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Abstract Colistin is one of the last-resort antibiotics in treating infections caused by multidrug-resistant (MDR) pathogens. Unfortunately, the emergence of colistin-resistant gram-negative strains limit its clinical application. Here, we identify an FDA-approved drug, valnemulin (Val), exhibit a synergistic effect with colistin in eradicating both colistin-resistant and colistin-susceptible gram-negative pathogens both in vitro and in the mouse infection model. Furthermore, Val acts synergistically with colistin in eliminating intracellular bacteria in vitro. Functional studies and transcriptional analysis confirm that the combinational use of Val and colistin could cause membrane permeabilization, proton motive force dissipation, reduction in intracellular ATP level, and suppression in bacterial motility, which result in bacterial membrane disruption and finally cell death. Our findings reveal the potential of Val as a colistin adjuvant to combat MDR bacterial pathogens and treat recalcitrant infections.

Objective: The aim of the present study is to explore the impact of the tet(A) type I variant (tetA-v1) on its fitness effect in Klebsiella pneumoniae. Methods: Clinical K. pneumoniae strains were utilized as parental strains to generate strains carrying only the plasmid vector (pBBR1MCS-5) or the tetA-v1 recombinant plasmid (ptetA-v1). Antimicrobial susceptibility testing was conducted to estimate the contribution of tetA-v1 to drug resistance. Plasmid stability was evaluated by serial passage over 10 consecutive days in the absence of tigecycline. Biological fitness was examined through growth curve analysis, in vitro competition assays and a neutropenic mouse thigh infection model. Results: A 2–4-fold increase in tigecycline MIC was observed following the acquisition of tetA-v1. Without tigecycline treatment, the stability of ptetA-v1 plasmids has been decreasing since day 1. The ptetA-v1 plasmid in Kp89, Kp91, and Kp93 exhibited a decrease of about 20% compared to the pBBR1MCS-5 plasmid. The acquisition of the tetA-v1 gene could inhibit the growth ability of K. pneumoniae strains both in vitro and in vivo. tetA-v1 gene imposed a fitness cost in K. pneumoniae, particularly in the CRKP strain Kp51, with a W value of approximately 0.56. Conclusion: The presence of tetA-v1 is associated with a significant fitness cost in K. pneumoniae in the absence of tigecycline, both in vitro and in vivo.

Semi-solid powder rolling (SSPR) is widely used to produce alloy strips with fine grains and excellent performances in the automotive, aerospace and shipbuilding industries. During SSPR, powder temperature, as a very important parameter, greatly affects strips’ microstructures and mechanical properties, which have been investigated by many researchers, but its effect on the forming process and mechanism has rarely been studied. Therefore, based on online experimental detection and transient simulation, the microstructures, strip temperatures, relative densities and rolling forces at different conditions were, respectively, measured, calculated, compared and analyzed in order to study the deformation process and mechanism during SSPR. The result shows that with the increase in powder temperature, the strip temperature and relative density increase, while the rolling force decreases. The grains of the strips are refined after SSPR, and fine and dense microstructures are obtained at 600 °C, which is the optimum powder temperature. In the main deformation sections (II and III), when the contact normal force exists and reaches a maximum, the relative density and rolling force increase rapidly. At these sections, the strips rolled at 600 °C are mainly in a porous solid state, and powder crushing dominates the strip deformation. Therefore, SSPR at 600 °C and below can be considered porous or powder hot rolling, integrating powder crushing, solidification, deformation, densification and grain coarsening. Moreover, as the simulated values are basically consistent with experimental values, the thermomechanical coupling model based on the Fourier equation and its parameters are confirmed to be reasonable.

The vibration modulation of the localized faults of sun gears is complicated because of the structure and motion features of planetary gearboxes. It is challenging to completely determine the vibration modulation mechanism. To address this issue, the influences of fluctuations in speed on the factors that affect vibration like the transfer path function, time-varying projection function, and meshing force were studied. Improved vibration amplitude and frequency modulation models were then established by combining the factors affecting vibration considering the speed fluctuations caused by the localized faults of sun gears. Regarding the features of vibration modulation of localized faults of sun gears, we concluded that both fault feature frequency and carrier rotational frequency modulate the harmonics of the meshing frequency, which form two groups of modulation sidebands. In addition, the harmonics of the fault feature frequency over the whole frequency range are modulated by the rotational frequency of the carrier, which is more dominant in the resonance domain. The experimental results of localized faults of sun gears strongly agree with those deduced using the proposed models. This research contributes an effective frequency indicator that can be used to confirm the condition of planetary gearboxes.