Tigecycline is one of the last-resort antibiotics to treat complicated infections caused by both multidrug-resistant (MDR) Gram-negative and Gram-positive bacteria 1 . Tigecycline resistance has sporadically occurred in recent years, primarily due to chromosome-encoding mechanisms, such as overexpression of efflux pumps and ribosome protection 2 , 3 . Here we report the emergence of plasmid-mediated mobile tigecycline resistance mechanism Tet(X4) in Escherichia coli isolates from China, which is capable of degrading all tetracyclines, including tigecycline and the FDA newly approved eravacycline. The tet (X4)-harboring IncQ1 plasmid is highly transferable, and can be successfully mobilized and stabilized in recipient clinical and laboratory strains of Enterobacteriaceae bacteria. It is noteworthy that tet (X4)-positive E. coli strains, including isolates co-harboring mcr-1 , have been widely detected in pigs, chickens, soil, and dust samples in China. In vivo murine models demonstrated that the presence of Tet(X4) led to tigecycline treatment failure. Consequently, the emergence of plasmid-mediated Tet(X4) challenges the clinical efficacy of the entire family of tetracycline antibiotics. Importantly, our study raises concern that the plasmid-mediated tigecycline resistance may further spread into a variety of ecological niches and into clinical high-risk pathogens. Collective efforts are in urgent need to preserve the potency of these essential antibiotics.
Background The recent emergence and dissemination of high-level mobile tigecycline resistance Tet(X) challenge the clinical effectiveness of tigecycline, one of the last-resort therapeutic options for complicated infections caused by multidrug-resistant Gram-negative and Gram-positive pathogens. Although tet(X) has been found in various bacterial species, less is known about phylogeographic distribution and phenotypic variance of different genetic variants. Methods Herein, we conducted a multiregional whole-genome sequencing study of tet(X)-positive Acinetobacter isolates from human, animal, and their surrounding environmental sources in China. The molecular and enzymatic features of tet(X) variants were characterized by clonal expression, microbial degradation, reverse transcription, and gene transfer experiments, while the tet(X) genetic diversity and molecular evolution were explored by comparative genomic and Bayesian evolutionary analyses. Results We identified 193 tet(X)-positive isolates from 3846 samples, with the prevalence ranging from 2.3 to 25.3% in nine provinces in China. The tet(X) was broadly distributed in 12 Acinetobacter species, including six novel species firstly described here. Besides tet(X3) (n = 188) and tet(X4) (n = 5), two tet(X5) variants, tet(X5.2) (n = 36) and tet(X5.3) (n = 4), were also found together with tet(X3) or tet(X4) but without additive effects on tetracyclines. These tet(X)-positive Acinetobacter spp. isolates exhibited 100% resistance rates to tigecycline and tetracycline, as well as high minimum inhibitory concentrations to eravacycline (2–8 μg/mL) and omadacycline (8–16 μg/mL). Genetic analysis revealed that different tet(X) variants shared an analogous ISCR2-mediated transposon structure. The molecular evolutionary analysis indicated that Tet(X) variants likely shared the same common ancestor with the chromosomal monooxygenases that are found in environmental Flavobacteriaceae bacteria, but sequence divergence suggested separation ~ 9900 years ago (7887 BC), presumably associated with the mobilization of tet(X)-like genes through horizontal transfer. Conclusions Four tet(X) variants were identified in this study, and they were widely distributed in multiple Acinetobacter spp. strains from various ecological niches across China. Our research also highlighted the crucial role of ISCR2 in mobilizing tet(X)-like genes between different Acinetobacter species and explored the evolutionary history of Tet(X)-like monooxygenases. Further studies are needed to evaluate the clinical impact of these mobile tigecycline resistance genes.
The interaction between gas flow and liquid flow, governed by fluid dynamic principles, is of substantial importance in both fundamental science and practical applications. For instance, a precisely designed gas shearing on liquid solution may lead to efficacious production of advanced nanomaterials. Here, we devised a needleless Kármán vortex solution blow spinning system that uses a roll-to-roll nylon thread to deliver spinning solution, coupled with vertically blowing airflow to draw high-quality nanofibers with large throughput. A wide variety of nanofibers including polymers, carbon, ceramics, and composites with tunable diameters were fabricated at ultrahigh rates. The system can be further upgraded from single thread to multiple parallel threads and to the meshes, boosting the production of nanofibers to kilogram scale without compromising their quality.
Direct numerical simulations of particle-laden turbulent channel flows at friction Reynolds number $Re_\tau$ from $600$ to $2000$ have been performed to examine the near-wall particle streaks. Different from the well-observed small-scale particle streaks in near-wall turbulence of low $Re_\tau$ , the present results show large-scale particle streaks through the computational domain formed for relatively high-inertia particles at high $Re_\tau$ . Transferred by large-scale sweep and ejection events ( $Q^-$ ), these high-inertia particles preferentially accumulate in near-wall regions beneath the large-scale low-speed flow streaks observed in the logarithmic region. The corresponding Stokes numbers are associated with the lifetime of large-scale $Q^-$ structures, which increases as the Reynolds number grows. The small-scale particle streaks with a typical Stokes number $St_\nu \approx 30$ are mainly driven by the $Q^-$ structures in the buffer layer, whose lifetime is approximately $30$ in viscous time unit. Therefore, we propose a new structure-based Stokes number normalized by the lifetime of $Q^-$ structures of different scales. The relevant flow scales that control the formation of the large-scale particle streaks are parameterized by the structure-based Stokes number. The small-scale (large-scale) particle streaks are most prominent when the buffer-layer (large-scale) structure-based Stokes number approaches unity. The present findings reveal that formation of near-wall particle streaks is governed by the $Q^-$ structures of different scales, and the particles with different inertia respond efficiently to the $Q^-$ structures of corresponding scales with respect to the particle translational motion.
Inhaled long-acting b 2 -adrenoceptor agonists (LABA) that act as bronchodilators and the oral anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor roflumilast are both approved therapies for chronic obstructive pulmonary disease (COPD). Here we describe the activity of a novel, inhaled, bifunctional, small molecule (, which has specific b 2 agonist and PDE4 inhibitory activity. GS-5759 demonstrated potent and full agonist activity at b 2 adrenoceptors (EC 50 5 8 6 4 nM) and is a potent inhibitor of the PDE4 enzyme (IC 50 5 5 6 3 nM). In cell assays, GS-5759 inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor a (TNFa) production in human peripheral mononuclear cells (PBMC) with an IC 50 5 0.3 nM [confidence interval (CI) 0.1-0.6] and in human neutrophils formyl-methionyl-leucyl-phenylalanine (fMLP)-induced super oxide anion production with an IC 50 5 3 nM . The addition of the b 2 antagonist ICI 118551 shifted the IC 50 in these cell assays to 4 and 38 nM, respectively, demonstrating the contribution of both b 2 agonist and PDE4 inhibitory activity to GS-5759. GS-5759 was also a potent inhibitor of profibrotic and proinflammatory mediator release from human lung fibroblasts. GS-5759 relaxed guinea pig airway smooth muscle strips precontracted with carbachol in a concentrationdependent manner with an EC 50 5 0.5 mM (CI 0.2-2) and had slow dissociation kinetics with an Off T 1/2 . 720 minutes at an EC 80 concentration of 3 mM. GS-5759 is a novel bifunctional molecule with both potent b 2 agonist and PDE4 inhibitor activity that could provide inhaled bronchodilator and anti-inflammatory therapy for COPD.
Finding allotropes with novel structures and intriguing properties is of great interest from both fundamental and applicable standpoints. Here, we propose a hitherto unknown boron allotrope, possessing intrinsic superconductivity and...
The wrong diurnal cycle of precipitation is a common weakness of current global climate models (GCMs). To improve the simulation of the diurnal cycle of precipitation and understand what physical processes control it, we test a convective trigger function described in Xie et al. (2019) with additional optimizations in the NCAR Community Atmosphere Model version 5 (CAM5). The revised trigger function consists of three modifications: 1) replacing the Convective Available Potential Energy (CAPE) trigger with a dynamic CAPE (dCAPE) trigger, 2) allowing convection to originate above the top of planetary boundary layer (i.e., the unrestricted air parcel launch level - ULL), and 3) optimizing the entrainment rate and threshold value of the dynamic CAPE generation rate for convection onset based on observations. Results from 1°-resolution simulations show that the revised trigger can alleviate the long-standing GCM problem of too early maximum precipitation during the day and missing the nocturnal precipitation peak that is observed in many regions, including the US Southern Great Plains (SGP). The revised trigger also improves the simulation of the propagation of precipitation systems downstream of the Rockies and the Amazon region. A further composite analysis over the SGP unravels the mechanisms through which the revised trigger affects convection. Additional sensitivity tests show that both the peak time and the amplitude of the diurnal cycle of precipitation are sensitive to the entrainment rate and dCAPE threshold values.
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