps even identical has remained undefined. Using the confluent layer of well-differentiated primary human bronchial epithelial (HBE) cells, here we triggered UJT by exposing the sedentary layer to mechanical compression9-12. Cells thereafter migrated cooperatively, aligned into packs locally, and elongated systematically. Nevertheless, cell-cell junctions, apico-basal polarity, and barrier function remained intact in response, and mesenchymal markers remained unapparent. As such, pEMT was not evident. When we triggered pEMT and associated cellular migration by exposing the sedentary layer to TGF-{beta}1, metrics of UJT versus pEMT diverged. To account for these striking physical observations a new mathematical model attributes the effects of pEMT mainly to diminished junctional tension but attributes those of UJT mainly to augmented cellular propulsion. Together, these findings establish that UJT is sufficient to account for vigorous epithelial layer migration even in the absence of pEMT. Distinct gateways to cellular migration therefore become apparent - UJT as it might apply to migration of epithelial sheets, and EMT/pEMT as it might apply to migration of mesenchymal cells on a solitary or collective basis, activated during development, remodeling, repair or tumor invasion. Through the actions of UJT and pEMT working independently, sequentially, or interactively, living tissue is therefore seen to comprise an active engineering material whose modules for plasticity, self-repair and regeneration, are far richer than had been previously appreciated.

biophysics↗