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Background: The lack of research on the dose-response relationship of adjuvants in reversing colistin resistance will lead to a lack of scientific theoretical basis for determining the dosage of adjuvants in clinical combination therapy plans or their compound formulations., Objectives: This study investigates the dose-response relationship of the deworming drug closantel (CST) on the reversal of colistin resistance in mcr-1-positive Escherichia coli (E. coli)., Methods: Firstly, the reversal effect of different concentrations of CST on colistin resistance in mcr-1-positive E. coli was analysed using broth microdilution method, checkerboard method and time-killing curves. Then, the inhibitory effect of CST on the development of colistin resistance, as well as the haemolytic and cytotoxic properties of CST, was analysed. Finally, the in vivo efficacy of the combination of CST and colistin was evaluated., Results: Both the checkerboard assays and the time-killing curves indicate that there is a special dose-response relationship between CST and its reversal effect on colistin resistance, which is not concentration-dependent. High reversal efficiency can be achieved within a low concentration range. However, as the CST concentration increases, the ability to reverse colistin resistance remains unchanged or decreases, which resulted in a gradual decrease in reversal efficiency. Additionally, CST can inhibit the development of colistin resistance and reduce the cytotoxicity of colistin. Importantly, in a mouse model of E. coli infection, the combination of CST and colistin showed a significant therapeutic effect., Conclusions: This study indicates a special dose-response relationship between CST and its reversal effect on colistin resistance, which was not concentration-dependent., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Excessive unmonitored use of fluoride has remained a threatening issue for a long time now as its long-term use is linked to several health issues. Similarly, chloroform is a highly carcinogenic solvent that requires proper monitoring. The increasing demand for a convenient, selective and sensitive fluoride and chloroform sensor intrigued us to utilize etoricoxib (ECX) as a sensor as it is highly safe and easily available. The photophysical properties of ECX, which were previously unexplored, were now studied with increasing water fractions and a significant aggregation-induced emission enhancement (AIEE) was seen through fluorescence spectroscopy. ECX was also successfully used for the trace level detection of chloroform through a significant emission enhancement. Similarly, the ECX-based sensor successfully detected fluoride ions by showing enhancement in emission intensity with maximum emission wavelength at 373 nm. Through fluorescence titration experiments, the effects of different conditions and interfering species on the sensing efficiency of ECX were studied, and the results showed that the sensor was highly selective and sensitive towards fluoride, with a limit of detection of 20 nM. Other than fluorescence spectroscopy, the type of interaction between the sensor and analyte was also studied through UV-Vis spectroscopy, revealing a non-covalent type of interaction, which was further validated through DFT studies. Frontier molecular orbital (FMO) analysis was performed along with density of state (DOS) studies to investigate the energy levels of the orbitals. Non-covalent interaction (NCI) and natural bond orbital (NBO) analysis provided information about the types of interaction and charge transfer. ECX has the potential to be used for real-time sensing applications and could be used for sensing moisture and fluoride in real samples., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

Background: Diabetes mellitus type 2 (T2DM) is formed by defective insulin secretion with the addition of peripheral tissue resistance of insulin action. It has been affecting over 400 million people all over the world., Aim: To explore the pathogenesis of T2DM and to develop and implement new prevention and treatment strategies for T2DM., Methods: Receiver operating characteristic (ROC) curve analysis was used to conduct diagnostic markers. The expression level of genes was determined by reverse transcription-PCR as well as Western blot. Cell proliferation assays were performed by cell counting kit-8 (CCK-8) tests. At last, T2DM mice underwent Roux-en-Y gastric bypass surgery., Results: We found that NPAS2 was significantly up-regulated in islet β cell apoptosis of T2DM. The ROC curve revealed that NPAS2 was capable of accurately diagnosing T2DM. NPAS2 overexpression did increase the level of KANK1 . In addition, the CCK-8 test revealed knocking down NPAS2 and KANK1 increased the proliferation of MIN6 cells. At last, we found that gastric bypass may treat type 2 diabetes by down-regulating NPAS2 and KANK1 ., Conclusion: This study demonstrated that NPAS2 induced β cell dysfunction by regulating KANK1 expression in type 2 diabetes, and it may be an underlying therapy target of T2DM., Competing Interests: Conflict-of-interest statement: The authors have no relevant financial or non-financial interests to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Phototherapy has garnered significant attention in the past decade. Photothermal and photodynamic synergistic therapy combined with NIR fluorescence imaging has been one of the most attractive treatment options because of the deep tissue penetration, high selectivity and excellent therapeutic effect. Benefiting from the superb photometrics and ease of modification, perylene diimide (PDI) and its derivatives have been employed as sensing probes and therapeutic agents in the biological and biomedical research fields, and exhibiting excellent potential. Herein, we reported the development of a novel organic small-molecule phototherapeutic agent, PDI-TN. The absorption of PDI-TN extends into the NIR region, which provides feasibility for NIR phototherapy. PDI-TN overcomes the traditional Aggregation-Caused Quenching (ACQ) effect and exhibits typical characteristics of Aggregation-Induced Emission (AIE). Subsequently, PDI-TN NPs were obtained by using an amphiphilic triblock copolymer F127 to encapsulate PDI-TN. Interestingly, the PDI-TN NPs not only exhibit satisfactory photothermal effects, but also can generate O 2 •- and 1 O 2 through type I and type II pathways, respectively. Additionally, the PDI-TN NPs emit strong fluorescence in the NIR-II region, and show outstanding therapeutic potential for in vivo NIR-II fluorescence imaging. To our knowledge, PDI-TN is the first PDI derivative used for NIR-II fluorescence imaging-guided photodynamic and photothermal synergistic therapy, which suggests excellent potential for future biological/biomedical applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Angelicin, which is found in Psoralea, can help prevent osteoporosis by stopping osteoclast formation, although the precise mechanism remains unclear., Methods: We evaluated the effect of angelicin on the oxidative stress level of osteoclasts using ovariectomized osteoporosis model rats and RAW264.7 cells. Changes in the bone mass of the femur were investigated using H&E staining and micro-CT. ROS content was investigated by DHE fluorescence labelling. Osteoclast-related genes and proteins were examined for expression using Western blotting, immunohistochemistry, tartrate-resistant acid phosphatase staining, and real-time quantitative PCR. The influence of angelicin on osteoclast development was also evaluated using the MTT assay, double luciferin assay, chromatin immunoprecipitation, immunoprecipitation and KAT6A siRNA transfection., Results: Rats treated with angelicin had considerably higher bone mineral density and fewer osteoclasts. Angelicin prevented RAW264.7 cells from differentiating into osteoclasts in vitro when stimulated by RANKL. Experiments revealed reduced ROS levels and significantly upregulated intracellular KAT6A, HO-1, and Nrf2 following angelicin treatment. The expression of genes unique to osteoclasts, such as MMP9 and NFATc1, was also downregulated. Finally, KAT6A siRNA transfection increased intracellular ROS levels while decreasing KAT6A, Nrf2, and HO-1 protein expression in osteoclasts. However, in the absence of KAT6A siRNA transfection, angelicin greatly counteracted this effect in osteoclasts., Conclusions: Angelicin increased the expression of KAT6A. This enhanced KAT6A expression helps to activate the Nrf2/HO-1 antioxidant stress system and decrease ROS levels in osteoclasts, thus inhibiting oxidative stress levels and osteoclast formation., (© 2024. The Author(s).)

Body temperature should be tightly regulated for optimal sleep. However, various extrinsic and intrinsic factors can alter body temperature during sleep. In a free-living study, we examined how sleep and cardiovascular health metrics were affected by sleeping for one week with (Pod ON) vs. without (Pod OFF), an active temperature-controlled mattress cover (the Eight Sleep Pod). A total of 54 subjects wore a home sleep test device (HST) for eight nights: four nights each with Pod ON and OFF (>300 total HST nights). Nightly sleeping heart rate (HR) and heart rate variability (HRV) were collected. Compared to Pod OFF, men and women sleeping at cooler temperatures in the first half of the night significantly improved deep (+14 min; +22% mean change; p = 0.003) and REM (+9 min; +25% mean change; p = 0.033) sleep, respectively. Men sleeping at warm temperatures in the second half of the night significantly improved light sleep (+23 min; +19% mean change; p = 0.023). Overall, sleeping HR (-2% mean change) and HRV (+7% mean change) significantly improved with Pod ON ( p < 0.01). To our knowledge, this is the first study to show a continuously temperature-regulated bed surface can (1) significantly modify time spent in specific sleep stages in certain parts of the night, and (2) enhance cardiovascular recovery during sleep.

With the increasing and inappropriate use of colistin, the emerging colistin-resistant isolates have been frequently reported during the last few decades. Therefore, new potential targets and adjuvants to reverse colistin resistance are urgently needed. Our previous study has confirmed a marked increase of colistin susceptibility (16-fold compared to the wild-type Salmonella strain) of cpxR overexpression strain JSΔ acrB Δ cpxR :: kan /p cpxR (simplified as JSΔΔ/p R ). To searching for potential new drug targets, the transcriptome and metabolome analysis were carried out in this study. We found that the more susceptible strain JSΔΔ/p R displayed striking perturbations at both the transcriptomics and metabolomics levels. The virulence-related genes and colistin resistance-related genes (CRRGs) were significantly downregulated in JSΔΔ/p R . There were significant accumulation of citrate, α-ketoglutaric acid, and agmatine sulfate in JSΔΔ/p R , and exogenous supplement of them could synergistically enhance the bactericidal effect of colistin, indicating that these metabolites may serve as potential adjuvants for colistin therapy. Additionally, we also demonstrated that AcrB and CpxR could target the ATP and reactive oxygen species (ROS) generation, but not proton motive force (PMF) production pathway to potentiate antibacterial activity of colistin. Collectively, these findings have revealed several previously unknown mechanisms contributing to increased colistin susceptibility and identified potential targets and adjuvants for potentiating colistin treatment of Salmonella infections. IMPORTANCE Emergence of multidrug-resistant (MDR) Gram-negative (G - ) bacteria have led to the reconsideration of colistin as the last-resort therapeutic option for health care-associated infections. Finding new drug targets and strategies against the spread of MDR G - bacteria are global challenges for the life sciences community and public health. In this paper, we demonstrated the more susceptibility strain JSΔΔ/p R displayed striking perturbations at both the transcriptomics and metabolomics levels and revealed several previously unknown regulatory mechanisms of AcrB and CpxR on the colistin susceptibility. Importantly, we found that exogenous supplement of citrate, α-ketoglutaric acid, and agmatine sulfate could synergistically enhance the bactericidal effect of colistin, indicating that these metabolites may serve as potential adjuvants for colistin therapy. These results provide a theoretical basis for finding potential new drug targets and adjuvants., Competing Interests: The authors declare no conflict of interest.

Cysteine (Cys) is a significant biological mercaptan that achieves key roles in several important physiological processes, such as reversible redox homeostasis in living organisms. Abnormal levels of Cys in the human body are directly related to many diseases. In this work, we constructed a sensitive sensor (Cys-NR) by connecting a Cys recognition group to a Nile red derivative. Due to photo-induced electron transfer (PET), the Cys-NR probe showed little fluorescence at 650 nm. With the addition of Cys to the assay solution, the chlorine unit of the probe was substituted by the thiol group of Cys. Further, the amino and sulfhydryl groups in cysteine underwent an intramolecular rearrangement, which led to the Cys-NR probe water solution turning from colorless to pink with an enhancement in fluorescence. The red fluorescence at 650 nm increased about 20 times. Based on the turn-on signal, a selective Cys detection method is developed. The probe signal is not affected by various potential interferences or other competing biothiols and the limit of detection (LOD) is determined to be 0.44 μM. In addition, the probe is further employed for imaging of Cys in live cells, revealing good biological imaging ability that could provide a new way of intracellular Cys detection., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

A growing body of research suggests that short-chain fatty acids (SCFAs), metabolites produced by intestinal symbiotic bacteria that ferment dietary fibers (DFs), play a crucial role in the health status of symbiotes. SCFAs act on a variety of cell types to regulate important biological processes, including host metabolism, intestinal function, and immune function. SCFAs also affect the function and fate of immune cells. This finding provides a new concept in immune metabolism and a better understanding of the regulatory role of SCFAs in the immune system, which impacts the prevention and treatment of disease. The mechanism by which SCFAs induce or regulate the immune response is becoming increasingly clear. This review summarizes the different mechanisms through which SCFAs act in cells. According to the latest research, the regulatory role of SCFAs in the innate immune system, including in NLRP3 inflammasomes, receptors of TLR family members, neutrophils, macrophages, natural killer cells, eosinophils, basophils and innate lymphocyte subsets, is emphasized. The regulatory role of SCFAs in the adaptive immune system, including in T-cell subsets, B cells, and plasma cells, is also highlighted. In addition, we discuss the role that SCFAs play in regulating allergic airway inflammation, colitis, and osteoporosis by influencing the immune system. These findings provide evidence for determining treatment options based on metabolic regulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Shao, Liao, Wang, Jia, Dong, Liu, He, Li and Zhang.)

The emergence and rapid spread of multidrug resistant (MDR) Gram-negative bacteria have posed a serious threat to global health and security. Because of the time-consuming, high cost and high risk of developing new antibiotics, a significant method is to use antibiotic adjuvants to revitalize the existing antibiotics. The purpose of the study is to research the traditional Chinese medicine baicalin with the function of inhibiting the efflux pump and EDTA whether their single or combination can increase the activity of colistin against colistin-resistant Salmonella in vitro and in vivo, and to explore its molecular mechanisms. In vitro antibacterial experiments, we have observed that baicalin and EDTA alone could enhance the antibacterial activity of colistin. At the same time, the combination of baicalin and EDTA also showed a stronger synergistic effect on colistin, reversing the colistin resistance of all Salmonella strains. Molecular docking and RT-PCR results showed that the combination of baicalin and EDTA not only affected the expression of mcr-1, but also was an effective inhibitor of MCR-1. In-depth synergistic mechanism analysis revealed that baicalin and EDTA enhanced colistin activity through multiple pathways, including accelerating the tricarboxylic acid cycle (TCA cycle), inhibiting the bacterial antioxidant system and lipopolysaccharide (LPS) modification, depriving multidrug efflux pump functions and attenuating bacterial virulence. In addition, the combinational therapy of colistin, baicalin and EDTA displayed an obvious reduction in bacterial loads cfus of liver and spleen compared with monotherapy and 2-drug combination therapy. In conclusion, our study indicates that the combination of baicalin and EDTA as a novel colistin adjuvant can provide a reliable basis for formulating the therapeutic regimen for colistin resistant bacterial infection., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Enabling dynamically tunable emissive systems offers opportunities for constructing smart materials. Clusteroluminescence, as unconventional luminescence, has attracted increasing attention in both fundamental and applied sciences. Herein, we report a supramolecular poly(disulfides) network with tunable clusteroluminescence. The reticular H-bonds synergize the rigidity and mobility of dynamic networks, and endow the resulting materials with mechanical adaptivity and robustness, simultaneously enabling efficient clusteroluminescence and phosphorescence at 77 K. Orthogonally tunable luminescence are achieved in two manners, i.e., slow backbone disulfide exchange and fast side-chain metal coordination. Further exploration of the reprocessability and chemical closed-loop recycling of intrinsic dynamic networks for sustainable materials is feasible. We foresee that the synergistic strategy of dynamic chemistry offers a novel pathway and potential opportunities for smart emissive materials., (© 2022 Wiley-VCH GmbH.)

Background: Fosfomycin is an important broad-spectrum bactericidal antibiotic to treat multidrug-resistant bacteria infections. It is generally accepted that heteroresistant bacteria are an intermediate stage in the formation of drug resistance, but there are few studies on the formation mechanism underlying fosfomycin heteroresistance (FHR)., Objectives: To reveal the characteristics and formation mechanisms of FHR in Escherichia coli isolates obtained from chickens., Methods: We identified the FHR according to the population analysis profile (PAP) test and in vitro time-kill assay. Growth curves for FHR E. coli and their subpopulations were measured. Also, the subpopulations were repeatedly cultured in fosfomycin-free medium for 5-20 overnight incubation periods. The formation mechanisms of FHR in E. coli isolates were identified through accumulation assay, carbohydrate utilization testing, real-time relative quantitative PCR analysis, DNA sequencing, transcriptomic analysis, intracellular ATP and cAMP-level assessment., Results: Four of six E. coli strains were confirmed to show FHR, with a total of six subpopulations. The subpopulations restored phenotypic susceptibilities to fosfomycin within 5-20 overnight incubation sessions, but four of six subpopulations still maintained FHR characteristics. Differing from their parental isolates, the uptake of fosfomycin in the subpopulations through GlpT was reduced remarkably. Further studies identified that the low expression of glpT was due to the decrease of intracellular cAMP levels in the subpopulations, which was caused by the decreased ATP levels in cells., Conclusions: Our findings revealed the formation mechanism of E. coli isolates showing FHR obtained from chicken in China and characterized the dynamic change traits in vitro of the subpopulations., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To characterize IncI1 and IncF18:A-:B1 multidrug-resistance plasmids from an avian Escherichia coli isolate, antibiotic susceptibility testing, conjugation assays, transformation assays, S1-PFGE, and WGS analysis were performed. The 119,457-bp plasmid pEC014-1 with a multidrug-resistance region (MRR) containing four different segments interspersed with six IS26 elements, belonged to incompatibility group I1 and sequence type 71. The 154,516-bp plasmid pEC014-2 with two replicons, typed as FII-18 and FIB-1, carried 14 resistance determinants including bla TEM-1b , bla OXA-1 , oqxAB, dfrA17, aac(6')-Ib-cr, sul1, sul2, tet(A), floR, catB3, hph(aph(4)-Ia), aacC4(aac(3)-IV), aadA5, arr-3, and a merEDACPTR loci in MRR, and additionally encoded three virulence loci: iroNEDCB, sitABCD, and iucABCD-iutA. Plasmid stability assays showed that pEC014-1 and pEC014-2 were stable in recipient E. coli C600 for at least 15 days of passage. Competition assays were carried out to evaluate the fitness impact of pEC014-2 carriage in vitro, revealing a decrease in host fitness. Growth kinetics showed that the growth rate for pEC014-1 or/and pEC014-2 bearing cells was significantly slower than that of the E. coli C600 host strain in the exponential stage (p < 0.01), with only cells carrying pEC014-1 sustaining rapid growth after 6 h of exponential growth. Our findings highlight the mosaic structures of epidemic plasmid IncI1/ST71 and F18:A-:B1 lineages and contribute to a better understanding of the evolution and dissemination of these multidrug resistance and virulence plasmids., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: In recent years, the extensive use of antibiotics worldwide has led to an increase in the number of drug-resistant bacterial strains, thus resulting in an increasingly severe degree of bacterial resistance. For thousands of years, traditional Chinese medicine (TCM) has provided natural and unique advantages in the treatment of infectious diseases. Therefore, it is important to develop further and use TCM to treat clinical infections caused by drug-resistant bacteria., Materials and Methods: A literature search was performed using PubMed, Web of Science, Google Scholar, and the China National Knowledge Infrastructure databases. The articles were analyzed to extract information on the antimicrobial effects of Chinese herbal medicines, compounded Chinese medicines, monomeric compounds of herbal origin, and the combined use of Chinese medicine and antimicrobial drugs and to determine the synergistic effect of the combination of Chinese medicine and antibiotics, as well as investigate the possibility of restoring the antibiotic sensitivity of drug-resistant strains., Results: The mechanisms underlying the antibacterial properties of TCM involve altering membrane permeability, inhibiting protein and nucleic acid synthesis, inhibiting enzyme activity in vivo, and controlling the ability of pathogenic bacteria. In addition, the mechanism underlying TCM-induced reversal of bacterial drug resistance is discussed, particularly in terms of the elimination of resistant (R) plasmids and the inhibition of extended-spectrum β-lactamases, bacterial biofilm formation, and bacterial efflux pump activity., Conclusions: This paper reviewed the recent relevant literature on antimicrobial action and its mechanisms, as well as the mechanisms of drug resistance reversal by TCM to provide a reference for clinical drug use, prevention and control of bacterial infection, and research and development of new drugs.

Developing molecular approaches to the creation of robust and water-resistant adhesive materials promotes a fundamental understanding of interfacial adhesion mechanisms as well as future applications of biomedical adhesive materials. Here, we present a simple and robust strategy that combines natural thioctic acid and mussel-inspired iron-catechol complexes to enable ultra-strong adhesive materials that can be used underwater and simultaneously exhibit unprecedentedly high adhesion strength on diverse surfaces. Our experimental results show that the robust crosslinking interaction of the iron-catechol complexes, as well as high-density hydrogen bonding, are responsible for the ultra-high interfacial adhesion strength. The embedding effect of the hydrophobic solvent-free network of poly(disulfides) further enhances the water-resistance. The dynamic covalent poly(disulfides) network also makes the resulting materials reconfigurable, thus enabling reusability via repeated heating and cooling. This molecule-engineering strategy offers a general and versatile solution to the design and construction of dynamic supramolecular adhesive materials., (© The Author(s) 2022. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

Antimicrobial resistance in Morganella morganii is increasing in recent years, which is mainly introduced via extra genetic and mobile elements. The aim of our study is to analyze the multidrug resistance (MDR) and characterize the mobile genetic elements (MGEs) in M. morganii isolates. Here, we report the characteristic of a pathogenic M. morganii isolate containing multidrug resistance genes that are mainly carried by a novel transposon Tn 7376 and a genomic island. Sequence analysis suggested that the Tn 7376 could be generated through homologous recombination between two different IS 26 -bounded translocatable units (TUs), namely, module A (IS 26 -Hp-IS 26 - mph (A)- mrx (A)- mphR -IS 6100 - chrA - sul1 - qacEΔ1 ) and module B (IS CR1 - sul1 - qacEΔ1 - cmlA1 - aadA1 - aadB - intI1 -IS 26 ), and the genomic island named MMGI-4 might derive from a partial structure of different original genomic islands that also carried IS 26 -mediated TUs. Notably, a 2,518-bp sequence linked to the module A and B contains a 570-bp dfrA24 gene. To the best of our knowledge, this is the first report of the novel Tn 7376 possessing a complex class 1 integron that carried an infrequent gene dfrA24 in M. morganii. IMPORTANCE Mobile genetic elements (MGEs), especially for IS 26 -bounded translocatable units, may act as a reservoir for a variety of antimicrobial resistance genes in clinically important pathogenic bacteria. We expounded this significant genetic characteristic by investigating a representative M. morganii isolate containing multidrug resistance genes, including the infrequent dfrA24 . Our study suggested that these acquired resistance genes were mainly driven by IS 26 -flanked important MGEs, such as the novel Tn 7376 and the MMGI-4. We demonstrated that IS 26 -related MGEs contributed to the emergence of the extra gene dfrA24 in M. morganii through some potential genetic events like recombination, transposition, and integration. Therefore, it is of importance to investigate persistently the prevalence these MEGs in the clinical pathogens to provide risk assessment of emergence and development of novel resistance genes.

Objective: To investigate the effect of internal external fixator assisted O-arm navigation imaging in the treatment of unstable pelvic fractures., Methods: From May 2019 to November 2019, 15 patients with unstable pelvic fractures were treated by intraoperative O-arm navigation imaging using INFIX technology. There were 6 males and 9 females. The age ranged from 24 to 66 years old. The course of disease ranged from 2 to 14 days. According to Tile classification, there were 1 case of B1 type, 8 cases of B2 type, 3 cases of C1 type, and 3 cases of C2 type. According to Young-Burgess classification, there were 8 cases of LC, 1 case of APC, 4 cases of VS, 2 cases of CM. Preoperative routine pelvic anteroposterior film, entrance position, exit position and pelvic CT three-dimensional reconstruction were performed. Intraoperative O-arm navigation system three-dimensional reconstruction and triplane scanning imaging were used to evaluate the effect of intraoperative reduction. The anterior pelvic ring was fixed with internal external fixator, and the posterior ring was fixed with sacroiliac screw, plate screw or lumbar iliac screw. The operation time, intraoperative bleeding and nail placement were observed and recorded. The quality of fracture reduction was evaluated by Matta standard, and the postoperative function was evaluated by Majeed function score., Results: Wound healing was good in all patients without vascular, nerve and local irritation complications. All the 15 patients were followed up for 10 to 16 months. The fracture reduction was evaluated according to the Matta scoring standard, 9 cases were excellent results, 5 cases were good, and 1 case was medium. The Majeed functional score was 0 to 95 points., Conclusion: The built-in external fixator assisted O-arm navigation imaging system in the treatment of unstable pelvic fractures. The reduction effect is evaluated in advance, the operation time is shortened, and the accuracy of internal fixation is improved. The operation is simple, safe and less bleeding. The operation is in line with the principles of minimally invasive medical treatment and precision medical treatment in orthopedics, which is conducive to the recovery of patients' postoperative function and rapid recovery.

Hepatocellular carcinoma (HCC) has emerged as the third cause of cancer-related death owing to lacking effective systemic therapies. Genomic DNA sequencing revealed the high frequency of loss-of-function mutations in ARID2, which encodes a subunit of SWI/SNF chromatin remodeling complex, however, the therapeutic strategy for the HCC patients with ARID2 mutations is still completely unclear. In this study, we first performed a high-throughput screening approach using a compound library consisting of 2 180 FDA-approved drugs and other compounds, to elicit the potential drugs for synthetic lethality to target ARID2-deficient HCC cells. Interestingly, JQ1, a selective inhibitor of bromodomain protein BRD4, uniquely suppressed the growth of ARID2- deficient HCC cells. Next JQ1 is further confirmed to predominantly induce cell lethality upon ARID2 depletion through exacerbating DNA damage, especially double strand breaks (DSBs). Functional assays demonstrated that both BRD4 inhibition and ARID2 deficiency synergistically impede two main DNA damage repair pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ), through attenuating the transcription of BRCA1, RAD51, and 53BP1, which encode the core molecules responsible for DSB repair. Mechanistically, both ARID2 and BRD4 exert a synergistic effect for maintaining transcriptional enhancer-promoter loops of these genes within chromatin conformation. However, as both ARID2 and BRD4 are disrupted, the expression of these DNA repair-related genes in response to DNA damage are hindered, resulting in DSB accumulation and cell apoptosis. Taken together, this study discloses that BRD4 inhibition may induce synthetic lethality in ARID2-deficient HCC cells, which might provide a potential therapeutic strategy for HCC patients with ARID2 mutations., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Streptococcus suis strain 1112S was isolated from a diseased pig in a feedlot from Henan, China, in 2019. The isolate harbored a linezolid resistance gene optrA . WGS data revealed that the optrA gene was associated with a single copy ETAf IS S1S , in tandem with erm (B) and tet (O), located in a novel 72,587 bp integrative and conjugative element (ICE). Notably, this novel element, designated ICE Ssu 1112S, also carried a novel bacitracin resistance locus. ICE Ssu 1112S could be excised from chromosome and transferred to the recipient strain S. suis P1/7 with a frequency of 5.9 × 10 -6 transconjugants per donor cell. This study provided the first description of the coexistence of optrA and a novel bacitracin locus on a multiple antibiotic resistant ICE and highlighted that ICE were major vehicle and contribute to the potential transfer of clinically relevant antibiotic resistance genes. IMPORTANCE Antimicrobial resistance (AMR) caused by the imprudent use of antimicrobials has become a global problem, which poses a serious threat to treatment of S. suis infection in pigs and humans. Importantly, AMR genes can horizontally spread among commensal organisms and pathogenic microbiota, thereby accelerating the dissemination of AMR determinants. These transfers are mainly mediated by mobile genetic elements, including ICEs. In S. suis, ICEs are the major vehicles that contribute to the natural transfers of AMR genes among different bacterial pathogens. However, ICEs that carry optrA and bacitracin resistance locus are rarely investigated in S. suis isolates. Here, we investigated a S. suis isolate carrying an optrA and a novel bacitracin resistance locus, which were co-located on a novel multiple antibiotic resistant ICE Ssu 1112S. Our study suggests that more research is needed to access the real significance of ICEs that horizontally spread clinical important resistance genes.

Background: The increasing use of colistin causes a serious breach in our last line of defence against MDR Gram-negative pathogens. Our previous study showed that CpxR overexpression increases the susceptibility of acrB and cpxR double-deleted Salmonella enterica serovar Typhimurium to colistin., Objectives: To identify the mechanism of CpxAR and efflux pumps that synergistically enhance the susceptibility of S. Typhimurium to colistin., Methods: A series of cpxR- and tolC-deleted mutants and a cpxR-complemented strain from a multidrug-susceptible standard strain of S. Typhimurium (JS) were generated in our previous study. Herein, we investigated the susceptibility of these strains to colistin through the broth microdilution method, time-kill curves and survival assays. Growth curves were measured by OD600 in LB broth, tryptone-soy broth (TSB) and M9-glucose (0.2%) minimal media. Finally, molecular mechanisms underlying the mode of action were elucidated by transcriptomic analysis., Results: We found that in contrast to JS (0.8 mg/L), the MIC of colistin for JSΔtolC::kan showed a 16-fold decrease (0.05 mg/L). Notably, JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were associated with a 256-fold decrease (0.0031 mg/L) compared with JS. Growth curves identified that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR displayed a markedly lower growth rate and poorer adaptability. In addition, time-kill curves and survival assays showed that JSΔcpxRΔtolC and JSΔcpxRΔtolC/pcpxR were more susceptible to colistin. Lastly, double deletion of cpxR and tolC enhanced oxidative damage through promoting oxidative phosphorylation, the tricarboxylic acid (TCA) cycle and trimethylamine N-oxide (TMAO) respiration., Conclusions: Our findings revealed that double deletion of cpxR and tolC significantly increases the susceptibility of S. Typhimurium to colistin., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including liver cancer. Previous studies have demonstrated that ARID1A deficiency can cause liver cancer metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms remain poorly understood. To address the effect of Arid1a deficiency on chromatin organization, we generated chromatin interaction matrices, and exploited the conformation changes upon Arid1a depletion in hepatocytes. Our results demonstrated that Arid1a deficiency induced A/B compartment switching, topologically associated domain (TAD) remodeling, and decrease of chromatin loops. Further mechanism studies revealed that ATPase BRG1 of SWI/SNF complex could physically interact with RAD21, a structural subunit of chromatin architectural element cohesin; whereas ARID1A deficiency significantly diminished the coupled BRG1-RAD21. Interestingly, the tumor-associated genes within the switched compartments were differentially expressed depending upon Arid1a depletion or not. As a consequence of ARID1A deficiency-induced conformational alteration, the dysregulation of some genes such as PMP22 and GSC, promoted the invasion capacity of liver cancer cells. This study provides an insight into liver cancer tumorigenesis and progression related to ARID1A mutations., (© 2021. The Author(s).)

To characterize the formation mechanism and characteristics of two cointegrate plasmids in Salmonella enterica serotype Enteritidis strain S13, plasmids from strain S13 and three corresponding transconjugants were subjected to whole genome sequencing and analyzed using bioinformatics tools. The traits of two fusion plasmids in transconjugants were characterized by stability and conjugation experiments. Sequence analysis indicated that strain S13 contained four plasmids, including mcr-1 -bearing pS13-1, bla CTX-M-55 -carrying pS13-2, tet (M)-bearing pS13-3, and floR -carrying pS13-4. IncN1-F33:A-:B- plasmid pS13-2, respectively, fused with IncFI:A-:B- plasmid pS13-3 and IncX1 plasmid pS13-4, which generated two cointegrate plasmids, designated pS13D and pS13F, which involved in two intermolecular replicative mechanisms mediated by IS 26 and the novel transposon Tn 6952 ( Δ Tn AS3 -IS 26 - Δ IS Ecp1 - ramA - Δ IS 26 - Δ Tn AS1 ), respectively. This is the first report of the fusion of the IncN1-F33:A-:B- plasmid and IncFI:A-:B- plasmid mediated by IS 26 , and with IncX1 plasmid mediated by Tn 6952. The formation and evolution of cointegrate plasmids could expand the resistance and host spectrum of fusion plasmids., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, He, Zhang, Pan, Wu, Yuan, Liu and Hu.)

To investigate the diversity and composition of gut microbiota in patients with lung adenocarcinoma and lung squamous cell carcinoma. A single-center and case-control study was conducted to consecutively enroll a total of 27 lung cancer patients, including 15 males and 12 females, who were seen at the Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine between September 2018 to October 2020. A total of 20 cases of healthy healthy physical examiners, including 9 males and 11 females were recruited as healthy control group (HC) during the same period. Clinical data and stool samples were collected from each participants, and lung cancer patients were divided into lung adenocarcinoma group (AC, 19 patients, 8 males and 11 females) and lung squamous cell carcinoma group (SCC, 8 patients, 7 males and 1 females) according to the pathology type. Genomic DNA were extracted to amplify 16S rDNA V3-V4 region, then the Illumina MiSeq high-throughput sequencing platform and QIIME software were used for sequencing and analyzing the structure of the gut microbiota, respectively. Analysis of variance, χ 2 test, K-W test were used to analyze the differences in age, gender,α diversity, and relative abundance of microbiota among the three groups. AC, SCC, and HC were aged (58.74±9.27), (63.38±6.12), and (55.65±7.79) years old, respectively. There were no difference in gender and age among the three groups (gender and age are respectively:χ 2 =5.155, P =0.076; F =2.598, P =0.086). And no significant difference in alpha diversity were found among the three groups (Chao and Shannon index were respectively: F =0.616, P =0.545; F =2.484, P =0.095), while β-diversity analysis indicated significant differences in the structure of intestinal flora among AC, SCC and HC ( P =0.001). LEfSe analysis showed that AC and SCC both have dominant bacterials. Megasphaera ( H =7.855, P =0.020) and Erysipelatoclostridium ( H =7.426, P =0.024) were enriched in patients with AC, while Enterococcus ( H =8.400, P =0.015), Veillonella ( H =9.957, P =0.007), and Eubacterium&#95;eligens&#95;group ( H =10.514, P =0.005) were enriched in patients with SCC. Lung cancer patients have gut microbiota imbalance, while lung adenocarcinoma and lung squamous cell carcinoma patients have no significant difference in gut microbiota diversity, but lung adenocarcinoma and lung squamous cell carcinoma have their own unique microbiota. This imbalance of the intestinal microenvironment is of great significance for studying the occurrence and development of different pathological types of lung cancer.

Background: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Up to 20%-30% of patients hospitalized with COVID-19 have evidence of cardiac dysfunction. Xuebijing injection is a compound injection containing five traditional Chinese medicine ingredients, which can protect cells from SARS-CoV-2-induced cell death and improve cardiac function. However, the specific protective mechanism of Xuebijing injection on COVID-19-induced cardiac dysfunction remains unclear., Methods: The therapeutic effect of Xuebijing injection on COVID-19 was validated by the TCM Anti COVID-19 (TCMATCOV) platform. RNA-sequencing (RNA-seq) data from GSE150392 was used to find differentially expressed genes (DEGs) from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) infected with SARS-CoV-2. Data from GSE151879 was used to verify the expression of Angiotensin I Converting Enzyme 2 (ACE2) and central hub genes in both human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) and adult human CMs with SARS-CoV-2 infection., Results: A total of 97 proteins were identified as the therapeutic targets of Xuebijing injection for COVID-19. There were 22 DEGs in SARS-CoV-2 infected hiPSC-CMs overlapped with the 97 therapeutic targets, which might be the therapeutic targets of Xuebijing injection on COVID-19-induced cardiac dysfunction. Based on the bioinformatics analysis, 7 genes (CCL2, CXCL8, FOS, IFNB1, IL-1A, IL-1B, SERPINE1) were identified as central hub genes and enriched in pathways including cytokines, inflammation, cell senescence and oxidative stress. ACE2, the receptor of SARS-CoV-2, and the 7 central hub genes were differentially expressed in at least two kinds of SARS-CoV-2 infected CMs. Besides, FOS and quercetin exhibited the tightest binding by molecular docking analysis., Conclusion: Our study indicated the underlying protective effect of Xuebijing injection on COVID-19, especially on COVID19-induced cardiac dysfunction, which provided the theoretical basis for exploring the potential protective mechanism of Xuebijing injection on COVID19-induced cardiac dysfunction., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To analyze characteristics and underlying evolutionary processes of IncC and IncI1 plasmids in a multidrug-resistant avian E. coli strain, antibiotic susceptibility testing, PCR, conjugation assays, and next-generation sequencing were performed. The type 1 IncC plasmid pEC009.1 harbored three antimicrobial resistance regions including ISEcp1-bla CMY-2 -blc-sugE, ARI-B resistance island, and ARI-A island that was a mosaic multidrug resistance region (MRR) comprised of a class 1 integron with cassette array |aac(6')-II(aacA7)|qacE∆1|sul1|, IS26-mphR(A)-mrx-mph(A)-IS26, IS26-fosA3-IS26, and mercury resistance cluster merRTPABDE. It is the first report of three different size circular forms derived from IS26-mphR(A)-mrx-mph(A)-IS26-fosA3-IS26 in ARI-A of type 1 IncC plasmid. In IncI1/ST136 pEC009.2, the truncated transposon Tn1722 carrying bla TEM-1b , rmtB, aac(3)-IId(aacC2d), and a class 1 integron with cassette array |dfrA12|orfF|aadA2|, inserted into the plasmid backbone generating 5-bp direct repeats (DRs, TATAA) at the boundaries of the region, which was highly similar to that of other IncI1 plasmids, and differed by the arrangements of resistance determinants. Comparison among two epidemic plasmid lineages showed complex MRRs respectively located in the specific position in type 1 IncC and IncI1/ST136 plasmids with conserved backbones, and these have evolved via multiple events involved in mobile elements-mediated loss and gain of resistance genes and accessory genes. Strains harboring these plasmids may serve as a reservoir for antibiotic resistance genes, thereby contributing to the rapid spread of resistance genes and posing a public health threat., (Copyright © 2021 Elsevier Inc. All rights reserved.)

To investigate the genetic features and biological costs of the plasmid pTW4 harboring tet(M) in an isolate of Escherichia coli ST162 from a duck. The complete nucleotide sequence of plasmid pTW4 was determined. The characteristics of plasmid pTW4 in E. coli were investigated by stability and direct competition assays. pTW4 is an IncHI 2 -type plasmid that contained the resistant genes tet(M), floR, strAB, sul2, rmtB, and bla CMY-2 . Tet(M) is located in the composite transposon Tn6539 within the multidrug resistant (MDR) region on this plasmid. Furthermore, the resistance gene rmtB and bla CMY-2 were found outside the MDR region. The plasmid pTW4 remained stable in the host strain E. coli J53 after passage under an antibiotic-free environment for 7 days. However, the strain E. coli J53/pTW4 showed a fitness disadvantage of 6% per ten generations in the process of growth competition with E. coli J53. In conclusion, the plasmid pTW4, a mobile MDR vehicle, may promote the dissemination of tet(M), floR, rmtB, strAB, sul2, and bla CMY-2 among bacteria and then, but it appears to confer growth disadvantage to the host.

Background: The two-component signalling systems PmrAB and PhoPQ of Salmonella have been extensively studied with regard to colistin resistance. We previously showed that overexpressed CpxR could significantly increase the colistin susceptibility (16-fold compared with the WT strain) of Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) through PmrAB and PhoPQ., Objectives: To identify the potential target genes of CpxR in PmrAB- and PhoPQ-related signalling pathways., Methods: His6-CpxR was prokaryotically expressed and purified by Ni-NTA resin affinity chromatography. β-Galactosidase activity assays were conducted to investigate whether CpxR could regulate the promoters of colistin resistance-related genes (CRRGs). Electrophoretic mobility shift assays (EMSAs) were used to further detect His6-CpxR complexes with promoters of CRRGs., Results: We demonstrated for the first time (to the best of our knowledge) that CpxR and the AcrAB-TolC efflux pump have reciprocal effects on CRRG transcription. Additionally, CpxR could regulate the colistin susceptibility of Salmonella Typhimurium by binding directly to the promoters of phoPQ, pmrC, pmrH and pmrD at the CpxR box-like sequences or indirectly through other regulators including pmrAB and mgrB., Conclusions: CpxR could regulate the colistin susceptibility of Salmonella Typhimurium by a multitarget mechanism., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The oxazolidinone drug linezolid is mainly used for severe infections caused by multidrug-resistant Gram-positive bacteria. However, emerging linezolid resistance is aggravating difficulties in the treatment of certain infectious diseases. The objective of this review was to provide a reference for researchers and clinicians to be able to better face together the serious challenge of antimicrobial resistance., Materials and Methods: A systematic literature search was performed using PubMed, Web of Science, Google Scholar, and the China National Knowledge Infrastructure (CNKI) database. The articles were scrutinized to extract information on oxazolidinone drug linezolid resistance, and the prevalence of the resistance gene optrA. We reviewed the latest advances in epidemic properties, resistance mechanism, and transfer mechanism of linezolid resistance genes in different isolates isolated from various samples worldwide., Results: Initially, it was thought that linezolid resistance was related to the change in drug target mediated by mutations in the 23S rRNA gene, rplC, rplD, and cfr. optrA was discovered in 2015, and is a gene encoding oxazolidinone resistance, which exists in both plasmids and chromosomes, but mostly plasmids. The emergence of the novel plasmid-borne ABC transporter gene optrA expanded the understanding of the mechanism of linezolid resistance., Conclusions: At present, the prevalence of linezolid resistance has become increasingly serious. The resistance gene optrA has been reported in Enterococcus, Staphylococcus squirrel and Streptococcus, which indicates that this gene has a strong ability to spread across bacteria, so the prevalence and spread of optrA gene should be monitored carefully.

ICE Hpa1 was identified in the genome of a serovar 8 Haemophilus parasuis ST288 isolate YHP170504 from a case of swine lower respiratory tract infection. The aim of the present study was to characterize the integrative conjugative element ICE Hpa1 and its multiresistance region. Susceptibility testing was determined by broth microdilution and the complete ICE Hpa1 was identified by WGS analysis. The full sequence of ICE Hpa1 was analyzed with bioinformatic tools. The presence of ICE Hpa1 , its circular intermediate and integration site were confirmed by PCR and sequence analysis. Transfer of ICE Hpa1 was confirmed by conjugation. ICE Hpa1 has a size of 68,922 bp with 37.42% GC content and harbors 81 genes responsible for replication and stabilization, transfer, integration, and accessory functions, as well as seven different resistance genes [ bla Rob- 3 , tet (B), aphA1 , strA , strB , aac(6)'-Ie-aph(2')-Ia , and sul2 ]. Conjugation experiments showed that ICE Hpa1 could be transferred to H. parasuis V43 with frequencies of 6.1 × 10 -6 . This is the first time a multidrug-resistance ICE has been reported in H. parasuis . Seven different resistance genes were located on a novel integrative conjugative element ICE Hpa1 , which suggests that the ICE Hpa1 is capable of acquiring foreign genes and serving as a carrier for various resistance genes., (Copyright © 2020 Sun, Cui, Liu, Li, Yi, Pan, Wu, Yuan, Hu and He.)

The objective of this study was to explore the genetic and biological features of the tet (M)-harboring plasmid pTS14 in Salmonella enterica strain S14 isolated from a chicken fecal sample. Plasmid pTS14 was identified by conjugation, S1-pulsed-field gel electrophoresis (PFGE), Southern hybridization, and plasmid sequencing. The biological characteristics of pTS14 were assessed via stability, growth kinetics, and starvation survival experiments. Strain S14, belonging to ST3007, harbored a 119-kb tet (M)-bearing IncF2:A1:B1 conjugative plasmid pTS14. The plasmid pTS14 contained a novel transposon Tn 6709 with the genetic structure IS 26 - tnpA1 - tnpA2 -Δ orf13 - LP - tet (M)- tnpX -Δ tnpR -IS 26 , and the resistance genes tet (B), tet (D), strAB , sul2 , and bla TEM-1b . In addition, pTS14 was found to be highly stable in the recipient strain E. coli J53. The transconjugant TS14 exhibited a higher survival ratio than E. coli J53 under permanent starvation-induced stress. The tet (M)-bearing IncF2 epidemic plasmid lineage may accelerate the dissemination of tet (M) and other genes by coselection, which could constitute a potentially serious threat to clinical treatment regimens., (Copyright © 2020 Liu, Liu, Cui, Chen, Li, He, Liu, Yuan, Hu and Pan.)

Objective: To investigate the features, changing trend, and rules of pneumoconiosis in Jiangsu Province, China, as well as the health status of patients with pneumoconiosis. Methods: From July to October 2019, the patients with pneumoconiosis, reported up to the end of 2018 in Jiangsu Province, were enrolled as respondents, and follow-up and retrospective investigation were performed. A total of 24405 patients with pneumoconiosis were investigated, and related data were collected from the monitoring system of cause of death for residents, pneumoconiosis network reporting system, occupational disease diagnosis institution, management institutions for the reporting of occupational diseases, and related residents' committee or village committee. The patients with pneumoconiosis, who had been reported, were followed up by telephone or on-site visit to obtain the information on their conditions. A descriptive analysis was performed for age of onset, working years, sex, category of industry, type of pneumoconiosis, annual disease onset, geographic distribution, and medical security. Results: Among the 24405 patients, a male/female ratio was 16.81∶1. Of all 24405 patients, 15948 (65.35%) had stage 1 pneumoconiosis, 5289 (21.67%) had stage 2 pneumoconiosis, and 1637 (6.71%) had stage 3 pneumoconiosis. The mean working years for dust exposure was 16.25±9.95 years for all patients, and the mean working years for dust exposure was 15.80±9.95 years for patients with stage 1 pneumoconiosis, 17.82±9.80 years for patients with stage 2 pneumoconiosis, and 16.31±9.90 years for patients with stage 3 pneumoconiosis. The highest number of cases of pneumoconiosis was reported in Wuxi (5744 cases, accounting for 23.54%) , followed by Zhenjiang (4160 cases, accounting for 17.05%) , Xuzhou (3851 cases, accounting for 15.78%) , Yancheng (3340 cases, accounting for 13.69%) , and Suzhou (2948 cases, accounting for 12.08%) . Major types of pneumoconiosis included silicosis (15392 cases, accounting for 63.07%) and coal workers' pneumoconiosis (5253 cases, accounting for 21.52%) . In this survey, 21115 completed follow-up, among whom 15924 survived and 5191 died, 15924 patients with pneumoconiosis survived, among whom 7461 (46.85%) had an age of ≥70 years and 2515 (15.79%) were exposed to dust for 5-9 years. The industries involved were mainly coal mining and washing industry (5687 cases, accounting for 35.71%) and public management, social security, and social organization (3349 cases, accounting for 21.03%) ; in terms of security, 7999 patients (50.23%) were covered by occupational injury insurance, 946 (5.94%) were compensated by employers, 4537 (28.49%) were covered by basic medical insurance for urban and rural residents, 1590 (9.98%) were covered by critical illness insurance, and 5458 (34.28%) were covered by other types of social security, such as medical assistance and poverty relief. Conclusion: Silicosis and coal worker's pneumoconiosis are the key points for the prevention and treatment of pneumoconiosis in Jiangsu Province, and supervision should be strengthened for industries and regions with serious dust hazards.

Hematopoietic stem cells (HSCs) and skeletal stem cells (SSCs) cohabit in the bone marrow. KITL (C-KIT ligand) from LEPR + adult bone marrow stromal cells is pivotal for HSC maintenance. In contrast, it remains unclear whether KITL/C-KIT signaling also regulates SSCs. Here, we lineage traced C-KIT + cells and found that C-KIT was expressed by fetal, but not postnatal skeletal progenitors. Fetal C-KIT + cells gave rise to 20% of LEPR + stromal cells in adult bone marrow, forming nearly half of all osteoblasts. Disruption of mTOR signaling in fetal C-KIT + cells impaired bone formation. Notably, conditional deletion of Kitl from PRX1 + fetal bone marrow stromal cells, but not LEPR + adult bone marrow stromal cells, significantly increased bone formation. Thus, our work identified C-KIT + skeletal progenitors as an important source of bones formed during development., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Treatment of diabetic neuropathic pain (DNP) continues to be a major challenge, and underlying mechanisms of DNP remain elusive. We investigated treatment effects of B vitamins on DPN- and DNP-associated alterations of neurochemical signaling in the nociceptive dorsal root ganglion (DRG) neurons and the spinal cord in rats., Methods: DNP was produced in male, adult, Sprague Dawley rats by single i.p. streptozotocin (STZ). Western blot analysis and immunohistochemistry were used to analyze protein expressions in DRG and ELISA to measure the proinflammatory cytokines in the spinal cord. Behaviorally expressed DNP was determined by measuring the sensitivity of hindpaw skin to mechanical and thermal stimulation., Results: There were 87.5% (77/88) rats which developed high blood glucose within 1-2 weeks following STZ injection. Of which, 70.13% ( n  = 54/77) animals exhibited DNP manifested as mechanical allodynia and/or thermal hyperalgesia. Intraperitoneal administration of vitamins B1/B6/B12 (100/100/2 mg/kg, one or multiple doses) significantly attenuated DNP without affecting the blood glucose. Expressions of P2X3 and TRPV1 in CGRP-positive and IB4-positive DRG neurons as well as the interleukin-1 β , tumor necrosis factor- α , and nerve growth factor in the lumbar spinal cord were greatly increased in DNP rats. Such DNP-associated neurochemical alterations were also greatly suppressed by the B-vitamin treatment., Conclusions: B-vitamin treatment can greatly suppress chronic DNP and DNP-associated increased activities of P2X3 and TRPV1 in DRG and the spinal proinflammatory cytokines, which may contribute to the pathogenesis of DNP. Systematic administration of B vitamins can be a strategy for DNP management in clinic., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 Duan-Duan He et al.)

Aim: This study aimed to excavate the roles of BCYRN1 in hepatocellular carcinoma (HCC). Methods: A comprehensive strategy of microarray data mining, computational biology and experimental verification were adopted to assess the clinical significance of BCYRN1 and identify related pathways. Results: BCYRN1 was upregulated in HCC and its expression was positively associated with both tumor, node, metastasis and worse survival rate in patients with HCC. Through combing plasma BCYRN1 with alpha fetoprotein, the diagnosis of HCC was remarkably improved. BCYRN1 may regulate some cancer-related pathways to promote HCC initiation via an lncRNA-miRNA-mRNA network. Conclusion: Our results propose BCYRN1 as a potential diagnostic and prognostic biomarker and offer a novel perspective to explore the etiopathogenesis of HCC.

T helper 17 (Th17) cells are regarded as key factors in the pathogenesis of multiple sclerosis (MS). Although the involvement of certain microRNAs (miRNAs) in the development of MS has been reported, their roles in Th17 cell differentiation and MS pathogenesis remain elusive. In this study, we identified that let-7f-5p expression is significantly downregulated in CD4 + T cells from MS patients and during the process of Th17 differentiation. The overexpression of let-7f-5p suppressed Th17 differentiation, whereas the knockdown of let-7f-5p expression enhanced this progress. We then explored the molecular mechanism through which let-7f-5p suppressed Th17 differentiation and identified signal transducer and activator of transcription 3 (STAT3), a pivotal transcription factor of Th17 cells, as a direct target of let-7f-5p. In contrast to the downregulated expression of let-7f-5p, STAT3 and p-STAT3 protein levels were dramatically upregulated and inversely correlated with let-7f-5p in peripheral blood CD4 + T cells from MS patients. In conclusion, let-7f-5p functions as a potential inhibitor of Th17 differentiation in the pathogenesis of MS by targeting STAT3 and may serve as a new therapeutic target.

Background: IS26-flanked transposons played an increasingly important part in the mobilization and development of resistance determinants. Heterogeneous resistance-encoding plasmid clusters with polymorphic MDR regions (MRRs) conferred by IS26 in an individual Escherichia coli isolate have not yet been detected., Objectives: To characterize the complete sequence of a novel blaCTX-M-65- and fosA3-carrying IncZ-7 plasmid with dynamic MRRs from an E. coli isolate, and to depict the mechanism underlying the spread of resistance determinants and genetic polymorphisms., Methods: The molecular characterization of a strain carrying blaCTX-M-65 and fosA3 was analysed by antimicrobial susceptibility testing and MLST. The transferability of a plasmid bearing blaCTX-M-65 and fosA3 was determined by conjugation assays, and the complete structure of the plasmid was obtained by Illumina, PacBio and conventional PCR mapping, respectively. The circular forms derived from IS26-flanked transposons were detected by reverse PCR and sequencing., Results: A novel IncZ-7 plasmid pEC013 (∼118kb) harbouring the blaCTX-M-65 and fosA3 genes was recovered from E. coli isolate EC013 belonging to D-ST117. The plasmid was found to have heterogeneous and dynamic MRRs in an individual strain and the IS26-flanked composite transposon-derived circular intermediates were identified and characterized in pEC013., Conclusions: The heterogeneous MRRs suggested that a single plasmid may actually be a cluster of plasmids with the same backbone but varied MRRs, reflecting the plasmid's heterogeneity and the survival benefits of having a response to antimicrobial-related threatening conditions in an individual strain., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Herbal compatibility of compound formulas can enhance therapeutic effects or reduce side effects of the monarch drugs, but majority of compatibility mechanisms are still unknown. Sangju-Yin, a well-known Chinese compound formula, is currently used to treat common cold in clinical., Purpose: In this study, we proposed a strategy to explore the compatibility mechanism of Sangju-Yin by investigating P450 enzymes-based metabolic interactions between monarch drugs and the other constituent herbs., Methods: Under the guidance of traditional Chinese medicine theory, the constituent herbs of Sangju-Yin were divided into four groups, including monarch drugs, monarch drugs with addition of minister drugs, monarch drugs with addition of minister and adjuvant drugs, as well as the whole recipe, namely monarch drugs with addition of minister, adjuvant and conductant drugs. Their effects on rats in vivo P450 (CYP1A2, CYP2A3, CYP2C6, CYP2C11 and CYP3A1) activities after oral administration were evaluated using probe drug assay based on LC-MS/MS. Moreover, effects of the four groups of herbs on mRNA expression of P450 enzymes after oral administration, as well as in vitro P450 activities after co-incubation, were investigated to explore the underlying mechanisms., Results: Comparing with monarch drugs, addition of different constituent herbs significantly enhanced CYP1A2 and CYP2C6 activities, and inhibited CYP2A3 and CYP3A1 activities, indicating their possible influences on plasma concentrations of active constituents in the monarch drugs. Mechanism study suggested that these herbs affected P450 activities by transcriptional regulation and/or direct interaction with the enzymes., Conclusion: This study clarified the compatibility mechanism of Sangju-Yin from the aspect of P450 enzymes-based metabolic interactions, which would benefit better understanding of the therapeutic basis of Sangju-Yin., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Objective: To analyze the status of job burnout among the community and township public health workers, and to provide scientific basis for formulating comprehensive prevention and control measures. Methods: A census sampling method was used to investigate the job burnout by using the self-made general demographic data questionnaire and the MBI-GS in HuaiAn. Results: A total of 1074 valid questionnaires were collected, and the total physical examination rate of job burnout was 58.7%, 51.3% were mild burnout, 7.4% were highly burnout. Multivariate ordered logistic regression analysis showed that sex ( OR =1.32), chronic disease ( OR =1.92)、and daily working hours greater than 7 h ( OR =1.40)、township health center ( OR =1.31) were independent risk factors for occupational burnout. The age "≥51" ( OR =0.45)、"41~" ( OR =0.58) are the independent protective factors for the occurrence of job burnout. Conclusion: Job burnout detection rate was high in the staff of essential public health service, sex, daily working hours, health status, age and work unit are the main factors influencing job burnout.

Tet(M)-type proteins confer resistance to tetracycline and related antibiotics by interacting with the ribosome. Genes encoding Tet(M) have been found in a range of bacteria, including Escherichia coli . In the current study, conjugation experiments were performed between seven different tetracycline-resistant, azide-susceptible E. coli strains isolated from ducks and tetracycline-sensitive, azide-resistant E.coli J53. Transconjugants were obtained from two of the strains at a frequency of 1.2 × 10 -8 . PCR, southern blotting and sequencing demonstrated that tet (M) in the transconjugants was located on a ~50 kb IncHI2-type plasmid and was part of a composite transposon, designated Tn6539. This transposon is flanked by two IS26 elements in opposite orientation and contains the Tn3Δ tnpA +Δ orf13 - lp - tet (M)+gamma delta+ tnpX +Δ tnpR sequences. The Δ orf13 - lp - tet (M) sequence was a highly conserved genetic fragment in E. coli harboring tet (M) and mainly located in the composite transposons flanked by IS6-family elements. In summary, Tn6539 is a new composite transposon capable of horizontal transfer of tet (M) among E. coli isolates.

Triethylamine-promoted cycloaddition reactions of N-phenacyl and N-alkoxycarbonylmethylbenzothiazolium bromides with aromatic aldehydes and malononitrile (ethyl cyanoacetate, pivaloylacetonitrile) in ethanol afforded functionalized tetrahydrobenzo[d]pyrrolo[2,1-b]thiazoles in good yields and various diastereoselectivity. The oxidation reaction of the functionalized tetrahydrobenzo[d]pyrrolo[2,1-b]thiazoles with DDQ in different solvents resulted in diverse benzothiazole derivatives and benzo[d]pyrrolo[2,1-b]thiazoles. The reaction mechanism and the stereochemistry of this tandem [3 [Formula: see text] 2] cycloaddition reaction and sequential oxidation reaction are illustrated based on analysis of the reactive intermediates and obtained products.

Objective: Curcumin being used to treat various chronic diseases while its poor bioavailability issue limited its wide clinical application as a therapeutic agent. The aim of this work was to prepare curcumin-loaded self-assembled micelles using soluplus and solutol ® HS15 (SSCMs) to enhance curcumin's solubility and thus oral bioavailability., Methods: Optimum formulation was investigated and the optimized ratio of drugs and excipients was obtained and the SSCMs were prepared via ethanol solvent evaporation method. The optimal SSCMs were characterized by transmission electron microscopy, drug content analysis including loading efficiency (LE%) and entrapment efficiency (EE%), and the cumulative amount of curcumin released from the micelles were all calculated using HPLC method. The in vitro cytotoxicity and the permeability of SSCMs were measured by Caco-2 cell monolayers and the oral bioavailability was evaluated by SD rats., Key Findings: The solubility of curcumin in self-assembled micelles was dramatically increased by 4200 times as compared to free curcumin. Caco-2 cells transport experiment exhibited that while soluplus and solutol ® HS15 were self-assembled into micelles, it could not only promote the permeability of curcumin across membrane for better absorption, but also could restrain the curcumin pumped outside due to the role of P-gp efflux mechanism of soluplus and solutol ® HS15. Furthermore, the prepared SSCMs formulation was almost nontoxic and had safety performance on Caco-2 cells model. Moreover, curcumin's oral bioavailability of SSCMs formulation in SD rats had doubled than that of free curcumin., Conclusions: The prepared SSCMs were characterized by PS, PDI, LE%, EE% data analysis. After the soluplus and solutol ® HS15 were self assembled into micelles, both the solubility and membrane permeability of curcumin were evaluated to have been enhanced, as well as the effect of efflux pump of curcumin was inhibited, hence to promote oral absorption and generate an increased bioavailability.

We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC 50  = 0.039 nM vs. 0.069 nM). And amide compound 2a and acrylamide compound 2c also had comparable inhibitory activity with dasatinib against the leukemia cell line HL60 (IC 50  = 0.25 nM and 0.26 nM vs. 0.11 nM). Against the leukemia progenitor cell line KG1a, triazole compounds 15a and 15d-15f and oxadiazole compounds 24a-24d were more potent than dasatinib. In particular, the hydroxyl compounds 15a and 24a were about 64 and 180 fold more potent than dasatinib against KG1a cells (IC 50  = 0.14 μM and 0.05 μM vs. 8.98 μM). Compounds 15a and 24a also inhibited colony formation in MCF-7 cells and inhibited cell migration in the cell wound scratch assay in B16BL6 cells. Moreover, hydroxyl compounds 15a and 24a had low toxicity in vivo., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Ginkgo biloba extract (GBE), derived from the leaves of Ginkgo biloba L., is one of the most widely used traditional Chinese medicines worldwide. Due to high structural diversity and low abundance of chemical constituents in GBE, conventional reversed-phase liquid chromatography has limited power to meet the needs of its quality control. In this study, an off-line hydrophilic interaction×reversed-phase two-dimensional liquid chromatography (HILIC×RP 2D-LC) system coupled with diode array detection (DAD) and quadrupole time-of-flight mass spectrometry (qTOF-MS) was established to comprehensively analyze the chemical constituents of GBE. After optimizing the chromatographic columns and mobile phase of 2D-LC, a Waters XBridge Amide column using acetonitrile/water/formic acid as the mobile phase was selected as the first dimension to fractionate GBE, and the obtained fractions were further separated on an Agilent Zorbax XDB-C18 column with methanol/water/formic acid as the mobile phase. As a result, a total of 125 compounds were detected in GBE. The orthogonality of the 2D-LC system was 69.5%, and the practical peak capacity was 3864 and 2994, respectively, calculated by two different methods. The structures of 104 compounds were tentatively characterized by qTOF-MS analysis, and 21 of them were further confirmed by comparing with reference standards. This established HILIC×RP 2D-LC-qTOF/MS system can greatly improve the separation and characterization of natural products in GBE or other complicated herbal extracts., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The present work is to study the chemical constituents from petroleum ether fraction of Tibetan medicine Swertia chirayita by column chromatography and recrystallization. The structures were identified by physical and chemical properties and spectral data as swerchirin (1), decussatin (2), 1,8-dihydroxy-3,5,7-trimethoxyxanthone (3), 1-hydroxy-3,5,7,8-tetramethoxyxanthone (4), bellidifolin (5), 1-hydroxy-3, 7-dimethoxyxanthone (6), methylswertianin (7), 1-hydroxy-3,5-dimethoxyxanthone (8), erythrodiol (9), oleanolic acid (10), gnetiolactone (11), scopoletin (12), sinapaldehyde (13), syringaldehyde (14), and β-sitosterol (15). Compounds 3, 4, 9, 11-14 were isolated from S. chirayita for the first time. Compounds 9 and 12 were firstly isolated from the genus Swertia. The cytotoxic activities of compounds 1, 2, 5, 7 and 8 against human pancreatic cancer cell lines SW1990 and BxPC-3,and the protective effects of these compounds against hydrogen peroxide (H2O2)-induced oxidative stress in human endothelium-derived EA.hy926 were investigated in vitro. The results showed no obvious effect at the high concentration of 50 μmol•L⁻¹., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

Epstein-Barr virus (EBV) is a well-documented aetiological factor for multiple sclerosis (MS). EBV encodes at least 44 microRNAs (miRNAs) that are readily detectable in the circulation of human. Previous studies have demonstrated that EBV-encoded miRNAs regulate host immune response and may serve as biomarkers for EBV-associated diseases. However, the roles of EBV miRNAs in MS are still unknown. To fill the gap, we conducted a comprehensive profiling of 44 mature EBV miRNAs in 30 relapsing-remitting MS (RRMS) patients at relapse and 30 matched healthy controls. Expression levels of ebv-miR-BHRF1-2-5p and ebv-miR-BHRF1-3 were elevated significantly in the circulation and correlated positively with the expanded disability status scale (EDSS) scores of MS patients. Receiver operating characteristic (ROC) analyses confirmed that the expression of these two miRNAs distinguished MS patients clearly from healthy controls. Luciferase assays revealed that ebv-miR-BHRF1-2-5p may directly target MALT1 (mucosa-associated lymphoid tissue lymphoma transport protein 1), a key regulator of immune homeostasis. In conclusion, we described the expression of EBV miRNAs in MS and preliminarily validated the potential target genes of significantly altered EBV miRNAs. The findings may pave the way for prospective study about the pathogenesis of MS., (© 2017 British Society for Immunology.)

Alzheimer's disease (AD) is a neurodegenerative disorder that is the most common cause of dementia in the elderly, and intracellular neurofibrillary tangles (NFTs) are one of the pathological features of AD. Recent studies have suggested long noncoding RNAs (lncRNAs) play important roles in AD. Competing endogenous RNAs (ceRNAs) is a mechanism that has recently been proposed, in which lncRNAs compete for common miRNA-binding sites with mRNAs. However, the roles of lncRNAs and ceRNA in AD NFTs is limited. In this study, we constructed a global triple network based on ceRNA theory, then an AD NFT lncRNA-mRNA network (NFTLMN) was generated. By analyzing the NFTLMN, three lncRNAs (AP000265.1, KB-1460A1.5 and RP11-145M9.4), which are highly related with AD NFTs were identified. To further explore the cross-talk between mRNAs and lncRNAs, a clustering module analysis was performed on the NFTLMN and two AD NFT related modules were identified. Our study provides a better understanding of the molecular basis of AD NFTs and may offer novel treatment strategies for AD., (Copyright © 2016. Published by Elsevier Inc.)

Chromatographic separation is still a critical subject for the quality control of traditional Chinese medicine. In this study, three different high performance liquid chromatographic (HPLC) systems employing commercially available columns packed with 1.8, 3.5 and 5.0 μm particles were respectively developed and optimized for the combinative fingerprint analysis and multi-ingredients quantification of Sangju Ganmao tablet (SGT). Chromatographic parameters including the repeatability of retention time and peak area, symmetry factor, resolution, number of theoretical plates and peak capacity were used to assess the chromatographic performance of different HPLC systems. The optimal chromatographic system using Agilent ZORBAX SB-C18 column (2.1 mm × 100 mm, 3.5 μm) as stationary phase was respectively coupled with diode array detector or mass spectrometry detector for the chromatographic fingerprint analysis and simultaneous quantification or identification of nine compounds of SGT. All the validation data conformed to the acceptable requirements. For the fingerprint analysis, 31 peaks were selected as the common peaks to evaluate the similarities of SGT from 10 different manufacturers using heatmap, hierarchical cluster analysis and principal component analysis. The results demonstrated that the combinations of the quantitative and chromatographic fingerprint analysis offer an efficient way to evaluate the quality consistency of SGT., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Sterile alpha motif and histidine aspartate domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is one of the novel restriction factors that potently supresses HIV-1 infection in myeloid cells at an early stage in the viral replication cycle. SAMHD1 activity is blocked by the action of viral accessory protein x (Vpx), which targets and recruits SAMHD1 for proteasomal degradation, in the SIVsm/HIV-2 lineage., Methods: The impact of SAMHD1 polymorphisms on viral replication in Chinese-origin rhesus macaques (CR) and cynomolgus macaques of Vietnamese origin (CM) have not been reported until now. Therefore, we aimed to explore the polymorphisms, as well as the impact of polymorphisms, on HIV- 2 and SIV infections among CR and CM., Results: We found two variants, T168C and T320C, located in the SAM domain of CR SAMHD1, which were significantly correlated with the HIV-2ROD/SIVmac239 virus load, suggesting that T168C and T320C probably affected HIV-2ROD and anti-SIVmac239 replication in CR, respectively. Conversely, T320C possibly affected CM SAMHD1-mediated HIV-2ROD restriction. However, none of the variants were correlated with CM SAMHD1-mediated SIVmac239 restriction., Conclusion: Based on these results, we concluded that SAMHD1 polymorphisms did not affect SIVmac239 replication in CM, but perhaps altered HIV-2ROD infection; however, different sites of the SAM domain of SAMHD1 were responsible for restricting the replication of different viruses in CR., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Viral selection pressure has acted on restriction factors that play an important role in the innate immune system by inhibiting the replication of viruses during primate evolution. Tripartite motif-containing (TRIM) family members are some of these restriction factors. It is becoming increasingly clear that gene expression differences, rather than protein-coding regions changes, could play a vital role in the anti-retroviral immune mechanism. Increasingly, recent studies have created genome-scale catalogues of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To improve our understanding of the molecular evolution mechanism of antiviral differences between species, we leveraged 14 130 DHSs derived from 145 cell types to characterize the regulatory landscape of the TRIM region. Subsequently, we compared the alignments of the DHSs across six primates and found 375 DHSs that are conserved in non-human primates but exhibit significantly accelerated rates of evolution in the human lineage (haDHSs). Furthermore, we discovered 31 human-specific potential transcription factor motifs within haDHSs, including the KROX and SP1, that both interact with HIV-1 Importantly, the corresponding haDHS was correlated with antiviral factor TRIM23 Thus, our results suggested that some viruses may contribute, through regulatory DNA differences, to organismal evolution by mediating TRIM gene expression to escape immune surveillance., (© 2016 The Author(s).)

Unlabelled: Neuropathic pain, often caused by nerve injury, is a major clinical challenge. Mechanisms that underlie neuropathic pain remain elusive and effective medications are limited. Numerous investigations of pain mechanisms have focused on alterations and phenotypic switches of the nociceptive transmitters and modulators, as well as on their receptors and downstream signaling pathways that have already exerted roles in the pain processes of mature nervous systems. We have demonstrated recently that nerve injury may elicit neuronal alterations that recapitulate events occurring during development. Signaling of the representative activated molecule Wnt thus becomes a trigger for the development of neuropathic pain and is a potential therapeutic target. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the β-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an "ON-OFF" switch for neuropathic pain status in rats. Peripheral nerve injury causes rapid-onset and long-lasting nuclear accumulation of YAP/TAZ/β-catenin in the spinal dorsal horn. Spinal inhibition or knock-down of either YAP or TAZ suppresses mechanical allodynia induced by nerve injury or the pain initiators lysophosphatidic acid and Wnt3a. Promoting the nuclear accumulation of YAP/TAZ leads to mechanical hypersensitivity in naive animals. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/β-catenin and can greatly suppress neuropathic pain and the associated neurochemical alterations. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening for potent analgesics for the treatment of neuropathic pain., Significance Statement: Mechanisms that underlie neuropathic pain remain elusive. We have demonstrated recently that nerve injury can activate Wnt signaling, which becomes a trigger for the development of neuropathic pain. We report that the transcriptional regulators YAP and TAZ, which orchestrate Wnt response via incorporation in the β-catenin destruction complex, are key in the pathogenesis of neuropathic pain and may serve as an "ON-OFF" switch for neuropathic pain status. Further, we discovered a new small molecule, dCTB, which targets YAP/TAZ/β-catenin and can greatly suppress neuropathic pain. Our study reveals that YAP and TAZ are core mechanisms underlying the pathogenesis of neuropathic pain and are targets in the screening of potent analgesics for the treatment of neuropathic pain., (Copyright © 2016 the authors 0270-6474/16/3610128-13$15.00/0.)