Antimicrobial activity and mechanism of action of Nu-3, a protonated modified nucleotide

BACKGROUND: "Nubiotics" are synthetic oligonucleotides and nucleotides with nuclease-resistant backbones, and are fully protonated for enhanced ability to be taken up by bacterial cells. Nu-3 [butyl-phosphate-5'-thymidine-3'-phosphate-butyl], one of the family members of Nubiotics was efficacious in the treatment of burn-wound infections by Pseudomonas aeruginosa in mice. Subsequent studies revealed that Nu-3 had a favorable toxicological profile for use as a pharmaceutical agent. This study evaluated the antibacterial activity of Nu-3 in vitro and its efficacy as a topical antibiotic. In addition, we investigated the possible mechanisms of Nu-3 action at the levels of DNA synthesis and bacterial membrane changes. METHODS: Antimicrobial minimum inhibitory concentrations (MIC) experiments with Nu-3 and controls were measured against a range of Gram-positive and Gram-negative bacteria, including some hospital isolates according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Analysis of the killing kinetics of Nu-3 was also performed against two strains (Staphylococcus aureus cvcc 2248 and Pseudomonas aeruginosa cvcc 5668). The mouse skin suture-wound infection model was used to evaluate the antibacterial activity of Nu-3. We used a 5-Bromo-2'-deoxy-uridine Labeling and Detection Kit III (Roche, Switzerland) to analyze DNA replication in bacteria according to the manufacturer's instruction. The BacLight™ Bacterial Membrane Potential Kit (Invitrogen) was used to measure the bacterial membrane potential in S. aureus. RESULTS: Nu-3 had a wide antibacterial spectrum to Gram-positive, Gram-negative and some resistant bacteria. The MIC values of Nu-3 against all tested MRSA and MSSA were roughly in a same range while MICs of Oxacillin and Vancomycin varied between the bacteria tested. In the mouse model of skin wound infection study, the treatment with 5% Nu-3 glycerine solution also showed comparable therapeutic effects to Ciprofloxacin Hydrochloride Ointment. While Nu-3 had no effect on DNA synthesis of the tested bacteria as demonstrated in a BrdU assay, it could cause bacterial cell membrane depolarization, as measured using a BacLight™ Bacterial Membrane Potential Kit. CONCLUSIONS: These results provide additional experimental data that are consistent with the hypothesis that Nu-3 represents a new class of antibacterial agents for treating topical infections and acts via a different mechanism from conventional antibiotics

A meta-analysis of Pemetrexed plus Platinum Chemotherapy versus Gemcitabine plus Platinum Chemotherapy for Advanced Non-small Cell Lung Cancer

Background and objective Whether pemetrexed plus platinum (PP) regimen is superior to gemcitabine plus platinum (GP) regimen for patients with advanced non-small cell lung cancer (NSCLC) is unclear. The aim of this study is to evaluate the efficacy and safety of PP versus GP regimens for patients with NSCLC. Methods We searched relevant randomized controlled trials (RCTs) from Pubmed, EMBASE, Cochrane Library, Chinese Journal Full-text Database, Chinese Biomedical Literature Database, Chinese Scientific Journals Full-text Database, and traced the related references to obtain the information that has not been found. We made quality assessment of qualified RCTs assessed by the exclusion and inclusion criteria and used RevMan 5.0 provided by the Cochrane Collaboration to perform meta-analysis. Results Four RCTs involving 2,235 patients were identified. There were no statistical differences between PP and GP regimens in one-year survival rate (OR=1.09, 95%CI: 0.91-1.29), the efficiency of disease (OR=1.00, 95%CI: 0.40-2.52), but overall survival (MD=0.26, 95%CI: 0.21-0.30), alopecia (OR=0.51, 95%CI: 0.39-0.66) and hematologic toxicity were significantly different. Conclusion The clinical efficiency of PP and GP regimens for advanced NSCLC was similar, but the side effects were different. The toxicity of PP regimen has the tendency to be more tolerable

Nonclassical photon-pair source based on noiseless photon echo

The Duan-Lukin-Cirac-Zoller (DLCZ) scheme is a potential method to establish remote entanglements and realize large-scale quantum networks. Here we propose a DLCZ-like scheme based on the noiseless photon echo in rare-earth ion-doped crystals. Correlated photon pairs with a controllable delay can be created by the direct optical rephasing. Theoretical analysis indicates that the protocol is efficient in the low-optical-depth regime. This protocol could be feasibly implemented to establish long-lived quantum correlations between a photon and a spin-wave excitation in rare-earth ion-doped crystals

Acute, Multiple-Dose Dermal and Genetic Toxicity of Nu-3: A Novel Antimicrobial Agent

Nu-3 [butyl-phosphate-5′-thymidine-3′-phosphate-butyl] is a modified nucleotide that has been shown to have antimicrobial activity against a range of bacteria including Pseudomonas aeruginosa. However, data on the toxicological profile of Nu-3 are still lacking. In the present study, the toxicity of Nu-3 was evaluated by the following studies: acute oral toxicity, dermal and mucous membrane irritation, multiple-dose toxicity and genotoxicity in vivo and vitro. The acute oral toxicity test in mice showed that Nu-3 had an LD50 of 2001mg/kg body weight. The irritation tests on rats revealed that Nu-3 was not irritant, with an irritation scoring of 0. The multiple-dose toxicity study in rats showed that Nu-3 did not cause significant changes in histology, selected serum chemistry, and hematological parameters compared to the controls. Rats administrated with multiple-doses of Nu-3 showed no visible toxic symptoms. Both in vitro and in vivo, Nu-3 exhibited no notable genetic toxicity. Overall, the data suggest that Nu-3 is hypotoxic or nontoxic antimicrobial compound that warrants being further developed for treating Pseudomonas aeruginosa infection

Collaborative Planning for Catching and Transporting Objects in Unstructured Environments

Multi-robot teams have attracted attention from industry and academia for their ability to perform collaborative tasks in unstructured environments, such as wilderness rescue and collaborative transportation.In this paper, we propose a trajectory planning method for a non-holonomic robotic team with collaboration in unstructured environments.For the adaptive state collaboration of a robot team to catch and transport targets to be rescued using a net, we model the process of catching the falling target with a net in a continuous and differentiable form.This enables the robot team to fully exploit the kinematic potential, thereby adaptively catching the target in an appropriate state.Furthermore, the size safety and topological safety of the net, resulting from the collaborative support of the robots, are guaranteed through geometric constraints.We integrate our algorithm on a car-like robot team and test it in simulations and real-world experiments to validate our performance.Our method is compared to state-of-the-art multi-vehicle trajectory planning methods, demonstrating significant performance in efficiency and trajectory quality