Variation of mutation rate at a particular site in a particular genotype, in other words mutation rate plasticity (MRP), can be caused by stress or ageing. However, mutation rate control by other factors is less well characterized. Here we show that in wild-type Escherichia coli (K-12 and B strains), the mutation rate to rifampicin resistance is plastic and inversely related to population density: lowering density can increase mutation rates at least threefold. This MRP is genetically switchable, dependent on the quorum-sensing gene luxS—specifically its role in the activated methyl cycle—and is socially mediated via cell–cell interactions. Although we identify an inverse association of mutation rate with fitness under some circumstances, we find no functional link with stress-induced mutagenesis. Our experimental manipulation of mutation rates via the social environment raises the possibility that such manipulation occurs in nature and could be exploited medically.
SummaryNLRP3 is a receptor important for host responses to infection, yet is also known to contribute to devastating diseases such as Alzheimer's disease, diabetes, atherosclerosis, and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, which inhibit the NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insight of this work is that the oxazaborine ring is a critical feature of the NBC series, and the main biological insight the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring-containing therapeutics.
(S)-4,5-Dihydroxypentane-2,3-dione [(S)-DPD, (1)] is a precursor for , a quorum sensing signalling molecule for inter- and intra-species bacterial communication. The synthesis of its fluoro-analogue, 4-fluoro-5-hydroxypentane-2,3-dione () is reported. An intermediate in this route also enables a new, shorter synthesis of the native (S)-DPD. 4-Fluoro-DPD (2) completely inhibited bioluminescence and bacterial growth of Vibrio harveyi BB170 strain at 12.5 μM and 100 μM, respectively.
2-[18F]-Fluoro-3-pyridinecarboxaldehyde ([18F]FPCA) is a novel, water-soluble prosthetic group. It's radiochemistry has been developed and fully-automated for application in chemoselective radiolabelling of amino(oxy)-derivatised RI-OR2-TAT peptide, (Aoa-k)-RI-OR2-TAT, using a GE TRACERlab FX-FN. RI-OR2-TAT is a brain-penetrant, retro-inverso peptide that binds to amyloid species associated with Alzheimer's Disease. Radiolabelled (Aoa-k)-RI-OR2-TAT was reproducibly synthesised and the product of the reaction with FPCA has been fully characterised. In-vivo biodistribution of [18F]RI-OR2-TAT has been measured in Wistar rats.
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