Publications by authors named "Ashish Phal"
Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca release and mitogen-activated protein kinase (MAPK) pathway activation.
View Article and Find Full Text PDFTissue repair is significantly compromised in the aging human body resulting in critical disease conditions (such as myocardial infarction or Alzheimer's disease) and imposing a tremendous burden on global health. Reprogramming approaches (partial or direct reprogramming) are considered fruitful in addressing this unmet medical need. However, the efficacy, cellular maturity and specific targeting are still major challenges of direct reprogramming.
View Article and Find Full Text PDFOver 90% of the U.S. adult population suffers from tooth structure loss due to caries.
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- Tooth enamel, the hardest material in the human body, is secreted by ameloblasts (AMs) but cannot regenerate once damaged due to the absence of these cells in erupted teeth.
- Researchers used single-cell RNA sequencing to analyze the developing human tooth and discovered key signaling pathways crucial for the differentiation of ameloblasts during fetal development.
- They also created a disease model for amelogenesis imperfecta using a 3D organoid system, which shows the potential for future advancements in regenerative dentistry.
Growth factors and cytokines signal by binding to the extracellular domains of their receptors and drive association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affects signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a designed fibroblast growth-factor receptor (FGFR) binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and MAPK pathway activation.
View Article and Find Full Text PDFArticle Synopsis
- Designing proteins that specifically bind to target sites based solely on the target's 3D structure is challenging, but the authors propose a new method that starts with a broad exploration of possible binding modes before focusing on the most promising ones.
- They successfully created binding proteins for 12 different proteins, which are smaller than 65 amino acids and demonstrate strong binding affinities after optimization.
- The study also resolved the crystal structures of five binder-target complexes, contributing valuable experimental data to improve our understanding of protein interactions and enhancing future designs for therapeutic and diagnostic use.
Bifurcation of cellular fates, a critical process in development, requires histone 3 lysine 27 methylation (H3K27me3) marks propagated by the polycomb repressive complex 2 (PRC2). However, precise chromatin loci of functional H3K27me3 marks are not yet known. Here, we identify critical PRC2 functional sites at high resolution.
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