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This Week in PNAS: Jul 17, 2018

In the early, online edition of the Proceedings of the National Academy of Sciences, researchers from the Universities of Virginia and Massachusetts present a strategy for reactivating MECP2 — the X-linked gene that undergoes loss-of-function mutation in the neurodevelopmental condition called Rett syndrome — from the inactive X chromosome in human cell lines and mouse models. Rett syndrome usually affects females, who carry mutated MECP2 and a wild type version of the gene, the team says, each expressed in half of cells due to X chromosome inactivation. Using small molecule inhibitors that target X chromosome inactivation factors, the authors say, they can overcome X inactivation of MECP2 to boost the gene's expression in mouse fibroblasts, human induced pluripotent stem cells, and adult mice. "Collectively," they say, "our results … establish the feasibility of pharmacological reactivation of [inactive X chromosome]-linked MECP2 as a therapeutic approach for [Rett syndrome]."

A team from the University of California, Berkeley, and the Lawrence Berkeley National Laboratory explore the characteristics of so-called "phosphosite" sequences neighboring tyrosine residues in the epidermal growth factor receptor (EGFR), a region that undergoes autophosphorylation to prompt downstream adaptor protein binding and signaling when the receptor gets activated. The researchers used high-throughput mutational screening to track the phosphorylation and adaptor protein binding consequences of altering three EGFR phosphosites. From these and other analyses, they note that "the sequences of phosphosites in the EGFR tail are restricted to a subset of the range of sequences that can be phosphorylated efficiently by EGFR," pointing to what they call a "trade-off" between effective phosphorylation and downstream binding.

Researchers from the University of Hong Kong and the University of British Columbia report on results from their chemical genetics-based search for small molecules capable of suppressing virulence in pathogenic forms of Staphylococcus aureus through multi-gene targeting. With the help of plasmids containing luminescent reporters and S. aureus virulence gene promoters, the team screened more than 50,240 compounds, narrowing in on 670 compounds that were selected for secondary screening based on their apparent ability to curb virulence promoter activity. The investigators took a closer look at one of these compounds, known as M21, demonstrating that it could reverse virulence in S. aureus, in part by inhibiting a bacterial protease enzyme called ClpP that contributes to virulence.