Suchergebnisse

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state. ; publishedVersion ; Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Computational approaches in drug discovery and development hold great promise, with artificial intelligence methods undergoing widespread contemporary use, but the experimental validation of these new approaches is frequently inadequate. We are initiating Critical Assessment of Computational Hit-finding Experiments (CACHE) as a public benchmarking project that aims to accelerate the development of small molecule hit-finding algorithms by competitive assessment. Compounds will be identified by participants using a wide range of computational methods for dozens of protein targets selected for different types of prediction scenarios, as well as for their potential biological or pharmaceutical relevance. Community-generated predictions will be tested centrally and rigorously in an experimental hub(s), and all data, including the chemical structures of experimentally tested compounds, will be made publicly available without restrictions. The ability of a range of computational approaches to find novel compounds will be evaluated, compared, and published. The overarching goal of CACHE is to accelerate the development of computational chemistry methods by providing rapid and unbiased feedback to those developing methods, with an ancillary and valuable benefit of identifying new compound-protein binding pairs for biologically interesting targets. The initiative builds on the power of crowd sourcing and expands the open science paradigm for drug discovery. ; ACKNOWLEDGEMENTS The Structural Genomics Consortium is a registered charity (no: 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], Janssen, Merck KGaA (aka EMD in Canada and US), Pfizer, Takeda and the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and Ontario Institute for Cancer Research, Royal Institution for ...