Summary The evolutionary stability of synthetic genetic circuits is key to both the understanding and application of genetic control elements. One useful but challenging situation is a switch between life and death depending on environment. Here are presented “essentializer” and “cryodeath” circuits, which act as kill switches in Escherichia coli. The essentializer element induces cell death upon the loss of a bi-stable cI/Cro memory switch. Cryodeath makes use of a cold-inducible promoter to express a toxin. We employ rational design and a toxin/antitoxin titering approach to produce and screen a small library of potential constructs, in order to select for constructs that are evolutionarily stable. Both kill switches were shown to maintain functionality in vitro for at least 140 generations. Additionally, cryodeath was shown to control the growth environment of a population, with an escape frequency of less than 1 in 105 after ten days of growth in the mammalian gut.
Summary:The evolutionary stability of synthetic genetic circuits is key to both the understanding and application of genetic control elements. One particularly useful but challenging situation is a switch between life and death depending on environment. Here are presented "essentializer" and "cryodeath" circuits, which act as kill switches in Escherichia coli. The essentializer element induces cell death upon the loss of a bi-stable cI/Cro memory switch. Cryodeath makes use of a cold-inducible promoter to express a toxin. We employ rational design and a novel toxin/antitoxin titering approach to produce and screen a small library of potential constructs, in order to select for constructs that are evolutionarily stable. Both kill switches were shown to maintain functionality in vitro for at least 140 generations. In addition, cryodeath was shown to control the growth environment of a bacterial population, with an escape rate of less than 1 in 10 5 after ten days in vivo.
Objectives: It is important to find biomarkers associated with transition to illness in individuals at clinical high-risk for psychosis (CHR). Here, we use free-water imaging, an advanced diffusion MRI technique, to identify white matter alterations in the brains of CHR subjects who subsequently develop psychosis (CHR-P) compared to those who do not (CHR-NP). Methods: Twenty-four healthy controls (HC) and 30 CHR individuals, 8 of whom converted to schizophrenia after a mean follow-up of 15.16 months, received baseline MRI scans. Maps of fractional anisotropy (FA), FA of cellular tissue (FA T ), and extracellular free-water (FW) were extracted using tract-based spatial statistics after which voxel-wise non-parametric group statistics and correlations with symptom severity were performed. Results: There were no significant differences between HCs and the combined CHR group. However, prior to conversion, CHR-P showed widespread lower FA compared to CHR-NP (p FWE < 0.05). FA changes in CHR-P were associated with significantly lower FA T and higher FW, compared to CHR-NP. Positive symptoms correlated significantly with diffusion parameters in similar regions as those discriminating CHR-P from CHR-NP. Conclusions: Our study suggests that cellular (FA T ) and extracellular (FW) white matter alterations are associated with positive symptom severity and indicate an elevated illness risk among CHR individuals.
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