Wnt/β-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth cells as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (Porcn Del /Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating that epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of Porcn Del organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable and that stromal production of Wnts can fully support normal murine intestinal homeostasis.
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Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and regulation. Here, by altering codon usage as a novel platform to control signaling output, we screened the Drosophila genome for modifiers specific to either weak or strong Ras-driven eye phenotypes. Our screen enriched for regions of the genome not previously connected with Ras phenotypic modification. We mapped the underlying gene from one modifier to the ribosomal gene RpS21. In multiple contexts, we show that RpS21 preferentially influences weak Ras/MAPK signaling outputs. These data show that codon usage manipulation can identify new, output-specific signaling regulators, and identify RpS21 as an in vivo Ras/MAPK phenotypic regulator.
Methods used to predict surgical case time often rely upon the current procedural terminology (CPT) code as a nominal variable to train machine-learned models, however this limits the ability of the model to incorporate new procedures and adds complexity as the number of unique procedures increases. The relative value unit (RVU, a consensus-derived billing indicator) can serve as a proxy for procedure workload and could replace the CPT code as a primary feature for models that predict surgical case length. Using 11,696 surgical cases from Duke University Health System electronic health records data, we compared boosted decision tree models that predict individual case length, changing the method by which the model coded procedure type; CPT, RVU, and CPT–RVU combined. Performance of each model was assessed by inference time, MAE, and RMSE compared to the actual case length on a test set. Models were compared to each other and to the manual scheduler method that currently exists. RMSE for the RVU model (60.8 min) was similar to the CPT model (61.9 min), both of which were lower than scheduler (90.2 min). 65.2% of our RVU model’s predictions (compared to 43.2% from the current human scheduler method) fell within 20% of actual case time. Using RVUs reduced model prediction time by ninefold and reduced the number of training features from 485 to 44. Replacing pre-operative CPT codes with RVUs maintains model performance while decreasing overall model complexity in the prediction of surgical case length.
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