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The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens demands urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. Herein, we identified the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimal inhibitory concentration of meropenem against blaNDM-5 positive Escherichia coli by 32-fold through cell-based high-throughput screening. Further pharmacological studies indicated that 5-FU exhibited the potentiation effects on carbapenem antibiotics against 42 Gram-negative bacteria producing either metallo-ß-lactamases (MBLs), such as NDM and IMP, or serine ß-lactamases (Ser-BLs), like KPC and OXA. These bacteria included E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., with 32 of them obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcriptional and expressional level of the blaNDM-5 gene. Additionally, the 5-FU combined with meropenem can enhance bacterial metabolism, and stimulate the production of Reactive Oxygen Species (ROS), thereby rendering bacteria more susceptible to meropenem. This drug combination could effectively elevate the survival rate from 16.7% to 83.3% compared to meropenem monotherapy, and reduce bacteria loads in tissues in a mouse systemic infection model. Collectively, these findings reveal that the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against carbapenem-resistant bacteria infections.
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Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/ß-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.
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Carcinoma Ductal Pancreático , Proliferação de Células , Canais de Cloreto , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Pancreáticas , Efeito Warburg em Oncologia , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Canais de Cloreto/metabolismo , Canais de Cloreto/genética , Linhagem Celular Tumoral , Animais , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Espécies Reativas de Oxigênio/metabolismo , Glicólise , Camundongos Nus , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
Low-salt pickled vegetables are in line with a healthier diet, yet ensuring consistent quality of such products is challenging. In this study, low-salt tuber mustard pickles fermented with Lactiplantibacillus plantarum LPP95 in the presence of chitosan and inulin were analyzed over a 30-day period, and quality changes were evaluated. Total acid productions along with high bacterial counts (106 CFU/mL) were observed in the initial 20 days during indoor storage temperature, in which the reduced fiber aperture was found significantly lead to an increase in crispness (16.94 ± 1.87 N) and the maintenance of a low nitrate content (1.23 ± 0.01 mg/kg). Moreover, the combined pickling treatment resulted in higher malic acid content, lower tartaric acid content, and a decrease in the content of bitter amino acids (e.g., isoleucine and leucine), thus leading to an increase in the proportion of sweet amino acids. Additionally, combined pickling led to the production of unique volatile flavor compounds, especially the distinct spicy flavor compounds isothiocyanates. Moreover, the combined pickling treatment resulted in an increase in the abundance of Lactiplantibacillus and promoted microbial diversity within the fermentation system. Thus, the synergistic effect among chitosan, inulin, and L. plantarum LPP95 significantly enhanced the quality of pickles. The study offers a promising strategy to standardize the quality of low-salt fermented vegetables.
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Quitosana , Inulina , Lactobacillus plantarum , Mostardeira , Quitosana/química , Mostardeira/química , FermentaçãoRESUMO
PURPOSE: Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored. EXPERIMENTAL DESIGN: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism. RESULTS: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism. CONCLUSIONS: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.
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Carcinoma Ductal Pancreático , Proliferação de Células , Colesterol , Homeostase , Neoplasias Pancreáticas , Humanos , Colesterol/metabolismo , Colesterol/biossíntese , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Animais , Linhagem Celular Tumoral , Camundongos , Regulação Neoplásica da Expressão Gênica , Progressão da Doença , Prognóstico , Caveolina 1/genética , Caveolina 1/metabolismo , Camundongos Nus , MasculinoRESUMO
BACKGROUND: This study investigated the molecular mechanism of long intergenic non-protein coding RNA 1605 (LINC01605) in the process of tumor growth and liver metastasis of pancreatic ductal adenocarcinoma (PDAC). METHODS: LINC01605 was filtered out with specificity through TCGA datasets (related to DFS) and our RNA-sequencing data of PDAC tissue samples from Renji Hospital. The expression level and clinical relevance of LINC01605 were then verified in clinical cohorts and samples by immunohistochemical staining assay and survival analysis. Loss- and gain-of-function experiments were performed to estimate the regulatory effects of LINC01605 in vitro. RNA-seq of LINC01605-knockdown PDAC cells and subsequent inhibitor-based cellular function, western blotting, immunofluorescence and rescue experiments were conducted to explore the mechanisms by which LINC01605 regulates the behaviors of PDAC tumor cells. Subcutaneous xenograft models and intrasplenic liver metastasis models were employed to study its role in PDAC tumor growth and liver metastasis in vivo. RESULTS: LINC01605 expression is upregulated in both PDAC primary tumor and liver metastasis tissues and correlates with poor clinical prognosis. Loss and gain of function experiments in cells demonstrated that LINC01605 promotes the proliferation and migration of PDAC cells in vitro. In subsequent verification experiments, we found that LINC01605 contributes to PDAC progression through cholesterol metabolism regulation in a LIN28B-interacting manner by activating the mTOR signaling pathway. Furthermore, the animal models showed that LINC01605 facilitates the proliferation and metastatic invasion of PDAC cells in vivo. CONCLUSIONS: Our results indicate that the upregulated lncRNA LINC01605 promotes PDAC tumor cell proliferation and migration by regulating cholesterol metabolism via activation of the mTOR signaling pathway in a LIN28B-interacting manner. These findings provide new insight into the role of LINC01605 in PDAC tumor growth and liver metastasis as well as its value for clinical approaches as a metabolic therapeutic target in PDAC.
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Fiber-integrated micro/nanostructures play a crucial role in modern industry, mainly owing to their compact size, high sensitivity, and resistance to electromagnetic interference. However, the three-dimensional manufacturing of fiber-tip functional structures beyond organic polymers remains challenging. It is essential to construct fiber-integrated inorganic silica with designed functional nanostructures for microsystem applications. Here, we develop a strategy for the 3D nanolithography of fiber-integrated silica from hybrid organic-inorganic materials by ultrafast laser-induced multiphoton absorption. Without silica nanoparticles and polymer additives, the acrylate-functionalized precursors can be locally cross-linked through a nonlinear effect. Followed by annealing at low temperature, the as-printed micro/nanostructures are transformed to high-quality silica with sub-100 nm resolution. Silica microcantilever probes and microtoroid resonators are directly integrated onto the optical fiber, showing strong thermal stability and quality factors. This work provides a promising strategy for fabricating desired fiber-tip silica micro/nanostructures, which is helpful for the development of integrated functional device applications.
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BACKGROUND: OCIAD2ï¼Ovarian carcinoma immunoreactive antigen-like protein 2ï¼ is a protein reported in various cancers. However, the role of OCIAD2 has not been explored in pan-cancer datasets. The purpose of this research lies in analyzing the expression level and prognostic-related value of OCIAD2 in different human cancers, as well as revealing the underlying mechanism in specific cancer type (pancreatic adenocarcinoma, PAAD). METHODS: The correlation between OCIAD2 expression level and clinical relevance in different human cancers was investigated from bioinformatical perspective (GTEx and TCGA). The OCIAD2 expression level and clinical significance in PAAD were explored in GEO datasets and tissue microarray. Functional experiments were used to determine the OCIAD2 cell functions in vitro and in vivo. GSEA, western blot and immunohistochemistry were used to uncover the potential mechanism. RESULTS: OCIAD2 expression level was closely correlated with clinical relevance in many cancer types through pan-cancer analysis, and we found OCIAD2 was highly expressed in PAAD and associated with poorer prognosis. OCIAD2 acted as the promotor of Warburg effect and influenced PAAD cells proliferation, migration and apoptosis. Mechanistically, OCIAD2 upregulation may boost glycolysis in PAAD via activating the AKT signaling pathway in PAAD. CONCLUSIONS: In PAAD, OCIAD2 promotes Warburg effect via AKT signaling pathway and targeting cancer cells metabolic reprogramming could be a potential treatment.
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Proteínas de Neoplasias , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Feminino , Humanos , Masculino , Camundongos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismoRESUMO
It is crucial to discover novel antimicrobial drugs to combat resistance. This study investigated the antibacterial properties of halicin (SU3327), an AI-identified anti-diabetic drug, against 13 kinds of common clinical pathogens of animal origin, including multidrug-resistant strains. Employing minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assessments, halicin demonstrated a broad-spectrum antibacterial effect. Time-killing assays revealed its concentration-dependent bactericidal activity against Escherichia coli ATCC 25922 (E. coli ATCC 25922), Staphylococcus aureus ATCC 29213 (S. aureus ATCC 29213), and Actinobacillus pleuropneumoniae S6 (APP S6) after 4 h of treatment at concentrations above the MIC. Halicin exhibited longer post-antibiotic effects (PAEs) and sub-MIC effects (PA-SMEs) for E. coli 25922, S. aureus 29213, and APP S6 compared to ceftiofur and ciprofloxacin, the commonly used veterinary antimicrobial agents, indicating sustained antibacterial action. Additionally, the results of consecutive passaging experiments over 40 d at sub-inhibitory concentrations showed that bacteria exhibited difficulty in developing resistance to halicin. Toxicology studies confirmed that halicin exhibited low acute toxicity, being non-mutagenic, non-reproductive-toxic, and non-genotoxic. Blood biochemical results suggested that halicin has no significant impact on hematological parameters, liver function, and kidney function. Furthermore, halicin effectively treated respiratory A. pleuropneumoniae infections in murine models. These results underscore the potential of halicin as a new antibacterial agent with applications against clinically relevant pathogens in veterinary medicine.
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The emergence of carbapenem-resistant Gram-negative pathogens presents a clinical challenge in infection treatment, prompting the repurposing of existing drugs as an essential strategy to address this crisis. Although the anticancer drug 5-fluorouracil (5-FU) has been recognized for its antibacterial properties, its mechanisms are not fully understood. Here, we found that the minimal inhibitory concentration (MIC) of 5-FU against Escherichia coli was 32-64 µg/mL, including strains carrying blaNDM-5, which confers resistance to carbapenems. We further elucidated the antibacterial mechanism of 5-FU against E. coli by using genetic and biochemical analyses. We revealed that the mutation of uracil phosphoribosyltransferase-encoding gene upp increased the MIC of 5-FU against E. coli by 32-fold, indicating the role of the upp gene in 5-FU resistance. Additionally, transcriptomic analysis of E. coli treated with 5-FU at 8 µg/mL and 32 µg/mL identified 602 and 1082 differentially expressed genes involved in carbon and nucleic acid metabolism, DNA replication, and repair pathways. The biochemical assays showed that 5-FU induced bacterial DNA damage, significantly increased intracellular ATP levels and the NAD+/NADH ratio, and promoted reactive oxygen species (ROS) production. These findings suggested that 5-FU may exert antibacterial effects on E. coli through multiple pathways, laying the groundwork for its further development as a therapeutic candidate against carbapenem-resistant bacterial infections.
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During long-term storage of the liquid propellant N2O4, it absorbs H2O to form the N2O4(H2O)n system, and this in turn generates HNO3, HNO2, and other substances in the storage tank because of corrosion, which seriously affects the performance of weaponry. In this work, we carried out computational simulations of N2O4 with different masses of water based on ReaxFF, analyzed the reaction intermediates and products, and investigated the mechanism of the reaction of N2O4 with H2O and of N2O4(H2O)n. The results show that the reaction product ω(HNO3+HNO2) undergoes a rapid growth in the early stage of the reaction and then tends toward dynamic equilibrium; the potential energy of the system decreases with the increase of ω(H2O), the reaction rate increases, and the rate of decomposition of HNO2 to form HNO3 increases. When ω(H2O) is 0.2 or 1.0%, the intermediate products are N2O4H2O or N2O4(H2O)2, respectively, and the reaction proceeds along two paths; when ω(H2O) ≥ 2.0%, N2O4(H2O)3 appears as the intermediate product, HNO3 and HNO2 are directly produced in one step, and a stable current loop can be formed within the whole system.
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As a new type of agricultural waste block substrate utilization, the initial wet base state of the substrate culture block needs to be dried. Therefore, studying the drying mechanism of substrate culture block is critical. In this study, the substrate culture block in a dry state was taken as the research object. Based on physical and chemical properties, the internal section of the substrate culture block was characterized by scanning electron microscopy and the pore condition of the particles was quantified. The results showed that the internal pore structure was uniform and favorable for plant root growth. Based on the pore structure, pore channel modeling was constructed to investigate the distribution of the internal multiphase medium and to distinguish between channels and pore-blind channels. The applicability of the modeling was verified and discussed. By measuring the drying rate of the substrate culture block and classifying its drying stages as fast speed, constant speed, and slow speed, it is clarified that the forms of moisture existence are bound-state water and free-state water, and the moisture migration is prioritized as surface adsorption water, interparticle water, particle attached water, and capillary water. Innovate a method to quantify the change of pore space in the drying process by pore coefficient ratio to evaluate the drying quality. The results show that when the pore coefficient ratio is about 40 %, its moisture content is 20 %â¼30 %, and the drying effect is best at this time. The physical drying test further confirmed the correctness of the conclusion of the drying stage division and water loss law. This study can provide a theoretical reference for the modeling study of the pore structure of the block matrix and the exploration of its drying mechanism.
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Campylobacter jejuni is recognized as a significant foodborne pathogen, and recent studies have indicated a rising trend of aminoglycosides resistance gene aph(2â³)-If among C. jejuni isolates from food-producing animals in China. However, systematic information about aph(2â³)-If-positive C. jejuni from food-producing animals and other sources worldwide based on whole-genome analysis remains a knowledge gap. In this study, we aimed to analyze the worldwide distribution, genetic environment and phylogenetic tree of aph(2â³)-If by utilizing Whole Genome Sequencing (WGS) data obtained, coupled with information in the GenBank database. A total of 160C. jejuni isolates in the GenBank database and 14C. jejuni isolates in our laboratory carrying aph(2â³)-If gene were performed for further analysis. WGS analysis revealed the global distribution of aph(2â³)-If among C. jejuni from 6 countries. Multilocus Sequence Typing(MLST) results indicated that 70 STs were involved in the dissemination of aph(2â³)-If, with ST10086 being the predominant ST. Whole-genome Multilocus Sequence Typing(wg-MLST) analysis according to times, countries, and origins of C. jejuni isolation further demonstrated a close relationship between aph(2â³)-If carrying C. jejuni isolates from farm and food. The findings also revealed the existence of 32 distinct types of genetic environments surrounding aph(2â³)-If among these isolates. Notably, Type 30, characterized by the arrangement ISsag10-deoD-ant(9)-hp-hp-aph(2â³)-If, emerged as the predominant genetic environment. In conclusion, our analysis provides the inaugural perspective on the worldwide distribution of aph(2â³)-If. This resistance gene demonstrates horizontal transferability and regional diffusion in a clonal pattern. The close association observed among aph(2â³)-If-positive C. jejuni strains isolated from poultry, food, and clinical environments underscores the potential for zoonotic transmission from these isolates.
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Aminoglicosídeos , Antibacterianos , Infecções por Campylobacter , Campylobacter jejuni , Farmacorresistência Bacteriana , Tipagem de Sequências Multilocus , Filogenia , Campylobacter jejuni/genética , Campylobacter jejuni/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Aminoglicosídeos/farmacologia , Animais , Antibacterianos/farmacologia , Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/veterinária , Infecções por Campylobacter/epidemiologia , Sequenciamento Completo do Genoma , Humanos , Prevalência , China , Microbiologia de Alimentos , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: A novel plasmid-mediated resistance-nodulation-division (RND) efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae tremendously threatens the use of convenient therapeutic options in the post-antibiotic era, including the "last-resort" antibiotic tigecycline. RESULTS: In this work, the natural alkaloid harmaline was found to potentiate tigecycline efficacy (4- to 32-fold) against tmexCD1-toprJ1-positive K. pneumoniae, which also thwarted the evolution of tigecycline resistance. Galleria mellonella and mouse infection models in vivo further revealed that harmaline is a promising candidate to reverse tigecycline resistance. Inspiringly, harmaline works synergistically with tigecycline by undermining tmexCD1-toprJ1-mediated multidrug resistance efflux pump function via interactions with TMexCD1-TOprJ1 active residues and dissipation of the proton motive force (PMF), and triggers a vicious cycle of disrupting cell membrane integrity and metabolic homeostasis imbalance. CONCLUSION: These results reveal the potential of harmaline as a novel tigecycline adjuvant to combat hypervirulent K. pneumoniae infections.
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Antibacterianos , Reposicionamento de Medicamentos , Harmalina , Infecções por Klebsiella , Klebsiella pneumoniae , Tigeciclina , Klebsiella pneumoniae/efeitos dos fármacos , Tigeciclina/farmacologia , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Animais , Camundongos , Antibacterianos/farmacologia , Harmalina/farmacologia , Harmalina/análogos & derivados , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana Múltipla , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Membrana Transportadoras/metabolismo , Proteínas de Membrana Transportadoras/genética , FemininoRESUMO
Despite carbapenems not being used in animals, carbapenem-resistant Enterobacterales (CRE), particularly New Delhi metallo-ß-lactamase-producing CRE (NDM-CRE), are prevalent in livestock. Concurrently, the incidence of human infections caused by NDM-CRE is rising, particularly in children. Although a positive association between livestock production and human NDM-CRE infections at the national level was identified, the evidence of direct transmission of NDM originating from livestock to humans remains largely unknown. Here, we conducted a cross-sectional study in Chengdu, Sichuan Province, to examine the prevalence of NDM-CRE in chickens and pigs along the breeding-slaughtering-retail chains, in pork in cafeterias of schools, and in colonizations and infections from children's hospital and examined the correlation of NDM-CRE among animals, foods and humans. Overall, the blaNDM increases gradually along the chicken and pig breeding (4.70%/2.0%) -slaughtering (7.60%/22.40%) -retail (65.56%/34.26%) chains. The slaughterhouse has become a hotspot for cross-contamination and amplifier of blaNDM. Notably, 63.11% of pork from the school cafeteria was positive for blaNDM. The prevalence of blaNDM in intestinal and infection samples from children's hospitals was 21.68% and 19.80%, respectively. whole genome sequencing (WGS) analysis revealed the sporadic, not large-scale, clonal spread of NDM-CRE along the chicken and pig breeding-slaughtering-retail chain, with further spreading via IncX3-blaNDM plasmid within each stage of whole chains. Clonal transmission of NDM-CRE is predominant in children's hospitals. The IncX3-blaNDM plasmid was highly prevalent among animals and humans and accounted for 57.7% of Escherichia coli and 91.3% of Klebsiella pneumoniae. Attention should be directed towards the IncX3 plasmid to control the transmission of blaNDM between animals and humans.
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Infecções por Enterobacteriaceae , Enterobacteriaceae , Criança , Humanos , Animais , Suínos , Enterobacteriaceae/genética , Estudos Transversais , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Galinhas , Escherichia coli/genética , beta-Lactamases/genética , Infecções por Enterobacteriaceae/epidemiologia , Infecções por Enterobacteriaceae/veterinária , Klebsiella pneumoniae/genética , PlasmídeosRESUMO
Aiming at the problems of poor adjustment effect, weak anti-disturbance ability, and low robustness of the traditional sliding mode algorithm for permanent magnet synchronous motor speed sensorless, a permanent magnet synchronous motor speed observation method combining super-twisting sliding mode control algorithm and fuzzy control is proposed to accelerate the convergence speed of the system and improve the anti-disturbance ability. Fuzzy rules are used to solve the problem of obtaining the upper bound of the boundary function in the super-twisting algorithm. Moreover, the fuzzy algorithm is used to output the variable sliding mode gain instead of the fixed sliding mode coefficient to improve the system robustness and suppress the jitter. The simulation results show that the overshoot of the control system is 4%, the lag time is not more than 0.003â ms, the speed error is not more than 1%, and the response and adjustment time is not more than 0.02â s. The proposed control strategy improves the tracking accuracy and response speed of the system, suppresses the sliding mode chattering, and enhances the anti-interference ability of the system.
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Patient reported outcomes is currently considered to be an important supplement to evaluate the effectiveness of enhanced recovery after surgery (ERAS) clinical practice. The Quality of Recovery-40 Questionnaire (QoR-40) is one of the most frequently used and validation tool to assess the subjective feelings of quality of life after surgery. The present study aimed to use the QoR-40 to evaluate the effectiveness of ERAS protocols in gastric cancer from the perspective of patient-reported quality of recovery. The study was designed as a prospective, non-randomized clinical trial, conducted in a single center. Patients in our hospital who were scheduled to undergo radical surgery for gastric cancer were divided into ERAS group and control group (Contr group). The QoR-40 were administered one day before surgery (Baseline) and on postoperative day 1, 3, 6, and 30. The difference in QoR-40 scores between the ERAS and Contr groups was compared by repeated-measures ANOVA. A total of 200 patients completed the study, including 100 patients in the ERAS group and 100 patients in the Contr group. The Baseline time point QoR-40 scores of the ERAS and Contr groups were 179.68 ± 14.46 and 180.12 ± 17.12, respectively, and no significant difference was noted between the two groups (p = 0.845). The postoperative QoR-40 score of the ERAS group was significantly higher than that of the Contr group, and the difference was statistically significant (p = 0.006). This study demonstrated that, in terms of patient-reported quality of recovery, the postoperative recovery effect of ERAS protocols in gastric cancer is significantly better than that of the traditional treatment model.
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Recuperação Pós-Cirúrgica Melhorada , Qualidade de Vida , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirurgia , Feminino , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Estudos Prospectivos , Idoso , Medidas de Resultados Relatados pelo Paciente , Resultado do Tratamento , Gastrectomia/métodos , Adulto , Recuperação de Função FisiológicaRESUMO
Rapid phenotypic detection assays, including Carba NP and its variants, are widely applied for clinical diagnosis of carbapenemase-producing Enterobacterales (CPE). However, these tests are based on the acidification of the pH indicator during carbapenem hydrolysis, which limits test sensitivity and speed, especially for the detection of CPE producing low-activity carbapenem (e.g., OXA-48 variants). Herein, we developed a novel rapid and sensitive CPE detection method (Carba PBP) that could measure substrate (meropenem) consumption based on penicillin-binding protein (PBP). Meropenem-specific PBP was used to develop a competitive lateral flow assay (LFA) for meropenem identification. For the detection of carbapenemase activity, meropenem concentration was optimized using a checkerboard assay. The performance of Carba PBP was evaluated and compared with that of Carba NP using a panel of 94 clinical strains characterized by whole-genome sequencing and carbapenem susceptibility test. The limit of detection of PBP-based LFA for meropenem identification was 7 ng mL-1. Using 10 ng mL-1 meropenem as the substrate, Carba PBP and Carba NP could detect 10 ng mL-1 carbapenemase within 25 min and 1,280 ng mL-1 CPE in 2 h, respectively. The sensitivity and specificity were 100% (75/75) and 100% (19/19) for Carba PBP and 85.3% (64/75) and 100% (19/19) for Carba NP, respectively. When compared with Carba NP, Carba PBP showed superior performance in detecting all the tested CPE strains (including OXA-48-like variants) within 25 min and presented two orders of magnitude higher analytical sensitivity, demonstrating potential for clinical diagnosis of CPE. IMPORTANCE This study successfully achieved the goal of carbapenemase activity detection with both high sensitivity and convenience, offering a convenient lateral flow assay for clinical diagnosis of carbapenemase-producing Enterobacterales.
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Proteínas de Bactérias , beta-Lactamases , Humanos , Proteínas de Ligação às Penicilinas/genética , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , beta-Lactamases/metabolismo , Carbapenêmicos/farmacologia , Sensibilidade e EspecificidadeRESUMO
We propose a humidity sensor using an excessively tilted fiber grating (Ex-TFG) coated with agarose fabricated using femtosecond laser processing. The processed grating showcases remarkable differentiation between TE and TM modes, achieving an exceptionally narrow bandwidth of approximately 1.5 nm and an impressive modulation depth of up to 15 dB for both modes. We exposed the agarose-coated TFG sensor to various relative humidity levels and monitored the resonance wavelength to test its humidity sensing capability. Our findings demonstrated that the sensor exhibited a rapid response time (2-4 s) and showed a high response sensitivity (18.5 pm/%RH) between the humidity changes and the resonant wavelength shifts. The high sensitivity, linearity, repeatability, low hysteresis, and excellent long-term stability of the TFG humidity sensor, as demonstrated in our experimental results, make it an attractive option for environmental monitoring or biomedical diagnosis.
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Infections caused by Enterobacterales producing New Delhi Metallo-ß-lactamases (NDMs), Zn(II)-dependent enzymes hydrolyzing carbapenems, are difficult to treat. Depriving Zn(II) to inactivate NDMs is an effective solution to reverse carbapenems resistance in NDMs-producing bacteria. However, specific Zn(II) deprivation and better bacterial outer membrane penetrability in vivo are challenges. Herein, authors present a pathogen-primed liposomal antibiotic booster (M-MFL@MB), facilitating drugs transportation into bacteria and removing Zn(II) from NDMs. M-MFL@MB introduces bismuth nanoclusters (BiNCs) as a storage tank of Bi(III) for achieving ROS-initiated Zn(II) removal. Inspired by bacteria-specific maltodextrin transport pathway, meropenem-loaded BiNCs are camouflaged by maltodextrin-cloaked membrane fusion liposome to cross the bacterial envelope barrier via selectively targeting bacteria and directly outer membrane fusion. This fusion disturbs bacterial membrane homeostasis, then triggers intracellular ROS amplification, which activates Bi(III)-mediated Zn(II) replacement and meropenem release, realizing more precise and efficient NDMs producer treatment. Benefiting from specific bacteria-targeting, adequate drugs intracellular accumulation and self-activation Zn(II) replacement, M-MFL@MB rescues all mice infected by NDM producer without systemic side effects. Additionally, M-MFL@MB decreases the bacterial outer membrane vesicles secretion, slowing down NDMs producer's transmission by over 35 times. Taken together, liposomal antibiotic booster as an efficient and safe tool provides new strategy for tackling NDMs producer-induced infections.
Assuntos
Antibacterianos , Carbapenêmicos , Camundongos , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos/uso terapêutico , Carbapenêmicos/farmacologia , Meropeném/farmacologia , Escherichia coli , Lipossomos , Espécies Reativas de Oxigênio , Testes de Sensibilidade MicrobianaRESUMO
Despite scattered studies that have reported mutations in the tet(A) gene potentially linked to tigecycline resistance in clinical pathogens, the detailed function and epidemiology of these tet(A) variants remains limited. In this study, we analyzed 64 Escherichia coli isolates derived from MacConkey plates supplemented with tigecycline (2 µg/mL) and identified five distinct tet(A) variants that account for reduced sensitivity to tigecycline. In contrast to varied tigecycline MICs (0.25 to 16 µg/mL) of the 64 tet(A)-variant-positive E. coli isolates, gene function analysis confirmed that the five tet(A) variants exhibited a similar capacity to reduce tigecycline sensitivity in DH5α carrying pUC19. Among the observed seven non-synonymous mutations, the V55M mutation was unequivocally validated for its positive role in conferring tigecycline resistance. Interestingly, the variability in tigecycline MICs among the E. coli strains did not correlate with tet(A) gene expression. Instead, a statistically significant reduction in intracellular tigecycline concentrations was noted in strains displaying higher MICs. Genomic analysis of 30 representative E. coli isolates revealed that tet(A) variants predominantly resided on plasmids (n = 14) and circular intermediates (n = 13). Within China, analysis of a well-characterized E. coli collection isolated from pigs and chickens in 2018 revealed the presence of eight tet(A) variants in 103 (4.2%, 95% CI: 3.4-5.0%) isolates across 13 out of 17 tested Chinese provinces or municipalities. Globally, BLASTN analysis identified 21 tet(A) variants in approximately 20.19% (49,423/244,764) of E. coli genomes in the Pathogen Detection database. These mutant tet(A) genes have been widely disseminated among E. coli isolates from humans, food animals, and the environment sectors, exhibiting a growing trend in tet(A) variants over five decades. Our findings underscore the urgency of addressing tigecycline resistance and the underestimated role of tet(A) mutations in this context.