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•Sub-lethal concentrations of ampicillin could induce the rapid evolution of antibiotic resistance of Pseudomonas aeruginosa.•Quorum sensing participated in resistance revolution ...induced by sub-lethal ampicillin in Pseudomonas aeruginosa.•The RhlI/R but not the LasI/R circuit is involved in resistance evolution under sub-lethal ampicillin conditions.
The rapid increase of antibiotic resistance is a serious challenge around the world. Antibiotics are present in various environments at sub-lethal concentrations, but how resistance emerges under sub-lethal conditions is not fully clear. In this study, we evolved Pseudomonas aeruginosa PAO1 under sub-lethal conditions, in the presence of either 15–30 μg/mL or 150–300 μg/mL of ampicillin. We found a ~ 5–6 fold increase in the minimum inhibitory concentration (MIC) among evolved isolates exposed to 15–30 μg/mL of ampicillin, and more than a 19-fold of increase in 150–300 μg/mL of ampicillin exposure. DNA sequencing revealed that mpl and ampD were frequently mutated in these resistant strains. We performed a transcriptome analysis of deletion mutations of mpl or ampD, compared to PAO1. Both showed a two-fold increase in expression of quorum sensing (QS) genes including lasR and rhlI/R; the heightened expression was positively correlated with the expression of the ampicillin resistance gene ampC. We queried if quorum sensing contributes to the increase in the ampicillin MIC. After adding the quorum quencher acylase I, the growth yield both decreased by roughly 50% for Δmpl in 2000 μg/mL of ampicillin and ΔampD in 4000 μg/mL of ampicillin. Addition of the QS signals into synthase mutants restored the higher MIC, but only for the rhlI/R circuit. This study highlights the involvement of QS in antibiotic resistance evolution, and shows the multifactorial contributors to the observed phenotypes.
Microbial contamination in farmlands is usually underestimated and understudied. Different fertilization times and manure origins might introduce and change the microorganism diversity in farmland ...soils and thus might influence the abundance and persistence of microbial contamination including antibiotic resistance genes (ARGs), human bacterial pathogens (HBPs), and virulence factor genes (VFGs).
A 0.5-/1.5-year fertilization experiment was performed, and metagenomic sequencing was conducted to quantify microbial contamination. The resistomes of soil samples revealed that ARGs against antibiotics which were extensively used in veterinary medicine as well as clinically critical ARGs (CCARGs) persisted in manure-amended soils. Here the extended-spectrum beta-lactamase and carbapenemase bla genes, the high-level mobilized colistin resistance gene mcr, the tigecycline resistance gene tet(X), and the vancomycin resistance gene van, all of which can circumvent the defense line of these "last-resort" antibiotics were selected to investigate CCARG pollution in farm environments.
A total of 254 potential HBPs and 2106 VFGs were detected in soil samples. Overall, our results revealed that (1) farmland soils could serve as a reservoir of some important bla, mcr, tet(X), and van gene variants, (2) the diversity and relative abundance of HBPs and VFGs increased significantly with incremental fertilization times and were discrepant among different manureamended soils, and (3) most CCARGs and VFGs coexisted in HBPs.
The results of this study suggested a biological risk of manure in spreading antimicrobial resistance and pathogenicity.
As more environmental contaminants emerging, antibiotics and antibiotic resistance genes (ARGs) have caused a substantial increase of antimicrobial resistance (AMR) in environment. Quorum sensing ...(QS) is a bacterial cell-to-cell communication process that regulates many traits and gene expression, including ARGs and the related genes that contribute to AMR development. Herein, we summarize the role, physiology, and genetic mechanisms of bacterial QS in AMR development in the environment. First, the effect of QS on AMR is introduced. Next, the role of QS in bacterial physiological behaviors that promote AMR development, including membrane permeability, tactic movement, biofilm formation, persister formation, and small colony variants (SCVs), is systematically analyzed. Furthermore, the regulation of QS on the expression of ARGs, generation of reactive oxygen species (ROS), which affects ARGs formation, and horizontal gene transfer (HGT), which accelerates the transmission of ARGs, are discussed to reveal the molecular mechanism for AMR development. This review provides a reference for a better understanding of AMR evolution and novel insights into AMR prevention.
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•Quorum sensing-mediate antimicrobial resistance is not systematically studied compared to virulence.•An evolutionary perspective on antimicrobial resistance were regulated by quorum sensing.•Quorum sensing is a potential target for prevention of antibacterial resistance.
Concerns regarding biological risk in environment have garnered increasing attention. Manure has been believed to be a significant source of antibiotic resistance genes (ARGs) in agricultural soil. ...Nevertheless, the profile of microbial contamination including ARGs, virulence factor genes (VFGs) and human bacterial pathogens (HBPs) in different manure-amended soils remain largely unknown. Here, we conducted the systematic metagenome-based study to explore changes in resistome, VFGs and HBPs in soils treated by frequently-used manures. The results revealed that many manure-borne ARGs, VFGs, and HBPs could be spreaded into soils, and their diversity and abundance were significantly different among chemical fertilizer, pig manure, chicken manure, cow dung and silkworm excrement application. A total of 157 potential HBPs accounting about 1.33% of total bacteria were detected. The main ARGs transferred from manures to soil conferred resistance to vancomycin and macrolide-lincosamide-streptogramin. The series analysis revealed positive co-occurrence patterns of ARGs-HBPs, VFGs-HBPs and ARGs-VFGs. Microbial contamination were more serious in pig manure and silkworm excrement sample than in the other samples, implying the usage of these two manures increased the risk of HBPs and dissemination of ARGs. This study confirmed the prevalence and discrepancy of resistome, VFGs and HBPs in different manure-amended soils.
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•A total of 157 potential human bacterial pathogens were detected, accounting about 1.33% of total bacteria screened.•Abundant and diverse virulence factor genes and antibiotic resistance genes were identified in the agricultural soils.•The coexistence of many antibiotic resistance genes and virulence factor genes was found in human bacterial pathogens.•Pig manure and silkworm excrement increased higher microbiological risks in farmland soil.
Metal nanoparticles (MNPs) have recently gained extensive attention due to their broad-spectrum prospect, particularly in biomedical application. Here, we reveal that long-term exposure to platinum ...nanoparticles (Pt NPs) increases the susceptibility of Pseudomonas aeruginosa PAO1 to imipenem and ciprofloxacin. We exposed PAO1 to Pt NPs (a series of doses, varying from 0.125 to 35 μg/mL) for 60 days and characterized the evolved strains (ES) and compared with wild type (WT) to understand the mechanism of heightened sensitivity. We found that overexpression of oprD and downregulation of mexEF-oprN facilitate the intracellular accumulation of antibiotic, thus increasing susceptibility. Furthermore, loss-of-function mutations were discovered in regulators lasR and mexT. Cloning intact lasR from wild-type (WT) into ES slightly improves imipenem resistance. Strikingly, cloning mexT from WT into ES reverts the imipenem and ciprofloxacin resistance to the original level. Briefly, the increase of membrane permeability controlled by mexT made PAO1 greatly susceptible to imipenem and ciprofloxacin, and the decrease of quorum sensing mediated by lasR made PAO1 slightly susceptible to imipenem. Overall, these results reveal an antibiotic susceptibility mechanism from prolonged exposure to MNPs, which provides a promising approach to prevent antibiotic resistance.
A novel delivery system comprising N-succinic anhydride (N-SAA) and D-fructose co-conjugated chitosan (NSCF)-modified polymeric liposomes (NSCF-PLip) were designed to enhance oral delivery of ...paclitaxel (PTX) by targeting monocarboxylate transporters (MCT) and glucose transporters (GLUT). The synthesized NSCF was characterised by FT-IR and 1H NMR spectra. The prepared 30.78 % (degree of substitution of N-SAA) NSCF-PTX-PLip were approximately 150 nm in size, with a regular spherical shape, the zeta potential of −25.4 ± 5.13 mv, drug loading of 2.35 % ± 0.05 %, and pH-sensitive and slow-release characteristics. Compared with PTX-Lip, 30.78 % NSCF-PTX-PLip significantly enhanced Caco-2 cellular uptake via co-mediation of MCT and GLUT, showing relatively specific binding of propionic acid and MCT. Notably, the NSCF modification of PTX-Lip had no appreciable influence on their original cellular uptake pathway. The fructose modification of 30.78 % NSC-PTX-PLip significantly increased the concentration after tmax, indicating their continuous and efficient absorption. Compared with PTX-Lip, the 30.78 % NSCF-PTX-PLip resulted in a 2.09-fold extension of MRT, and a 6.06-fold increase of oral bioavailability. It significantly increased tumour drug distribution and tumour growth inhibition rate. These findings confirm that 30.78 % NSCF-PLip offer a potential oral delivery platform for PTX and targeting the dual transporters of MCT and GLUT is an effective strategy for enhancing the intestinal absorption of drugs.
Depth-Image-Based-Rendering (DIBR) procedure aims to create virtual viewpoint using the adjacent viewpoints and the corresponding depth maps for free-viewpoint video applications. However, this ...processing inevitably introduces visual artifacts which differ from those of natural images, mainly including holes, stretching, and blurring. To accurately evaluate the quality of 3D-synthesized images, a robust blind metric is developed by analysis of Local and Global Statistical Properties (LGSP). On the one hand, for local features, since the DIBR processing tends to damage the amount of information at the disoccluded regions in 3D-synthesized images, we extract the local two-dimensional entropy features from the spatial domain and log-Gabor domain guided by the corresponding saliency map to measure local information variation. Moreover, local statistical features are extracted from fractal dimension maps to capture local texture variations due to significant local texture degradation engendered by the DIBR procedure. On the other hand, for global features, to measure the DIBR-induced geometric distortion, steerable pyramid decomposition is utilized to extract its cross-scale and cross-orientation joint statistical features. Meanwhile, log-energies features are extracted from multi-scale and multi-orientation wavelet subbands to characterize its global blurring. Finally, the combined local and global quality-aware features are utilized to train the quality prediction model using regression function to establish the mapping between visual features and subjective scores. Extensive experiments over three public 3D-synthesized image benchmark databases show that our metric outpaces the newly-developed 3D-synthesized image metrics and the popular 2D image metrics.
The differentiation fate of bone marrow mesenchymal stem cells (BMSCs) affects the progression of steroid-induced osteonecrosis of the femoral head (SONFH). We find that lncRNA DGCR5 encodes a ...102-amino acid polypeptide, RIP (Rac1 inactivated peptide), which promotes the adipogenic differentiation of BMSCs and aggravates the progression of SONFH. RIP, instead of lncRNA DGCR5, binds to the N-terminal motif of RAC1, and inactivates the RAC1/PAK1 cascade, resulting in decreased Ser675 phosphorylation of β-catenin. Ultimately, the nuclear localization of β-catenin decreases, and the differentiation balance of BMSCs tilts toward the adipogenesis lineage. In the femoral head of rats, overexpression of RIP causes trabecular bone disorder and adipocyte accumulation, which can be rescued by overexpressing RAC1. This finding expands the regulatory role of lncRNAs in BMSCs and suggests RIP as a potential therapeutic target.
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•LncRNA DGCR5 encodes a small peptide, RIP•RIP regulates enhanced adipogenesis and inhibited osteogenesis in BMSCs•RIP binds to the N-terminal motif of RAC1, which leads to the reduction of RAC1-GTP•RIP represses the nuclear localization of β-catenin
Jiang et al. find that lncRNA DGCR5 encodes a 102-amino acid polypeptide, RIP (Rac1 inactivated peptide), which binds to RAC1, resulting in the reduction of RAC1-GTP and Ser675 phosphorylation of β-catenin. Ultimately, the nuclear localization of β-catenin decreases, and the differentiation balance of BMSCs tilts toward the adipogenesis lineage.
PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp (RGDRGD) 30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N terminus. The active endostatin fragment of PEP06 ...directly targets tumor cells and exerts an antitumoral effect. However, little is known about the kinetics and degradation products of PEP06 in vitro or in vivo. In this study, we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species; we further identified the degradation characteristics of its cleavage products. PEP06 underwent rapid enzymatic degradation in multiple types of living cells, and the liver, kidney, and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of PEP06. We identified metabolites of PEP06 using full-scan mass spectrometry (MS) and tandem MS (MS2), wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide, formed by successive losses of amino acids. The metabolites were C and N terminal truncated products of PEP06. The structures of 11 metabolites (M6, M7, M16, M17, M21, M25, M33, M34, M39, M40, and M42) were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized metabolites. We have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06, which can support further drug research.
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•An LC-HRMS assay for PEP06, a promising drug targeted to the tumor, was developed.•The in vitro metabolic stability of PEP06 was incubated with living cells.•Forty-three metabolites of PEP06 were characterized in vitro for the first time.
To explore the relationship between occupational stress and psychological disorder among oilfield workers.
In 2013, 1485 psychological normal oilfield workers using the stratified cluster sampling in ...Xinjiang Autonomous Region were investigated, and the follow-up was conducted in 2015. Occupational stress and mental health status were assessed by questionnaire for the occupation stress and self-rating symptom.
The people with mental disorder was 556, the incidence rate was40. 29%. The level of occupational stress level low-high group( RR = 2. 689, 95% CI1. 342-5. 391) and middle-high group( RR = 2. 878, 95% CI 1. 205-6. 875) of mental disorder were higher than the low-low group, the level of Personal Strain Questionnaire low-middle group( RR = 2. 500, 95% CI 1. 700-3. 763) and low-high group( RR =3. 907, 95% CI 1. 955-7. 651) and middle-middle group( RR = 2. 141, 95% CI 1. 016-4. 512) of mental disorder were higher than low-low group. Without drinking( RR =0. 779, 95% CI = 0. 622-0. 976) was protective factor
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