xanax dosage death A phenotype as a function of the mean and/or variability of one or more protein’s levels defines a phenotypic landscape. Conventional therapy assumes monotone phenotypic landscapes. However, uncovering the actual landscape requires protein-level tuning. c, Schematic diagram of the two-step strategy for repeatable AAVS1 site-specific integration of genetic payloads, such as synthetic gene circuits. Left: LP insertion into AAVS1 with CRISPR–Cas9. Right: RMCE-based LP-specific integration of the mNF gene circuit that controls the expression of the eGFP::BACH1 bifunctional fusion. Step 2 is repeatable by using different selection markers. espCas9, enhanced specificity SpCas9; NeoR, neomycin resistance gene. d, Synthetic mNF gene circuit for dox-controlled tuning of the TetR co-expressed with either the GFP reporter (mNF-GFP) protein levels or GFP::BACH1 fusion (mNF-BACH1) protein levels after site-specific integration. KS, Kozak sequence; TetO, tetracycline operator. Credit: Nature Chemical Biology (2023). DOI: 10.1038/s41589-023-01344-z” width=”800″ height=”530″>
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