Targeting nucleotide metabolic pathways in colorectal cancer by integrating scRNA-seq, spatial transcriptome, and bulk RNA-seq data.

BACKGROUND: Colorectal cancer is a malignant tumor of the digestive system originating from abnormal cell proliferation in the colon or rectum, often leading to gastrointestinal symptoms and severe health issues. Nucleotide metabolism, which encompasses the synthesis of DNA and RNA, is a pivotal cellular biochemical process that significantly impacts both the progression and therapeutic strategies of colorectal cancer METHODS: For single-cell RNA sequencing (scRNA-seq), five functions were employed to calculate scores related to nucleotide metabolism. Cell developmental trajectory analysis and intercellular interaction analysis were utilized to explore the metabolic characteristics and communication patterns of different epithelial cells. These findings were further validated using spatial transcriptome RNA sequencing (stRNA-seq). A risk model was constructed using expression profile data from TCGA and GEO cohorts to optimize clinical decision-making. Key nucleotide metabolism-related genes (NMRGs) were functionally validated by further in vitro experiments. RESULTS: In both scRNA-seq and stRNA-seq, colorectal cancer (CRC) exhibited unique cellular heterogeneity, with myeloid cells and epithelial cells in tumor samples displaying higher nucleotide metabolism scores. Analysis of intercellular communication revealed enhanced signaling pathways and ligand-receptor interactions between epithelial cells with high nucleotide metabolism and fibroblasts. Spatial transcriptome sequencing confirmed elevated nucleotide metabolism states in the core region of tumor tissue. After identifying differentially expressed NMRGs in epithelial cells, a risk prognostic model based on four genes effectively predicted overall survival and immunotherapy outcomes in patients. High-risk group patients exhibited an immunosuppressive microenvironment and relatively poorer prognosis and responses to chemotherapy and immunotherapy. Finally, based on data analysis and a series of cellular functional experiments, ACOX1 and CPT2 were identified as novel therapeutic targets for CRC. CONCLUSION: In this study, a comprehensive analysis of NMRGs in CRC was conducted using a combination of single-cell sequencing, spatial transcriptome sequencing, and high-throughput data. The prognostic model constructed with NMRGs shows potential as a standalone prognostic marker for colorectal cancer patients and may significantly influence the development of personalized treatment approaches for CRC.

Prognostic value of FGFR2 alterations in patients with iCCA undergoing surgery or systemic treatments: A meta-analysis.

BACKGROUND: Over recent years, there has been a notable rise in the incidence of intrahepatic cholangiocarcinoma (iCCA), which presents a significant challenge in treatment due to its complex disease characteristics and prognosis. Notably, the identification of fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement, a potential oncogenic driver primarily observed in iCCA, raises questions about its impact on the prognostic outcomes of patients undergoing surgical intervention or other therapeutic approaches. METHODS: A comprehensive search from inception to July 2023 was conducted across PubMed, Embase, Web of Science, and the Cochrane Library databases. The objective was to identify relevant publications comparing the prognosis of FGFR2 alterations and no FGFR2 alterations groups among patients with iCCA undergoing surgical resection or other systemic therapies. The primary outcome indicators, specifically Overall Survival (OS) and Disease-Free Survival (DFS), were estimated using Hazard Ratios (HRs) with 95% confidence intervals (CIs), and statistical significance was defined as p < .05. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Statistical analyses were performed using Review Manager 5.4 software and Stata, version 12.0. RESULTS: Six studies, involving 1314 patients (FGFR2 alterations group n = 173 and no FGFR2 alterations group n = 1141), were included in the meta-analysis. The analysis revealed that the FGFR2 alterations group exhibited a significantly better OS prognosis compared to the no FGFR2 alterations group, with a fixed-effects combined effect size HR = 1.31, 95%CI = 1.001-1.715, p = .049. Furthermore, meta-regression and subgroup analysis showed that the length of the follow-up period did not introduce heterogeneity into the results. This finding indicates the stability and reliability of the study outcomes. CONCLUSION: The current study provides compelling evidence that FGFR2 alterations are frequently associated with improved survival outcomes for patients with iCCA undergoing surgical resection or other systemic treatments. Additionally, the study suggests that FGFR2 holds promise as a safe and dependable therapeutic target for managing metastatic, locally advanced or unresectable iCCA. This study offers a novel perspective in the realm of targeted therapy for iCCA, presenting a new and innovative approach to its treatment.

Adsorption of norfloxacin from wastewater by biochar with different substrates.

The type of feedstock and pyrolysis temperature are the main reasons affecting the properties of the resulting biochar. Therefore, this paper investigates the effects of different feedstocks (peanut shell, corn straw and soybean straw) and different pyrolysis temperatures (300, 450 and 600 â„ƒ) on the structural morphology and elemental composition of the resulting biochar. The optimum pyrolysis temperature of 600 â„ƒ was selected based on the comparison of the adsorption of NFX (norfloxacin) by the biochar prepared at different temperatures. Characterization of biochar materials using x-ray diffractometer, fourier transform infrared spectrometer and scanning electron microscope to study the changes in the physicochemical and structural properties of biochar. The results showed that the pH, surface area and ash content of biochar are increased with increasing temperature. The results of isothermal adsorption and adsorption kinetics experiments showed that the adsorption processes of the three biochar species on NFX were consistent with the Langmuir model and Pseudo-second order kinetic model. The adsorption process occurred in the surface layer of the biochar and was dominated by chemisorption. The inhibition of the adsorption of NFX was more obvious with the higher valence state of cations and the higher ion concentration. The adsorption mechanism of biochar on NFX includes pore filling, hydrogen bonding and electrostatic interactions.

A strategy to improve the solubility and bioavailability of the insoluble drug piperlongumine through albumin nanoparticles.

Piperlongumine (PL) is a biologically active alkaloid derived from peppers, has significant cytotoxic effects on cancer with no cytotoxicity. This study used NabTM technology to prepare PL albumin nanoparticles (PL-BSA-NPs) to improve water solubility and bioavailability. We carried out a pharmacological evaluation of the PL-BSA-NPs. The morphological profile of the PL-BSA-NPs was relatively uniform, with an average particle size of approximately 210 nm, with drug load of 2.1% and encapsulation rate of 87.6%. PL-BSA-NPs were stable for 4 weeks when stored at 4°C. In vitro release behavior of the PL-BSA-NPs showed a sustained release, with a cumulative release of 67.24% in approximately 24 hours. The pharmacokinetic properties of PL-BSA-NPs were shown that PL-BSA-NPs could maintain a certain level of blood drug concentration for a long time, thus demonstrating the sustained release and increased bioavailability of PL. Finally, we investigated the in vitro antitumor activity of the PL-BSA-NPs and found that PL can significantly inhibit HepG2 cell proliferation, and that PL-BSA-NPs enhanced the inhibitory effect of PL on this proliferative effect. Thus, we concluded that PL can destroy liver cancer cells by increasing ROS levels. These results suggested that PL-BSA-NPs show promising potential as a targeted anti-tumor drug.

Tetra (C60) lanthanum phthalocyanine: design, synthesis and investigation of the third-order nonlinear optical properties.

The construction of molecules with effective photoinduced intramolecular electron transfer (PET) and energy transfer (ET) processes is critical for the enhancement of the nonlinear optical (NLO) properties. A novel D-π-A type compound, namely tetra (C60)-LaPc, has been constructed from a molecular design perspective, wherein tetra-formyl phthalocyanine is used as a donor, four C60 as acceptors and the phenylacetylene group is introduced into it as π-electron bridge, which can increase the molecular conjugation, reduce the spatial site resistance and expand the coplanarity of the molecule, thus making the intramolecular charge transfer easier. Tetra (C60)-LaPc achieves excellent NLO properties with a giant nonlinear absorption coefficient (45 cm GW-1 and large third-order susceptibility (4.05 × 10-10 esu), which are superior to those of LaPc and C60. In addition to exhibiting a superior nonlinear optical response at 532 nm compared to the single component, tetra (C60)-LaPc also broadens the limiting range to the near-infrared region, showing a significant enhancement of the optical nonlinearity at 1064 nm. This can be attributed to the synergistic effect of the different non-linear absorption mechanisms between C60 and LaPc and the efficient PET process.

Realization and Detection of Nonergodic Critical Phases in an Optical Raman Lattice.

The critical phases, being delocalized but nonergodic, are fundamental phases different from both the many-body localization and ergodic extended quantum phases, and have so far not been realized in experiment. Here we propose an incommensurate topological insulating model of AIII symmetry class to realize such critical phases through an optical Raman lattice scheme, which possesses a one-dimensional (1D) spin-orbit coupling and an incommensurate Zeeman potential. We show the existence of both noninteracting and many-body critical phases, which can coexist with the topological phase, and show that the critical-localization transition coincides with the topological phase boundary in noninteracting regime. The dynamical detection of the critical phases is proposed and studied in detail based on the available experimental techniques. Finally, we demonstrate how the proposed critical phases can be achieved within the current ultracold atom experiments. This work paves the way to observe the novel critical phases.

Leptin-induced basal Akt phosphorylation and its implication in exercise-mediated improvement of insulin sensitivity.

Physical exercise is an efficient therapeutical tool in the management of insulin resistance (IR) and related metabolic diseases. Leptin, the well-known obesity hormone and the absence of which leads to IR, showed controversial effects on IR as research continues. Thus, in this study, a detailed investigation of the effect of leptin on exercise-mediated improvement of insulin sensitivity and its underlying mechanism was carried out. Using a rat model of chronic or acute swimming exercise training, we found that serum leptin increased 1 h after either acute exercise or the last session of chronic exercise, when impaired insulin action was observed in previous reports. However, chronic exercise reducd basal serum leptin levels and promoted insulin sensitivity compared with sedentary controls or rats subjected to one bout of aerobic exercise. Our animal results indicated the potential linkage between leptin and insulin sensitivity, which is further investigated in the skeletal muscle L6 cells. Leptin treatment in L6 cells promoted the basal levels of insulin signaling as well as glucose uptake, while blocking JAK2 signaling with either pharmacological intervention (JAK2 inhibitor AG490) or genetic manipulation (siRNA knockdown) decreased the basal levels of insulin signaling. Furthermore, leptin treatment inhibited insulin-stimulated insulin signaling and glucose uptake, while blocking JAK2 signaling restored leptin-attenuated insulin sensitivity. Taken together, our results demonstrated that reduced serum leptin, at least in part, contributes to exercise-mediated improvement of insulin sensitivity, indicating JAK2 as a potent therapeutical target of insulin resistance.

Hydroxypropyl chitosan/ε-poly-l-lysine based injectable and self-healing hydrogels with antimicrobial and hemostatic activity for wound repair.

The biggest obstacle to treating wound healing continues to be the production of simple, inexpensive wound dressings that satisfy the demands associated with full process of repair at the same time. Herein, a series of injectable composite hydrogels were successfully prepared by a one-pot method by utilizing the Schiff base reaction as well as hydrogen bonding forces between hydroxypropyl chitosan (HCS), ε-poly-l-lysine (EPL), and 2,3,4-trihydroxybenzaldehyde (TBA), and multiple cross-links formed by the reversible coordination between iron (III) and pyrogallol moieties. Notably, hydrogel exhibits excellent physicochemical properties, including injectability, self-healing, water retention, and adhesion, which enable to fill irregular wounds for a long period, providing a suitable moist environment for wound healing. Interestingly, the excellent hemostatic properties of the hydrogel can quickly stop bleeding and avoid the serious sequelae of massive blood loss in acute trauma. Moreover, the powerful antimicrobial and antioxidant properties also protect against bacterial infections and reduce inflammation at the wound site, thus promoting healing at all stages of the wound. The study of biohydrogel with multifunctional integration of wound treatment and smart medical treatment is clarified by this line of research.

Nano-Titanium Oxide-Coated Carbon Nanotubes for Photothermal Therapy in the Treatment of Colorectal Cancer.

Recent studies have shown that carbon nanotubes display good potential in tumor photothermal therapy. In this study, we aimed to investigate the therapeutic potential of nano-titanium oxide-coated multi-walled carbon nanotubes (MCNTs) against colorectal cancer (CRC). Firstly, we modified TiO2 nanosheets on the surface of MCNTs to obtain nano-TiO2-coated MCNTs. Next, we conducted cell compatibility validation on nano-TiO2-coated MCNTs, and found that nano-TiO2-coated MCNTs were safe within a certain concentration range (0∼200 µg/ml). Interestingly, nano-TiO2-coated MCNTs displayed a good killing effect in CRC cells under NIR laser irradiation. Subsequently, nano-TiO2-coated MCNTs markedly promoted the proapoptotic effects of NIR laser irradiation, and significantly inhibited the expression of cell cycle proteins CCNA1 and CCND1 in CRC cells under NIR laser irradiation, which indicated that nano-TiO2-coated MCNTs exerted anti-CRC effects under NIR laser irradiation by regulating cell apoptosis and cell cycle. Furthermore, nano-TiO2-coated MCNTs accelerated inhibitory effects on the AKT signaling pathway under NIR laser irradiation. Finally, a cell line-derived xenograft model was established, and the results showed that nano-TiO2-coated MCNTs significantly exhibited superior tumor-killing ability under NIR laser irradiation in vivo. Collectively, our results demonstrate that nano-TiO2-coated MCNTs with NIR laser irradiation may serve as an effective strategy for the treatment of CRC. This article is protected by copyright. All rights reserved.

Diagnostic value of new biliary biopsy cannulae for malignant bile duct strictures via endoscopic retrograde cholangiopancreatography pathway.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) plays a major role in the diagnosis of malignant biliary strictures. ERCP fluoroscopy-guided biliary biopsy is more sensitive than brushing, but it is more difficult to perform and less successful. Therefore, a new technique of biliary biopsy using a new biliary biopsy cannula via the ERCP route was developed in our center with the aim of improving the diagnosis rate of malignant biliary strictures. METHODS: This is a retrospective study that included 42 patients who underwent ERCP-guided biliary brushing and biliary biopsy for biliary strictures using a new biliary biopsy cannula in our department from January 2019 to May 2022. The final diagnosis was determined after brushing, biliary biopsy under the new biliary biopsy cannula or adequate follow-up. Diagnostic rates were calculated and analyzed for relevant factors. RESULTS: The satisfactory rates of pathological specimens of 42 patients who underwent bile duct biopsy with bile duct brush and new bile duct biopsy cannula were 57.14% and 95.24% respectively. Cholangiocarcinoma was diagnosed in 45.23% and 83.30% of the samples by biliary brush examination and biliary biopsy using the new biliary biopsy cannula, respectively (p < 0.001). CONCLUSIONS: The ERCP route using a new biliary biopsy cannula for biliary biopsy technique can improve pathology positivity and benefit ratio. It provides a new approach in the diagnosis of malignant stenosis in the bile duct.

Effect of the clinical decision assessment system on clinical outcomes of delirium in hospitalized older adults: study protocol for a pair-matched, parallel, cluster randomized controlled superiority trial.

BACKGROUND: Prompt recognition of delirium is the first key step in its proper management. A previous study has demonstrated that nurses' delirium screening using the usual paper version assessment tool has no effect on clinical outcomes. Clinical decision assessment systems have been demonstrated to improve patients' adherence and clinical outcomes. Therefore, We developed a clinical decision assessment system (3D-DST) based on the usual paper version (3-min diagnostic interview for CAM-defined delirium), which was developed for assessing delirium in older adults with high usability and accuracy. However, no high quality evidence exists on the effectiveness of a 3D-DST in improving outcomes of older adults compared to the usual paper version. METHODS: A pair-matched, open-label, parallel, cluster randomized controlled superiority trial following the SPIRIT checklist. Older patients aged 65 years or older admitted to four medical wards of a geriatric hospital will be invited to participate in the study. Prior to the study, delirium prevention and treatment interventions will be delivered to nurses in both the intervention and control groups. The nurses in the intervention group will perform routine delirium assessments on the included older patients with 3D-DST, while the nurses in the control group will perform daily delirium assessments with the usual paper version. Enrolled patients will be assessed twice daily for delirium by a nurse researcher using 3D-DST. The primary outcome is delirium duration. The secondary outcomes are delirium severity, incidence of delirium, length of stay, in-hospital mortality, adherence to delirium assessment, prevention, and treatment of medical staff. DISCUSSION: This study will incorporate the 3D-DST into clinical practice for delirium assessment. If our study will demonstrate that 3D-DST will improve adherence with delirium assessment and clinical outcomes in older patients, it will provide important evidence for the management of delirium in the future. TRIAL REGISTRATION: Chinese Clinical Trial Registry, Identifier: ChiCTR1900028402. https://www.chictr.org.cn/showproj.aspx?proj=47127 . PROTOCOL VERSION: 1, 29/7/22.

Effect of indocyanine green near-infrared light imaging technique guided lymph node dissection on short-term clinical efficacy of minimally invasive radical gastric cancer surgery: a meta-analysis.

Objective: In recent years, the utilization of indocyanine green near-infrared (ICG NIR) light imaging-guided lymph node dissection in the context of minimally invasive radical gastric cancer has emerged as a novel avenue for investigation. The objective of this study was to assess the influence of employing this technique for guiding lymph node dissection on the short-term clinical outcomes of minimally invasive radical gastric cancer surgery. Methods: The present study conducted a comprehensive search for short-term clinical outcomes, comparing the group undergoing ICG NIR light imaging-guided lymph node dissection with the control group, by thoroughly examining relevant literature from the inception to July 2023 in renowned databases such as PubMed, Embase, Web of Science, and Cochrane Library. The primary endpoints encompassed postoperative complications, including abdominal infection, abdominal bleeding, pneumonia, anastomotic fistula, and overall incidence of complications (defined as any morbidity categorized as Clavien-Dindo class I or higher within 30 days post-surgery or during hospitalization). Additionally, secondary outcome measures consisted of the time interval until the initiation of postoperative gas and food intake, as well as various other parameters, namely postoperative hospital stay, operative time, intraoperative blood loss, total number of harvested lymph nodes, and the number of harvested metastatic lymph nodes. To ensure methodological rigor, the Cochrane Collaboration Risk of Bias Tool and the Newcastle-Ottawa Scale (NOS) were employed to assess the quality of the included studies, while statistical analyses were performed using Review Manager 5.4 software and Stata, version 12.0 software. Results: A total of 19 studies including 3103 patients were ultimately included (n=1276 in the ICG group and n=1827 in the non-ICG group). In this meta-analysis, the application of ICG near-infrared light imaging in minimally invasive radical gastric cancer surgery effectively improved the occurrence of postoperative Clavien-Dindo grade II or higher complications in patients (RR=0.72, 95% CI 0.52 to 1.00) with a statistically significant P=0.05; in reducing intraoperative blood loss and shortening While reducing intraoperative blood loss and shortening postoperative hospital stay, it could ensure the thoroughness of lymph node dissection in minimally invasive radical gastric cancer surgery (MD=5.575, 95% CI 3.677-7.473) with significant effect size (Z=5.76, p<0.00001). Conclusion: The utilization of indocyanine green near-infrared light imaging technology in the context of minimally invasive radical gastric cancer surgery demonstrates notable efficacy in mitigating the occurrence of postoperative complications surpassing Clavien-Dindo grade II, while concurrently augmenting both the overall quantity of lymph node dissections and the identification of positive lymph nodes, all the while ensuring the preservation of surgical safety. Furthermore, the implementation of this technique proves particularly advantageous in the realm of robotic-assisted radical gastric cancer surgery, thus bearing significance for enhancing the short-term prognostic outcomes of patients.

Identification of high-risk factors associated with mortality at 1-, 3-, and 5-year intervals in gastric cancer patients undergoing radical surgery and immunotherapy: an 8-year multicenter retrospective analysis.

Background: Combining immunotherapy with surgical intervention is a prevailing and radical therapeutic strategy for individuals afflicted with gastric carcinoma; nonetheless, certain patients exhibit unfavorable prognoses even subsequent to this treatment regimen. This research endeavors to devise a machine learning algorithm to recognize risk factors with a high probability of inducing mortality among patients diagnosed with gastric cancer, both prior to and during their course of treatment. Methods: Within the purview of this investigation, a cohort of 1015 individuals with gastric cancer were incorporated, and 39 variables encompassing diverse features were recorded. To construct the models, we employed three distinct machine learning algorithms, specifically extreme gradient boosting (XGBoost), random forest (RF), and k-nearest neighbor algorithm (KNN). The models were subjected to internal validation through employment of the k-fold cross-validation technique, and subsequently, an external dataset was utilized to externally validate the models. Results: In comparison to other machine learning algorithms employed, the XGBoost algorithm demonstrated superior predictive capacity regarding the risk factors that affect mortality after combination therapy in gastric cancer patients for a duration of one year, three years, and five years posttreatment. The common risk factors that significantly impacted patient survival during the aforementioned time intervals were identified as advanced age, tumor invasion, tumor lymph node metastasis, tumor peripheral nerve invasion (PNI), multiple tumors, tumor size, carcinoembryonic antigen (CEA) level, carbohydrate antigen 125 (CA125) level, carbohydrate antigen 72-4 (CA72-4) level, and H. pylori infection. Conclusion: The XGBoost algorithm can assist clinicians in identifying pivotal prognostic factors that are of clinical significance and can contribute toward individualized patient monitoring and management.

Using machine learning to identify patients at high risk of developing low bone density or osteoporosis after gastrectomy: a 10-year multicenter retrospective analysis.

INTRODUCTION: Osteoporosis that emerges subsequent to gastrectomy poses a significant threat to the long-term health of patients. The primary objective of this investigation was to formulate a machine learning algorithm capable of identifying substantial preoperative, intraoperative, and postoperative risk factors. This algorithm, in turn, would enable the anticipation of osteoporosis occurrence after gastrectomy. METHODS: This research encompassed a cohort of 1125 patients diagnosed with gastric cancer, including 108 individuals with low bone density or osteoporosis. A total of 40 distinct variables were collected, comprising patient demographics, pertinent medical history, medication records, preoperative examination attributes, surgical procedure specifics, and intraoperative details. Four distinct machine learning algorithms-extreme gradient boosting (XGBoost), random forest (RF), support vector machine (SVM), and k-nearest neighbor algorithm (KNN)-were employed to establish the predictive model. Evaluation of the models involved receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Shapley additive explanation (SHAP) was employed for visualization and analysis. RESULTS: Among the four prediction models employed, the XGBoost algorithm demonstrated exceptional performance. The ROC analysis yielded excellent predictive accuracy, showcasing area under the curve (AUC) values of 0.957 and 0.896 for training and validation sets, respectively. The calibration curve further confirmed the robust predictive capacity of the XGBoost model. The DCA demonstrated a notably higher benefit rate for patients undergoing intervention based on the XGBoost model. Moreover, the AUC value of 0.73 for the external validation set indicated favorable extrapolation of the XGBoost prediction model. SHAP analysis outcomes unveiled numerous high-risk factors for osteoporosis development after gastrectomy, including a history of chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), hypoproteinemia, postoperative neutrophil-to-lymphocyte ratio (NLR) exceeding 3, steroid usage history, advanced age, and absence of calcitonin use. CONCLUSION: The osteoporosis prediction model derived through the XGBoost machine learning algorithm in this study displays remarkable predictive precision and carries significant clinical applicability.

Nordihydroguaiaretic acid reverses the antibacterial activity of colistin against MCR-1-positive bacteria in vivo/in vitro by inhibiting MCR-1 activity and injuring the bacterial cell membrane.

BACKGROUND: Colistin (polymyxin E) is an effective antibiotic for the treatment of most multidrug-resistant Gram-negative bacteria. However, some bacteria, including bacterial spp. belonging to the Enterobacteriaceae family, have an acquired resistance against polymyxins, which is attributed to they possess plasmid-carried resistance genes (mcr-1 and its variants). So, there is an urgent need to develop new therapeutic strategies to target broad spectrum resistant spp. from Enterobacteriaceae family in response to the loss of the protective barrier of last-line antibiotics. Here, we report the adjuvant capacity of nordihydroguaiaretic acid (NDGA) for restoring the antibacterial activity of colistin against MCR-1-positive E. coli ZJ487 in vivo/in vitro. METHODS: A checkerboard assay, time-killing analysis, isobolograms, growth curves and inducible resistance test showed the effect of NDGA combined with colistin in vitro. TLC was used to detect the inhibitory effect of NDGA on MCR-1. Colony determination and hematoxylin and eosin (HE) staining were used to assess the synergistic effect of NDGA and colistin in mice. RESULTS: Our results showed that NDGA in combination with colistin showed a synergistic bactericidal action without inducing resistance. NDGA directly inhibited MCR-1 activity and resulted in measurable injury to the bacterial cell membrane to recover the antibacterial effect of colistin. Most importantly, NDGA in combination with colistin exhibited an in vivo synergistic effect in murine peritonitis infection models, as evidenced by the survival rate of MCR-1-positive E. coli ZJ487-infected mice which increased from 6.67 to 50.0%. CONCLUSION: Our study demonstrated that NDGA effectively rescues the efficiency of colistin against MCR-positive E. coli ZJ487 by simultaneously inhibiting both, the MCR activity and the injury to the cell membrane of bacteria.

Multilayer Dielectric Nanocomposites with Cross-Linked Dielectric Transition Interlayers for High-Temperature Applications.

In energy storage and transportation systems, polymer dielectrics are widely applied in smart grids, electric vehicles, and power conditioning owing to their incomparable power density and high reliability. However, the dielectric constant (ε) and breakdown strength (Eb) normally cannot be increased simultaneously, which results in insufficient discharged energy density especially at high temperatures. In this work, enhanced Eb and high energy density are archived in multilayer polymer nanocomposites by introducing cross-linked dielectric transition layers. Specifically, the sandwiched composite achieves a huge discharge energy density of 4.64 J cm-3 with a charged-discharged efficiency of 84% at 150 °C and 500 MV m-1. The formation of cross-linked dielectric transition layers between layers of the multilayer nanocomposite could effectively restrain the growth of the electrical tree and greatly increase the Eb. This work presents a strategy for designing high-performance multilayered dielectric polymer nanocomposites by introducing cross-linked dielectric transition layers to reduce the loss from interlayer interfaces.

A novel inhibitor of monooxygenase reversed the activity of tetracyclines against tet(X3)/tet(X4)-positive bacteria.

BACKGROUND: Tigecycline is one of the few last-resort antibiotics for the treatment of carbapenem-resistant Enterobacteriaceae infection, the incidence of which has been rapidly increasing. However, the emergence and spread of tigecycline resistance genes tet(X) (including tet(X3) and tet(X4)) has largely compromised the efficient usage of tetracyclines in the clinical settings. METHODS: The synergistic effect was determined by a checkerboard minimum inhibitory concentration (MIC) assay, a time-killing assay and scanning electron microscopy (SEM) analysis. In-depth mechanisms were defined using an enzyme inhibition assay, western blotting, RT-PCR analysis, molecular dynamics (MD) simulations, biolayer interferometry (BLI) assay and metabolomics analysis. FINDINGS: Herein, our work identified a natural compound, plumbagin, as an effective broad-spectrum inhibitor of Tet(X) (also known as monooxygenase) by simultaneously inhibiting the activity and the production of Tet(X3)/Tet(X4). Plumbagin in combination with tetracyclines showed a synergistic bactericidal effect against Tet(X3)/Tet(X4)-producing bacteria. Mechanistic studies revealed that direct engagement of plumbagin with the catalytic pocket of Tet(X3)/Tet(X4) induced an alternation in its secondary structure to inhibit the activity of these monooxygenases. As a consequence, monotherapy or combination therapy with plumbagin increases the oxidative stress and metabolism in bacteria. Moreover, in a mouse systemic infection model of tet(X4)-positive E. coli, the combination of plumbagin and methacycline exhibited remarkable treatment benefits, as shown by a reduced bacterial load and the alleviation of pathological injury. INTERPRETATION: Plumbagin, as an inhibitor of Tet(X3)/Tet(X4), represents a promising lead drug, as well as an adjunct with tetracyclines to treat bacterial infections, especially for extensively drug-resistant bacteria harbouring Tet(X3)/Tet(X4). FUNDING: The National Natural Science Foundation of China.

Realization of an ideal Weyl semimetal band in a quantum gas with 3D spin-orbit coupling.

Weyl semimetals are three-dimensional (3D) gapless topological phases with Weyl cones in the bulk band. According to lattice theory, Weyl cones must come in pairs, with the minimum number of cones being two. A semimetal with only two Weyl cones is an ideal Weyl semimetal (IWSM). Here we report the experimental realization of an IWSM band by engineering 3D spin-orbit coupling for ultracold atoms. The topological Weyl points are clearly measured via the virtual slicing imaging technique in equilibrium and are further resolved in the quench dynamics. The realization of an IWSM band opens an avenue to investigate various exotic phenomena that are difficult to access in solids.

Dynamical classification of topological quantum phases.

Topological phase of matter is now a mainstream of research in condensed matter physics, of which the classification, synthesis, and detection of topological states have brought excitements over the recent decade while remain incomplete with ongoing challenges in both theory and experiment. Here we propose to establish a universal non-equilibrium characterization of the equilibrium topological quantum phases classified by integers, and further propose the high-precision dynamical schemes to detect such states. The framework of the dynamical classification theory consists of basic theorems. First, we uncover that classifying a d-dimensional (dD) gapped topological phase of generic multibands can reduce to a (d-1)D invariant defined on so-called band inversion surfaces (BISs), rendering a bulk-surface duality which simplifies the topological characterization. Further, we show in quenching across phase boundary the (pseudo) spin dynamics to exhibit unique topological patterns on BISs, which are attributed to the post-quench bulk topology and manifest a dynamical bulk-surface correspondence. For this the topological phase is classified by a dynamical topological invariant measured from an emergent dynamical spin-texture field on the BISs. Applications to quenching experiments on feasible models are proposed and studied, demonstrating the new experimental strategies to detect topological phases with high feasibility. This work opens a broad new direction to classify and detect topological phases by non-equilibrium quantum dynamics.