bioRxiv Science⌕ Search

Biology subjects

Dennison, H.

Publications and source records attributed to Dennison, H..

2 recordsLinked to original sources

Building from the ground up: augmentation strategies to improve protein language model performance on protein sets

An important underlying requirement for deep learning models is the availability of large datasets, however, in sciences such as chemistry and biology, generating experimental data of sufficient size represents a significant bottleneck. In this work, we probed the extent and nature of limited input data, characterize how several protein language models (pLMs) learned on suboptimal datasets, and investigated augmentation approaches to improve predictive model performance. We found that narrowing the distribution of protein-protein complexes in a limited dataset permits an order-of-magnitude decrease in training dataset size, if a model is only expected to generalize to in-distribution data. Similar results were found in active learning (AL), where both in- and out-of-distribution Matthews Correlation Coefficient (MCC) showed a small but consistent increase upon augmentation of the training set with complexes produced by ESM-3, a generative pLM.

biophysics↗

Vessel Organoids Reveal FOXF1 Variant-Specific Regulation of Mesoderm and Capillary Development

How allelic variants in lineage-regulating transcription factors drive diverging human developmental outcomes remains poorly understood. This is partly due to the lack of human model systems. Here, we used vessel organoids from human induced pluripotent stem cells (hiPSCs) to resolve variant-specific functions of Forkhead Box F1 (FOXF1), a critical regulator of mesoderm and vascular development. Using three patient-derived hiPSC lines harboring unique FOXF1 variants, we show that heterozygous variants cause capillary maldevelopment of varying severity. Single-nucleus multiomic analysis revealed variant-specific mechanisms - a severe variant impairs differentiation of nascent mesoderm to lateral plate mesoderm and disrupts vascular progenitor specification, while moderate variants permit mesoderm differentiation but rewire vascular progenitor states and function. Restoration of wild-type FOXF1 via lipid nanoparticle-mediated mRNA delivery rescued capillary formation in a variant- and developmental-stage-dependent manner. Together, these findings demonstrate that different variants disrupt stage-specific FOXF1 functions in human mesoderm-to-vascular development, underscoring the importance of variant-specific therapeutic strategies. HIGHLIGHTS O_LIHuman vessel organoids reveal variant-specific roles of FOXF1 in mesoderm patterning and capillary development. C_LIO_LISevere FOXF1 variant c.253T>A (p.F85I) impairs nascent mesoderm-to-lateral plate mesoderm differentiation and disrupts vascular progenitor specification. C_LIO_LI Moderate FOXF1 variants differentially rewire endothelial and mural progenitor cell states and function. C_LIO_LILipid nanoparticle-mediated FOXF1 mRNA delivery rescues capillary formation in a variant- and developmental-stage-dependent manner. C_LI

developmental biology↗