Intestinal barrier derangement allows intestinal bacteria and their products to translocate to the systemic circulation. Pseudomonas aeruginosa (PA) superimposed infection in critically ill patients increases gut permeability and leads to gut-driven sepsis. PA infections are challenging due to multi-drug resistance (MDR), biofilms, and/or antibiotic tolerance. Inhibition of the quorum-sensing transcriptional regulator MvfR(PqsR) is a desirable anti-PA anti-virulence strategy as MvfR controls multiple acute and chronic virulence functions. Here we show that MvfR promotes intestinal permeability and report potent anti-MvfR compounds, the N-Aryl Malonamides (NAMs), resulting from extensive structure-activity-relationship studies and thorough assessment of the inhibition of MvfR-controlled virulence functions. This class of anti-virulence non-native ligand-based agents has a half-maximal inhibitory concentration in the nanomolar range and strong target engagement. Using a NAM lead in monotherapy protects murine intestinal barrier function, abolishes MvfR-regulated small molecules, ameliorates bacterial dissemination, and lowers inflammatory cytokines. This study demonstrates the importance of MvfR in PA-driven intestinal permeability. It underscores the utility of anti-MvfR agents in maintaining gut mucosal integrity, which should be part of any successful strategy to prevent/treat PA infections and associated gut-derived sepsis in critical illness settings. NAMs provide for the development of crucial preventive/therapeutic monotherapy options against untreatable MDR PA infections.
The HITRAN2020 database will be publicly released this year. It is a coordinated effort of experimentalists, theoreticians, atmospheric and planetary scientists who measure, calculate and validate the HITRAN data. The lists for most of the HITRAN molecules in the line-by-line section were updated in comparison with the previous compilation HITRAN2016 a . The extent of the updates ranges from updating a few lines of certain molecules to complete replacements of the lists and introducing additional isotopologues. Six new molecules (SO, CH 3 F, GeH 4 , CS 2 , CH 3 I, and NF 3 ) were also added to HITRAN. In addition, the accuracy of the parameters for major atmospheric absorbers has been increased, often featuring sub-percent uncertainties. The number of parameters was also increased significantly, now incorporating, for instance, non-Voigt line profiles for many gases; broadening by water vapor b ; update of collision-induced absorption sets c .The new edition will continue taking advantage of the modern structure and interface available at www.hitran.org and the HITRAN Application Programming Interface d . Their functionality has been extended for the new edition. This talk will provide a brief overview of HITRAN2020 e and its main improvements with respect to the previous edition.
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