Biomimetic Design of a Dynamic M-O-V Pyramid Electron Bridge for Enhanced Nitrogen Electroreduction.

Electrochemical nitrogen reduction reaction (eNRR) offers a sustainable route for ammonia synthesis; however, current electrocatalysts are limited in achieving optimal performance within narrow potential windows. Herein, inspired by the heliotropism of sunflowers, we present a biomimetic design of Ru-VOH electrocatalyst, featuring a dynamic Ru-O-V pyramid electron bridge for eNRR within a wide potential range. In situ spectroscopy and theoretical investigations unravel the fact that the electrons are donated from Ru to V at lower overpotentials and retrieved at higher overpotentials, maintaining a delicate balance between N2 activation and proton hydrogenation. Moreover, N2 adsorption and activation were found to be enhanced by the Ru-O-V moiety. The catalyst showcases an outstanding Faradaic efficiency of 51.48% at -0.2 V (vs RHE) with an NH3 yield rate exceeding 115 µg h-1 mg-1 across the range of -0.2 to -0.4 V (vs RHE), along with impressive durability of over 100 cycles. This dynamic M-O-V pyramid electron bridge is also applicable to other metals (M = Pt, Rh, and Pd).

General and Scalable Synthesis of Mesoporous 2D MZrO2 (M = Co, Mn, Ni, Cu, Fe) Nanocatalysts by Amorphous-to-Crystalline Transformation.

In modern heterogeneous catalysis, it remains highly challenging to create stable, low-cost, mesoporous 2D photo-/electro-catalysts that carry atomically dispersed active sites. In this work, a general shape-preserving amorphous-to-crystalline transformation (ACT) strategy is developed to dope various transition metal (TM) heteroatoms in ZrO2, which enabled the scalable synthesis of TMs/oxide with a mesoporous 2D structure and rich defects. During the ACT process, the amorphous MZrO2 nanoparticles (M = Fe, Ni, Cu, Co, Mn) are deposited within a confined space created by the NaCl template, and they transform to crystalline 2D ACT-MZrO2 nanosheets in a shape-preserving manner. The interconnected crystalline ACT-MZrO2 nanoparticles thus inherit the same structure as the original MZrO2 precursor. Owing to its rich active sites on the surface and abundant oxygen vacancies (OVs), ACT-CoZrO2 gives superior performance in catalyzing the CO2-to-syngas conversion as demonstrated by experiments and theoretical calculations. The ACT chemistry opens a general route for the scalable synthesis of advanced catalysts with precise microstructure by reconciliating the control of crystalline morphologies and the dispersion of heteroatoms.

The causal relationship between COVID-19 and seventeen common digestive diseases: a two-sample, multivariable Mendelian randomization study.

OBJECTIVES: In clinical practice, digestive symptoms such as nausea, vomiting are frequently observed in COVID-19 patients. However, the causal relationship between COVID-19 and digestive diseases remains unclear. METHODS: We extracted single nucleotide polymorphisms associated with the severity of COVID-19 from summary data of genome-wide association studies. Summary statistics of common digestive diseases were primarily obtained from the UK Biobank study and the FinnGen study. Two-sample Mendelian randomization analyses were then conducted using the inverse variance-weighted (IVW), Mendelian randomization-Egger regression (MR Egger), weighted median estimation, weighted mode, and simple mode methods. IVW served as the primary analysis method, and Multivariable Mendelian randomization analysis was employed to explore the mediating effect of body mass index (BMI) and type 2 diabetes. RESULTS: MR analysis showed that a causal association between SARS-CoV-2 infection (OR = 1.09, 95% CI 1.01-1.18, P = 0.03), severe COVID-19 (OR = 1.02, 95% CI 1.00-1.04, P = 0.02), and COVID-19 hospitalization (OR = 1.04, 95% CI 1.01-1.06, P = 0.01) with gastroesophageal reflux disease (GERD). Mediation analysis indicated that body mass index (BMI) served as the primary mediating variable in the causal relationship between SARS-CoV-2 infection and GERD, with BMI mediating 36% (95% CI 20-53%) of the effect. CONCLUSIONS: We found a causal relationship between SARS-CoV-2 infection and gastroesophageal reflux disease. Furthermore, we found that the causal relationship between SARS-CoV-2 infection and GERD is mainly mediated by BMI.

Myeloid-derived growth factor suppresses VSMC dedifferentiation and attenuates postinjury neointimal formation in rats by activating S1PR2 and its downstream signaling.

Restenosis after angioplasty is caused usually by neointima formation characterized by aberrant vascular smooth muscle cell (VSMC) dedifferentiation. Myeloid-derived growth factor (MYDGF), secreted from bone marrow-derived monocytes and macrophages, has been found to have cardioprotective effects. In this study we investigated the effect of MYDGF to postinjury neointimal formation and the underlying mechanisms. Rat carotid arteries balloon-injured model was established. We found that plasma MYDGF content and the level of MYDGF in injured arteries were significantly decreased after balloon injury. Local application of exogenous MYDGF (50 µg/mL) around the injured vessel during balloon injury markedly ameliorated the development of neointimal formation evidenced by relieving the narrow endovascular diameter, improving hemodynamics, and reducing collagen deposition. In addition, local application of MYDGF inhibited VSMC dedifferentiation, which was proved by reversing the elevated levels of osteopontin (OPN) protein and decreased levels of α-smooth muscle actin (α-SMA) in the left carotid arteries. We showed that PDGF-BB (30 ng/mL) stimulated VSMC proliferation, migration and dedifferentiation in vitro; pretreatment with MYDGF (50-200 ng/mL) concentration-dependently eliminated PDGF-BB-induced cell proliferation, migration and dedifferentiation. Molecular docking revealed that MYDGF had the potential to bind with sphingosine-1-phosphate receptor 2 (S1PR2), which was confirmed by SPR assay and Co-IP analysis. Pretreatment with CCG-1423 (Rho signaling inhibitor), JTE-013 (S1PR2 antagonist) or Ripasudil (ROCK inhibitor) circumvented the inhibitory effects of MYDGF on VSMC phenotypic switching through inhibiting S1PR2 or its downstream RhoA-actin monomers (G-actin) /actin filaments (F-actin)-MRTF-A signaling. In summary, this study proves that MYDGF relieves neointimal formation of carotid arteries in response to balloon injury in rats, and suppresses VSMC dedifferentiation induced by PDGF-BB via S1PR2-RhoA-G/F-actin-MRTF-A signaling pathway. In addition, our results provide evidence for cross talk between bone marrow and vasculature.

Frizzled receptors (FZDs) in Wnt signaling: potential therapeutic targets for human cancers.

Frizzled receptors (FZDs) are key contributors intrinsic to the Wnt signaling pathway, activation of FZDs triggering the Wnt signaling cascade is frequently observed in human tumors and intimately associated with an aggressive carcinoma phenotype. It has been shown that the abnormal expression of FZD receptors contributes to the manifestation of malignant characteristics in human tumors such as enhanced cell proliferation, metastasis, chemotherapy resistance as well as the acquisition of cancer stemness. Given the essential roles of FZD receptors in the Wnt signaling in human tumors, this review aims to consolidate the prevailing knowledge on the specific status of FZD receptors (FZD1-10) and elucidate their respective functions in tumor progression. Furthermore, we delineate the structural basis for binding of FZD and its co-receptors to Wnt, and provide a better theoretical foundation for subsequent studies on related mechanisms. Finally, we describe the existing biological classes of small molecule-based FZD inhibitors in detail in the hope that they can provide useful assistance for design and development of novel drug candidates targeted FZDs.

Design, synthesis, and anti-tumor activity of derivatives of ring A and C-28 of asiatic acid.

Based on computer-aided drug design (CADD), the active groups of the known active small molecule compounds that can bind to EGFR target protein were analyzed through the molecular docking method. Then, 12 novel asiatic acid derivatives were synthesized by introducing active groups at ring A and C-28 positions of asiatic acid. The structures of these novel compounds were determined by NMR and MS. Furthermore, the anti-tumor activities of these derivatives on human lung cancer cells (A549) and human breast cancer cells (MCF-7) were evaluated by MTT assay. In conclusion, compounds I4 and II3 have stronger anti-cancer activity than parent compounds, the activities were stronger than gefitinib and comparable to afatinib, which may be potential candidate compounds for tumor therapy.

Machine Learning-Accelerated Discovery of A2BC2 Ternary Electrides with Diverse Anionic Electron Densities.

This study combines machine learning (ML) and high-throughput calculations to uncover new ternary electrides in the A2BC2 family of compounds with the P4/mbm space group. Starting from a library of 214 known A2BC2 phases, density functional theory calculations were used to compute the maximum value of the electron localization function, indicating that 42 are potential electrides. A model was then trained on this data set and used to predict the electride behavior of 14,437 hypothetical compounds generated by structural prototyping. Then, the stability and electride features of the 1254 electride candidates predicted by the model were carefully checked by high-throughput calculations. Through this tiered approach, 41 stable and 104 metastable new A2BC2 electrides were predicted. Interestingly, all three kinds of electrides, i.e., electron-deficient, electron-neutral, and electron-rich electrides, are present in the set of predicted compounds. Three of the most promising new electrides (two electron-rich, Nd2ScSi2 and La2YbGe2, and one electron-deficient Y2LiSi2) were then successfully synthesized and characterized experimentally. Furthermore, the synthesized electrides were found to exhibit high catalytic activities for NH3 synthesis under mild conditions when Ru-loaded. The electron-deficient Y2LiSi2, in particular, was seen to exhibit a good balance of catalytic activity and chemical stability, suggesting its future application in catalysis.

Hydrogel Electrolyte Enabled High-Performance Flexible Aqueous Zinc Ion Energy Storage Systems toward Wearable Electronics.

To cater to the swift advance of flexible wearable electronics, there is growing demand for flexible energy storage system (ESS). Aqueous zinc ion energy storage systems (AZIESSs), characterizing safety and low cost, are competitive candidates for flexible energy storage. Hydrogels, as quasi-solid substances, are the appropriate and burgeoning electrolytes that enable high-performance flexible AZIESSs. However, challenges still remain in designing suitable and comprehensive hydrogel electrolyte, which provides flexible AZIESSs with high reversibility and versatility. Hence, the application of hydrogel electrolyte-based AZIESSs in wearable electronics is restricted. A thorough review is required for hydrogel electrolyte design to pave the way for high-performance flexible AZIESSs. This review delves into the engineering of desirable hydrogel electrolytes for flexible AZIESSs from the perspective of electrolyte designers. Detailed descriptions of hydrogel electrolytes in basic characteristics, Zn anode, and cathode stabilization effects as well as their functional properties are provided. Moreover, the application of hydrogel electrolyte-based flexible AZIESSs in wearable electronics is discussed, expecting to accelerate their strides toward lives. Finally, the corresponding challenges and future development trends are also presented, with the hope of inspiring readers.

Comparing carbon nanoparticles and indocyanine green for sentinel lymph node mapping in endometrial cancer: A randomized-controlled single-center trial.

BACKGROUND AND OBJECTIVES: To compare the feasibility and diagnostic value of sentinel lymph node (SLN) mapping with carbon nanoparticles (CNPs) and indocyanine green (ICG) in endometrial cancer (EC). METHODS: This was a single-center, open-label, randomized controlled trial. Between August 1, 2020 and April 30, 2022, patients with early-stage EC were assessed for enrollment. All patients underwent SLN mapping with ICG or CNPs ± pelvic and/or para-aortic lymphadenectomy. The detection rate (DR), its impact factors, the sensitivity and the negative predictive value (NPV) of SLN mapping were analyzed. RESULTS: In total, 206 patients, with 103 per group, were included. The overall and bilateral DRs of the two groups were comparable without significant differences. There was no difference regarding the distribution of mapped SLNs. The sensitivity was 66.7% for both groups, and the NPVs were not significantly different. Furthermore, the sensitivity and NPV reached 100% when calculated either per hemipelvis or only in patients with bilateral SLN detection. CONCLUSIONS: SLN mapping by CNPs in EC is feasible with high DRs and diagnostic accuracy compared with ICG. CNPs might be an alternative to ICG for SLN mapping when near-infrared imaging equipment is lacking, especially in stage IA patients.

Metatranscriptome Revealed the Efficacy and Safety of a Prospective Approach for Agricultural Wastewater Reuse: Achieving Ammonia Retention during Biological Treatment by a Novel Natural Inhibitor Epsilon-Poly-l-Lysine.

Appropriate inhibitors might play important roles in achieving ammonia retention in biological wastewater treatment and its reuse in agriculture. In this study, the feasibility of epsilon-poly-l-lysine (ε-PL) as a novel natural ammonia oxidation inhibitor was investigated. Significant inhibition (ammonia oxidation inhibition rate was up to 96.83%) was achieved by treating the sludge with ε-PL (400 mg/L, 12 h soaking) only once and maintaining for six cycles. Meanwhile, the organic matter and nitrite removal was not affected. This method was effective under the common environmental conditions of biological wastewater treatment. Metatranscriptome uncovered the possible action mechanisms of ε-PL. The ammonia oxidation inhibition was due to the co-decrease of Nitrosomonas abundance, ammonia oxidation genes, and the cellular responses of Nitrosomonas. Thauera and Dechloromonas could adapt to ε-PL by stimulating stress responses, which maintained the organic matter and nitrite removal. Importantly, ε-PL did not cause the enhancement of antibiotic resistance genes and virulent factors. Therefore, ε-PL showed a great potential of ammonia retention, which could be applied in the biological treatment of wastewater for agricultural reuse.

Genome-wide identification and expression analysis of the trihelix transcription factor family in sesame (Sesamum indicum L.) under abiotic stress.

BACKGROUND: The plant trihelix gene family is among the earliest discovered transcription factor families, and it is vital in modulating light, plant growth, and stress responses. METHODS: The identification and characterization of trihelix family members in the sesame genome were analyzed by bioinformatics methods, and the expression patterns of sesame trihelix genes were assessed by quantitative real-time PCR. RESULTS: There were 34 trihelix genes discovered in the genome of sesame, which were irregularly distributed among 10 linkage groups. Also, the genome contained 5 duplicate gene pairs. The 34 trihelix genes were divided into six sub-families through a phylogenetic study. A tissue-specific expression revealed that SiTH genes exhibited spatial expression patterns distinct from other trihelix genes in the same subfamily. The cis-element showed that the SiTHs gene promoter contained various elements associated with responses to hormones and multiple abiotic stresses. Additionally, the expression patterns of 8 SiTH genes in leaves under abiotic stresses demonstrated that all selected genes were significantly upregulated or downregulated at least once in the stress period. Furthermore, the SiTH4 gene was significantly induced in response to drought and salt stress, showing that SiTH genes may be engaged in the stress response mechanisms of sesame. CONCLUSION: These findings establish a foundation for further investigation of the trihelix gene-mediated response to abiotic stress in sesame.

Expression of EMT-related genes in lymph node metastasis in endometrial cancer: a TCGA-based study.

BACKGROUND: Endometrial cancer (EC) with metastasis in pelvic/para-aortic lymph nodes suggests an unsatisfactory prognosis. Nevertheless, there is still rare literature focusing on the role of epithelial-mesenchymal transition (EMT) in lymph node metastasis (LNM) in EC. METHODS: Transcriptional data were derived from the TCGA database. Patients with stage IA-IIIC2 EC were included, constituting the LN-positive and LN-negative groups. To evaluate the extent of EMT, an EMT signature composed of 315 genes was adopted. The EMT-related genes (ERGs) were obtained from the dbEMT2 database, and the differentially expressed ERGs (DEERGs) between these two groups were screened. On the basis of DEERGs, pathway analysis was carried out. We eventually adopted the logistic regression model to build an ERG-based gene signature with predictive value for LNM in EC. RESULTS: A total of 498 patients were included, with 75 in the LN-positive group. Median EMT score of tumor tissues from LN-negative group was - 0.369, while that from the LN-positive group was - 0.296 (P < 0.001), which clearly exhibited a more mesenchymal phenotype for LNM cases on the EMT continuum. By comparing expression profiles, 266 genes were identified as DEERGs, in which 184 were upregulated and 82 were downregulated. In pathway analysis, various EMT-related pathways were enriched. DEERGs shared between molecular subtypes were comparatively few. The ROC curve and logistic regression analysis screened 7 genes with the best performance to distinguish between the LN-positive and LN-negative group, i.e., CIRBP, DDR1, F2RL2, HOXA10, PPARGC1A, SEMA3E, and TGFB1. A logistic regression model including the 7-gene-based risk score, age, grade, myometrial invasion, and histological subtype was built, with an AUC of 0.850 and a favorite calibration (P = 0.074). In the validation dataset composed of 83 EC patients, the model exhibited a satisfactory predictive value and was well-calibrated (P = 0.42). CONCLUSION: The EMT status and expression of ERGs varied in LNM and non-LNM EC tissues, involving multiple EMT-related signaling pathways. Aside from that, the distribution of DEERGs differed among molecular subtypes. An ERG-based gene signature including 7 DEERGs exhibited a desirable predictive value for LNM in EC, which required further validation based upon clinical specimens in the future.

Single- and combined-phthalate exposures are associated with biological ageing among adults.

BACKGROUND: Previous research has emphasized the effects of lifestyle and genetics on ageing. However, the association between exposure to phthalates, which are extensively used in cosmetics and personal care products, and ageing is still unclear. METHOD: Data for 4711 subjects from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2010 were incorporated in the present study. The acceleration of the Klemera-Doubal method-biological age (KDM-BA) and phenotypic Age (PhenoAge) were measured by the composite of 13 biomarkers. Multiple-linear and weighted-quantile sum (WQS) regression models were constructed to explore the relationships of single- and combined-phthalate exposures, as indicated by urinary phthalate metabolites, with KDM-BA and PhenoAge. A generalized additive model (GAM) was fitted to explore the potential nonlinear relationships among the above variables. RESULTS: Except for mono-(carboxynonyl), all urinary phthalate metabolites were associated with biological ageing, with correlation coefficients ranging from 0.241 to 0.526; however, mono-ethyl presented a negative correlation. The WQS models revealed mixed effects of combined urinary phthalate metabolites on ageing, with a 0.22-year ((95 % CI) 0.09, 0.32) increase in KDM-BA acceleration and a 0.27-year ((95 % CI) 0.13, 0.37) increase in PhenoAge acceleration for each decile increase in urinary phthalate metabolites. Moreover, MCPP, MEOHP, and MBzP seemed to be the top three phthalates in terms of biological ageing, with weights of 33.3 % and 32.2 %, 29.2 % and 17.2 %, and 21.5 % and 30.1 % in KDM-BA and PhenoAge acceleration, respectively. CONCLUSION: Single-phthalate exposure was mostly associated with the ageing process, and combined-phthalate exposure presented mixed effects on biological ageing, emphasizing phthalate exposure as a significant risk factor for ageing.

Analysis of immunohistochemical characteristics and recurrence after complete remission with fertility preservation treatment in patients with endometrial carcinoma and endometrial atypical hyperplasia.

OBJECTIVE: To investigate the relationship between immunohistochemical characteristics and recurrence after complete remission (CR) with fertility preservation treatment in patients with endometrial cancer (EC) and endometrial atypical hyperplasia (AH). METHODS: The clinical data and immunohistochemical results of 53 patients with EC and 68 patients with AH admitted to Peking University People's Hospital from January 2010 to January 2021 were retrospectively analyzed. Patients were divided into two groups according to whether recurrence after complete remission (CR): group 1: recurrence after CR; group 2: no recurrence after CR, for statistical analysis. RESULTS: (1) The expression rate of ER in group 1 was lower than that in group 2, (P < 0.05). The expression rate of Ki-67 in group 1 was significantly higher than that in group 2, (P < 0.01). The expression rates of PR, P16, P53, and PTEN were not significantly different between the two groups (P > 0.05); (2) combination index ER/ Ki-67 row ROC curve analysis, there was a significant difference (P < 0.01), the best cut-off value was 3.55, sensitivity 0.730, specificity 1.000, Youden index 0.730. The 3-year RFS of high rate patients was 100%, and that of low rate patients was 42.3%, P < 0.01. CONCLUSIONS: The expression rate of Ki-67 is of great significance in predicting the recurrence of EC after fertility preservation therapy. The best cut-off value of combination index ER/ Ki-67 (3.55) was better than a single immunohistochemical marker in predicting recurrence of EC after fertility preservation treatment.

Comparison of sentinel lymph node distribution and lymphatic drainage pathway between high- and low-risk endometrial cancers.

PURPOSE: This study aimed to compare the distribution and drainage pathway of sentinel lymph nodes between high- and low-risk endometrial cancers. METHODS: In total, 429 patients with endometrial cancer who underwent sentinel lymph node biopsy in Peking University People's Hospital from July 2015 to April 2022 were retrospectively enrolled. There were 148 patients in the high-risk group and 281 patients in the low-risk group. RESULTS: The unilateral and bilateral detection rates of sentinel lymph nodes were 86.5% and 55.9%, respectively. The highest detection rate was achieved in the subgroup with a combined use of indocyanine green (ICG) and carbon nanoparticles (CNP) (94.4% for unilateral detection and 66.7% for bilateral detection). The upper paracervical pathway (UPP) was detected in 93.3% of cases in the high-risk group and 96.0% of cases in the low-risk group (p = 0.261). The lower paracervical pathway (LPP) was detected in 10.0% of cases in the high-risk group and 17.9% of cases in the low-risk group (p = 0.048). Remarkably increased detection rates of SLN in the common iliac (7.5%) and para-aortic or precaval areas (2.9%) were observed in the high-risk group. In contrast, a markedly decreased detection rate of SLN in the internal iliac area (1.9%) was observed in the high-risk group. CONCLUSION: The highest detection rate of SLN was observed in the subgroup with a combined use of ICG and CNP. The detection of UPP is important for both high-risk and low-risk cases, while LPP detection plays a more important role in the low-risk group. Lymphadenectomy in the common iliac and para-aortic or precaval areas is essential for patients with high-risk EC. Removal of internal iliac lymph nodes is essential for patients with low-risk EC, in case of ineffective SLN mapping.

Design, synthesis and anti-tumor activity of asiatic acid derivatives as VEGF inhibitors.

The VEGF receptor is mock-coupled with a known active compound and the active groups of the inhibitor which can bind to VEGF were analyzed. Using asiatic acid as a lead compound, 10 novel skeleton candidate compounds were designed through introduction of the active groups onto the special location and synthesized simultaneously. Furthermore, the structure of these compounds was determined by 1H NMR, 13C NMR and MS and 9 compounds were identified as the new compounds. Moreover, the in vitro anti-tumor activities of these new compounds were determined by MTT assay on two cancer cell lines (HepG2 and SGC-7901). The results showed that compounds I1 and II2 have more potent anticancer activity than positive control drugs such as gefitinib and paclitaxel.

Design, synthesis, and antitumor activity of novel oleanolic acid analogues targeting EGFR.

Based on the simulated docking of Epidermal growth factor receptor inhibitors with known active small molecule compounds, computer-aided drug design technology was used to analyze key amino acid fragments and determine the active groups binding with key sites. Then, twelve novel analogues of oleanolic acid (OA) were synthesized by introducing active groups at the C-3 and C-28 positions of OA. The structures of these novel analogues were confirmed by NMR and MS. Furthermore, the antitumor activities of these novel analogues were evaluated by MTT assay. As a result, compounds I3 and II3 showed stronger cytotoxicity on tumor cells than positive controls. In conclusion, our study synthesized twelve novel analogues of OA and determined compounds I3 and II3 had better antitumor effect, which may be potential candidate compounds for tumor therapy.

Synthesis and anti-tumor activity of asiatic acid derivatives targeting VEGFR.

To discovery novel VEGFR inhibitors, 12 novel asiatic acid derivatives were designed by computer-aided drug design (CADD) technology. Then, these novel asiatic acid derivatives were synthesized by introducing active groups at ring A and C-28 positions of asiatic acid. The structures of these novel analogues were confirmed by NMR and MS. Moreover, the anti-tumor activities of these novel asiatic acid derivatives on human hepatoma cells HepG2 and human gastric cancer cells SGC7901 were evaluated by MTT assay. As a result, compounds I2 and II4 showed stronger cytotoxicity on tumor cells than asiatic acid and positive control drugs such as gefitinib and paclitaxel. In conclusion, our study synthesized twelve novel asiatic acid derivatives and determined compounds I2 and II4 had better anti-tumor effect which may be potential candidate compounds for tumor therapy.

Higher spreading risk of antibacterial biocide and heavy metal resistance genes than antibiotic resistance genes in aerobic granular sludge.

Metagenomic approach was applied to simultaneously reveal the antibiotic resistance genes (ARGs) and antibacterial biocide & metal resistance genes (BMRGs), and the corresponding microbial hosts with high mobility during aerobic granular sludge (AGS) formation process. The results showed that the relative abundance of BMRGs was 88-123 times that of ARGs. AGS process was easier to enrich BMRGs, leading to a greater risk of drug resistance caused by BMRGs than that by ARGs. The enrichments of ARGs and BMRGs in AGS were closely related to several enhanced microbial metabolisms (i.e., cell motility, transposase and ATP-binding cassette transporters) and their corresponding regulatory genes. Several enhanced KEGG Orthologs (KO) functions, such as K01995, K01996, K01997 and K02002, might cause a positive impact on the spread of ARGs and BMRGs, and the main contributors were the largely enriched glycogens accumulating organisms. The first dominant ARGs (adeF) was carried by lots of microbial hosts, which might be enriched and propagated mainly through horizontal gene transfer. Candidatus Competibacter denitrificans simultaneously harbored ARG (cmx) and Cu related RGs (corR). Many enriched bacteria contained simultaneously multiple BMRGs (copR and corR) and mobile genetic elements (integrons and plasmids), granting them high mobility capabilities and contributing to the spread of BMRGs. This study might provide deeper understandings of the proliferation and mobility of ARGs and BMRGs, importantly, highlighted the status of BMRGs, which laid the foundation for the controlling widespread of resistance genes in AGS.

Unraveling the impact and mechanism of antipyretic paracetamol on intergenera conjugative plasmid transfer.

Antimicrobial resistance has been considered as a great threat to biosecurity and human health. And the transmission of antibiotic resistance genes (ARGs) by conjugated plasmid is a key factor in the prevalence of antimicrobial resistance. Paracetamol (PRC), one of nonopioid analgesics, is an extensively used antipyretic and mild analgesic worldwide available for numerous prescriptions. It was unclear whether PRC could promote the spread of ARGs. Here, it was demonstrated that PRC promoted intergenera conjugative plasmid transfer in an established conjugation model. Both donor and recipient strains treated by PRC emerged the variations of reactive oxygen species (ROS), SOS response and cell membrane permeability. Correspondingly, transcriptome analysis revealed that the gene expression involved in cell membrane permeability and SOS response was up-regulated significantly after PRC exposure. More directly, PRC also increased the expressions of conjugation related genes of trbG and trbP in donor. This study proved for the first time that PRC could enhance the intergenera conjugative plasmid transfer. Collectively, these findings manifested the potential threat associated with the existence of non-antibiotic substance PRC, which could provide an important insight into antimicrobial resistance spread.