In Vitro/Vivo Activity of Potential MCR-1 Inhibitor in Combination With Colistin Againsts mcr-1-Positive Klebsiella pneumonia

Carbapenem resistance among strains of the nosocomial pathogen Klebsiella pneumoniae is increasing worldwide, causing serious clinical infections and higher mortality rates. Polymyxins are some of the few “last resort” options for treatment of carbapenem-resistant Enterobacteriaceae, including K. pneumoniae, however, the emergence of plasmid-mediated colistin resistance gene mcr-1 has largely rendered polymyxin-class antibiotics ineffective in a clinical setting. We previously identified a natural compound, pterostilbene, which has a synergistic effect in combination with polymyxins. Here, we aimed to determine whether pterostilbene application can restore the bactericidal activity of polymyxins against mcr-1-positive K. pneumoniae. Checkerboard MIC studies confirmed that pterostilbene reduces the MIC of colistin against mcr-1-positive clinical K. pneumoniae isolates, with the bacteria going from resistant to sensitive, and also demonstrated a synergistic effect with colistin (FIC index = 0.11 ± 0.04 or 0.28 ± 0.00). Time-killing assays showed that individually, both pterostilbene and colistin failed to eradicate K. pneumoniae strains, while in combination, the two drugs effectively eliminated K. pneumoniae ZJ02 and K. pneumoniae ZJ05 by 1–3 h post-inoculation. The combined disk test also showed increases in the zones of inhibition only for mcr-1-positive Escherichia coli and K. pneumoniae isolates. A mouse infection model demonstrated that the survival rate of mice at 7 days post-intraperitoneal injection with a lethal dose of K. pneumoniae ZJ05 was significantly promoted from 0 to 67% following combination therapy. This is the first time a MCR-1 inhibitor has successfully been used in combination with colistin against human clinical MCR-1 producing K. pneumoniae ZJ05 isolate

Application of toxicology data reliability assessment method, a toxicological data reliability evaluation tool, in the neurotoxic hazard assessment of glutamate acid and its salts

Objective This paper aims to evaluate data reliability of the neurotoxic hazard assessment of glutamate and its salts and provide recommendations, as well as to improve toxicology data reliability assessment method (TRAM) via trial application. Methods TRAM was used to evaluate the reliability of 60 articles which were selected by the method of systematic review documentation retrieval. The evaluation was based on types of toxicological data involved in each paper (laboratory animal data or human data) and they were scored by reliability criteria. The quality percentage was obtained via calculations to judge reliability categories and give recommendations. It’s necessary to note that the evaluation of each paper was independently completed by two persons in related fields. Results After three rounds of evaluation, the reliability of 12 articles were evaluated as "high" and recommended for priority use. The reliability of 43 articles was rated as "moderate" and can be used. The reliability of 5 articles was evaluated as "low" and not recommended to use. Conclusion TRAM takes both reporting quality and methodological quality into consideration, especially including human data reliability evaluation method which is absent in the other toxicology data reliability assessment tools. TRAM is more suitable for food safety risk assessment. It provides a better objective and scientific guarantee for hazard identification and risk assessment

TLR3 Regulated Poly I:C-Induced Neutrophil Extracellular Traps and Acute Lung Injury Partly Through p38 MAP Kinase

Acute lung injury (ALI) is the leading cause of morbidity and mortality in critically ill patients. Neutrophil extracellular traps (NETs) have been well documented in the ALI model of bacterial infection. In the present study, we demonstrated that poly I:C could induce pulmonary NETs. Upon poly I:C intratracheal inoculation, neutrophil infiltration in the bronchoalveolar lavage fluid (BALF) was significantly increased. Furthermore, the inflammatory cytokines IL-1β, IL-6, and TNF-α in the lung were also significantly elevated. Neutrophil depletion abolished NETs and decreased both neutrophil infiltration and IL-1β in the lung. As expected, DNase I, an inhibitor of MPO and NADPH, decreased pulmonary inflammation and NETs. Blocking of the poly I:C receptor TLR3 reduced lung inflammation and NETs. The MAPK kinase inhibitor p38 diminished the formation of NETs and restored the expression of the tight junction protein claudin-5 in the mouse lung when challenged with poly I:C. In summary, poly I:C induced the formation of pulmonary NETs and ALI, which may be associated with the activation of p38 MAPK and the decreased expression of claudin-5

Low-mass dark matter search results from full exposure of PandaX-I experiment

We report the results of a weakly-interacting massive particle (WIMP) dark matter search using the full 80.1\;live-day exposure of the first stage of the PandaX experiment (PandaX-I) located in the China Jin-Ping Underground Laboratory. The PandaX-I detector has been optimized for detecting low-mass WIMPs, achieving a photon detection efficiency of 9.6\%. With a fiducial liquid xenon target mass of 54.0\,kg, no significant excess event were found above the expected background. A profile likelihood analysis confirms our earlier finding that the PandaX-I data disfavor all positive low-mass WIMP signals reported in the literature under standard assumptions. A stringent bound on the low mass WIMP is set at WIMP mass below 10\,GeV/c$^2$, demonstrating that liquid xenon detectors can be competitive for low-mass WIMP searches.Comment: v3 as accepted by PRD. Minor update in the text in response to referee comments. Separating Fig. 11(a) and (b) into Fig. 11 and Fig. 12. Legend tweak in Fig. 9(b) and 9(c) as suggested by referee, as well as a missing legend for CRESST-II legend in Fig. 12 (now Fig. 13). Same version as submitted to PR