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Glycosylation is an important post-modification reaction in plant secondary metabolism, and contributes to structural diversity of bioactive natural products. In plants, glycosylation is usually catalyzed by UDP-glycosyltransferases. Flavonoid 2′-O-glycosides are rare glycosides. However, no UGTs have been reported, thus far, to specifically catalyze 2′-O-glycosylation of flavonoids. In this work, UGT71AP2 was identified from the medicinal plant Scutellaria baicalensis as the first flavonoid 2′-O-glycosyltransferase. It could preferentially transfer a glycosyl moiety to 2′-hydroxy of at least nine flavonoids to yield six new compounds. Some of the 2′-O-glycosides showed noticeable inhibitory activities against cyclooxygenase 2. The crystal structure of UGT71AP2 (2.15 Å) was solved, and mechanisms of its regio-selectivity was interpreted by pKa calculations, molecular docking, MD simulation, MM/GBSA binding free energy, QM/MM, and hydrogen‒deuterium exchange mass spectrometry analysis. Through structure-guided rational design, we obtained the L138T/V179D/M180T mutant with remarkably enhanced regio-selectivity (the ratio of 7-O-glycosylation byproducts decreased from 48% to 4%) and catalytic efficiency of 2′-O-glycosylation (kcat/Km, 0.23 L/(s·μmol), 12-fold higher than the native). Moreover, UGT71AP2 also possesses moderate UDP-dependent de-glycosylation activity, and is a dual function glycosyltransferase. This work provides an efficient biocatalyst and sets a good example for protein engineering to optimize enzyme catalytic features through rational design.

Abstract Aims This study investigated the S2I2N0–3 score, a simple tool comprising stroke history, insulin‐treated diabetes, and N‐terminal pro‐brain natriuretic peptide, for forecasting mortality and morbidity in heart failure (HF) with reduced ejection fraction (HFrEF). Methods and results Analysing 890 GUIDE‐IT HFrEF trial participants, we stratified them by baseline S2I2N0–3 risk score into three risk groups. We examined the score's association with five adverse outcomes over short (90 days) and extended periods (median follow‐up of 15 months) using Cox and competing risk models. Our analysis revealed significant positive associations between the S2I2N0–3 strata and adverse outcomes. When analysed as a continuous variable, each point increment of the S2I2N0–3 score was associated with a higher risk of short‐ and long‐term cardiovascular death [short term: hazard ratio (HR) 1.43, 95% confidence interval (CI) 1.03–1.98; long term: HR 1.18, 95% CI 1.02–1.38], all‐cause death (HR 1.52, 95% CI 1.12–2.07; HR 1.18, 95% CI 1.03–1.36), HF hospitalization (HR 1.39, 95% CI 1.20–1.62; HR 1.18, 95% CI 1.06–1.31), any hospitalization (HR 1.19, 95% CI 1.06–1.34; HR 1.09, 95% CI 1.00–1.19), and the composite outcome of cardiovascular death and HF hospitalization (HR 1.39, 95% CI 1.21–1.60; HR 1.17, 95% CI 1.06–1.30). The S2I2N0–3 demonstrated reliable prognostic value, with C‐indices ranging from 0.619 to 0.753 across outcomes and time points. When compared with the Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) score using Z‐statistics, net reclassification index, and integrated discrimination improvement, the S2I2N0–3 showed comparable predictive power for all outcomes during both short‐ and long‐term follow‐ups. Conclusions The S2I2N0–3 risk score had modest predictive values for both short‐ and long‐term clinical outcomes in HFrEF patients, offering equivalent performance to the established MAGGIC score.

Precisely controlling gene expression is beneficial for optimizing biosynthetic pathways for improving the production. However, promoters in nonconventional yeasts such as Ogataea polymorpha are always limited, which results in incompatible gene modulation. Here, we expanded the promoter library in O. polymorpha based on transcriptional data, among which 13 constitutive promoters had the strengths ranging from 0–55% of PGAP, the commonly used strong constitutive promoter, and 2 were growth phase-dependent promoters. Subsequently, 2 hybrid growth phase-dependent promoters were constructed and characterized, which had 2-fold higher activities. Finally, promoter engineering was applied to precisely regulate cellular metabolism for efficient production of β-elemene. The glyceraldehyde-3-phosphate dehydrogenase gene GAP was downregulated to drive more flux into pentose phosphate pathway (PPP) and then to enhance the supply of acetyl-CoA by using phosphoketolase-phosphotransacetylase (PK-PTA) pathway. Coupled with the phase-dependent expression of synthase module (ERG20∼LsLTC2 fusion), the highest titer of 5.24 g/L with a yield of 0.037 g/(g glucose) was achieved in strain YY150U under fed-batch fermentation in shake flasks. This work characterized and engineered a series of promoters, that can be used to fine-tune genes for constructing efficient yeast cell factories.

Abstract Cancer models play critical roles in basic cancer research and precision medicine. However, current in vitro cancer models are limited by their inability to mimic the three-dimensional architecture and heterogeneous tumor microenvironments (TME) of in vivo tumors. Here, we develop an innovative patient-specific lung cancer assembloid (LCA) model by using droplet microfluidic technology based on a microinjection strategy. This method enables precise manipulation of clinical microsamples and rapid generation of LCAs with good intra-batch consistency in size and cell composition by evenly encapsulating patient tumor-derived TME cells and lung cancer organoids inside microgels. LCAs recapitulate the inter- and intratumoral heterogeneity, TME cellular diversity, and genomic and transcriptomic landscape of their parental tumors. LCA model could reconstruct the functional heterogeneity of cancer-associated fibroblasts and reflect the influence of TME on drug responses compared to cancer organoids. Notably, LCAs accurately replicate the clinical outcomes of patients, suggesting the potential of the LCA model to predict personalized treatments. Collectively, our studies provide a valuable method for precisely fabricating cancer assembloids and a promising LCA model for cancer research and personalized medicine.

Abstract Purpose To investigate the computed tomography (CT) characteristics of air-containing space and its specific patterns in neoplastic and non-neoplastic ground glass nodules (GGNs) for clarifying their significance in differential diagnosis. Materials and methods From January 2015 to October 2022, 1328 patients with 1,350 neoplastic GGNs and 462 patients with 465 non-neoplastic GGNs were retrospectively enrolled. Their clinical and CT data were analyzed and compared with emphasis on revealing the differences of air-containing space and its specific patterns (air bronchogram and bubble-like lucency [BLL]) between neoplastic and non-neoplastic GGNs and their significance in differentiating them. Results Compared with patients with non-neoplastic GGNs, female was more common (P

Objective: The purpose of this research was to examine the potential anticancer properties of Xiao Tan San Jie Fang (XTSJF) and its potential mechanism of action against colorectal cancer. Materials and Methods: HCT116 cells were induced into HCT116 spheres in DMEM/F12 medium by treatment with epidermal growth factor + fibroblast growth factor + leukemia inhibitory factor + B27. The proliferation ability and stemness of HCT116 spheres was examined. Various concentrations of XTSJF were used to treat HCT116 spheres to observe the impact on proliferation, apoptosis, and expression of stem cell markers. Next, Wnt/β-catenin pathway-related factor proteins were detected. Results: The findings revealed that XTSJF suppressed cell growth and induced cell death in HCT116 cells in a dosage-dependent manner. Similarly, XTSJF promotes apoptosis, inhibits cell proliferation, prolongs survival, and maintains the expression of stem cells through the Wnt/-catenin/TCF4 axis. XTSJF also inhibits AKT activity and subsequently activates glycogen synthesis kinase-3β expression, inhibiting Wnt/beta-catenin pathway activity and downstream target gene transcript expression. The Wnt/β-catenin signaling pathway is inhibited by the XTSJF, leading to the suppression of colon cancer stem cell proliferation. Conclusion: Xiaotan Sanjie Prescription inhibited colon cancer stem cell growth through Wnt/β-catenin signaling pathway.

Abstract Next generation sequencing (NGS) is typically used to reveal tumor gene variation feature for targeted therapy of various types of human cancers, including non-small cell lung cancer (NSCLC). Here, we report the role and potential applicable value of combining DNA and RNA sequencing in gene variation detection in NSCLC. 386 NSCLC patients with stage II-IV were enrolled and detected using NGS sequencing of DNA and RNA panels that covered all well-documented target driver genes from the Chinese Society of Clinical Oncology (CSCO). The rate of epidermal growth factor receptor (EGFR) single nucleotide variation (SNV)/indel, mesenchymal-epithelial transition factor (MET) copy number variation (CNV) and anaplastic lymphoma kinase (ALK) fusion were 52.1%, 4.1% and 6.0% in the NSCLC cohort. The landscapes of SNV/indel, CNV and gene fusion in the cohort were depicted as well. Meanwhile, we assessed detection efficacy of DNA and RNA sequencing in gene fusion. Detected number and types of gene fusion using the RNA sequencing were better than those using the DNA sequencing. Gene fusion with intergenic region was only detected by DNA sequencing and MET exon 14 skipping (METΔex14) was more easily identified by RNA sequencing. Finally, we investigated clinical correlations of SNV/indel/CNV/fusion with clinicopathologic features in the NSCLC cohort. Taken together, RNA sequencing significantly complements deficiency of DNA sequencing for gene fusion, which cooperatively presents comprehensive and reliable gene variation features and facilitate the identification of potential drug targets for NSCLC patients.

BackgroundType 2 diabetes mellitus (T2DM) is widely acknowledged as a vital warning sign contributing to cognitive dysfunction. However, there is still a lack of consensus on whether hypoglycemic events resulting from poor glycemic control increase the risk of cognitive dysfunction in people with diabetes, and the potential dose–response correlation between hypoglycemic events and cognitive dysfunction remains unexplored. The primary objective of the current study was to assess the contribution of hypoglycemic events to cognitive dysfunction in T2DM patients and the dose–response correlation between the two.MethodsA comprehensive search of nine major databases was executed from inception to May 2023. We screened all observational studies examining the connection between hypoglycemia and cognitive dysfunction. The DerSimonian-Laird method was used to compute the combined risk ratio (RR) and its 95% confidence interval (CI). Additionally, dose–response analysis was employed to investigate the correlation between the frequency of hypoglycemia and the likelihood of cognitive dysfunction.ResultsA total of 30 studies of different levels in 17 articles with 3,961,352 participants were included in this review. The pooled RR for the connection of hypoglycemia and the likelihood of cognitive dysfunction was 1.47 (95% CI: 1.35–1.60). Subgroup analyses showed that the pooled RR for the likelihood of cognitive dysfunction was 1.20 (95% CI: 1.11–1.31) for one episode of hypoglycemia, 1.41 (95% CI: 1.05–1.88) for two episodes of hypoglycemia, and 1.62 (95% CI: 1.20–2.91) for three or more episodes of hypoglycemia. Dose–response analysis showed a linear dose–response relationship between hypoglycemia and the likelihood of cognitive dysfunction (exp (b) = 1.178694, z = 7.12, p

Accurate state of charge (SOC) estimation of lithium-ion batteries is a fundamental prerequisite for ensuring the normal and safe operation of electric vehicles, and it is also a key technology component in battery management systems. In recent years, lithium-ion battery SOC estimation methods based on data-driven approaches have gained significant popularity. However, these methods commonly face the issue of poor model generalization and limited robustness. To address such issues, this study proposes a closed-loop SOC estimation method based on simulated annealing-optimized support vector regression (SA-SVR) combined with minimum error entropy based extended Kalman filter (MEE-EKF) algorithm. Firstly, a probability-based SA algorithm is employed to optimize the internal parameters of the SVR, thereby enhancing the precision of original SOC estimation. Secondly, utilizing the framework of the Kalman filter, the optimized SVR results are incorporated as the measurement equation and further processed through the MEE-EKF, while the ampere-hour integral physical model serves as the state equation, effectively attenuating the measurement noise, enhancing the estimation accuracy, and improving generalization ability. The proposed method is validated through battery testing experiments conducted under three typical operating conditions and one complex and random operating condition with wide temperature variations under only one condition training. The results demonstrate that the proposed method achieves a mean absolute error below 0.60% and a root mean square error below 0.73% across all operating conditions, showcasing a significant improvement in estimation accuracy compared to the benchmark algorithms. The high precision and generalization capability of the proposed method are evident, ensuring accurate SOC estimation for electric vehicles.

In response to the issues of overheating of the shell and insufficient impact energy of the hydraulic rock drill, this paper focuses on the hydraulic rock drill with alternating front and rear return chambers. By establishing nonlinear and linear dynamic models, the influence of stroke amount and flow compensation on the hydraulic system is investigated, and an optimization method for impact characteristics is proposed. Considering factors such as hydraulic clamping force, fluid leakage, and rock properties, a feedback control numerical model is established for the impact system. This model is based on principles drawn from wave dynamics and fluid dynamics theories. It elucidates the dynamic characteristics of the impact piston, reversing valve, and high-pressure accumulator. Combining three linear models, this study investigates the influence of the advance amount of the return signal chamber and the gas pre-charge pressure of the high-pressure accumulator on the impact characteristics. A thorough laser experiment has been created to evaluate the actual rock drilling capabilities of the impact system. Proposed optimal parameters are tested experimentally to compare the impact performance before and after the enhancement. The results indicate an increase in impact power, validating the effectiveness of the proposed improvement method.

PurposeBased on comparison of different machine learning (ML) models, we developed the model that integrates traditional hand-crafted (HC) features and ResNet50 network-based deep transfer learning (DTL) features from multiparametric MRI to predict Ki-67 status in sinonasal squamous cell carcinoma (SNSCC).MethodsTwo hundred thirty-one SNSCC patients were retrospectively reviewed [training cohort (n = 185), test cohort (n = 46)]. Pathological grade, clinical, and MRI characteristics were analyzed to choose the independent predictor. HC and DTL radiomics features were extracted from fat-saturated T2-weighted imaging, contrast-enhanced T1-weighted imaging, and apparent diffusion coefficient map. Then, HC and DTL features were fused to formulate the deep learning-based radiomics (DLR) features. After feature selection and radiomics signature (RS) building, we compared the predictive ability of RS-HC, RS-DTL, and RS-DLR.ResultsNo independent predictors were found based on pathological, clinical, and MRI characteristics. After feature selection, 42 HC and 10 DTL radiomics features were retained. The support vector machine (SVM), LightGBM, and ExtraTrees (ET) were the best classifier for RS-HC, RS-DTL, and RS-DLR. In the training cohort, the predictive ability of RS-DLR was significantly better than those of RS-DTL and RS-HC (p< 0.050); in the test set, the area under curve (AUC) of RS-DLR (AUC = 0.817) was also the highest, but there was no significant difference of the performance between DLR-RS and HC-RS.ConclusionsBoth the HC and DLR model showed favorable predictive efficacy for Ki-67 expression in patients with SNSCC. Especially, the RS-DLR model represented an opportunity to advance the prediction ability.

Objective To retrospectively analyze the indexes of autologous blood transfusion during heart valve replacement, in order to provide reference for allogeneic blood transfusion during heart valve replacement surgery under direct vision. Methods The data of 180 patients who underwent heart valve replacement in our hospital from January 2020 to December 2021 were analyzed retrospectively. The patients were divided into allogeneic and non-allogeneic blood transfusion group based on whether allogeneic blood was transfused during the operation, and the general data and 24 hours pre- and post-operative clinical examination indexes were compared. Results Multivariate logistic regression analysis showed that age (OR=1.110, 95% CI: 1.058-1.165, P

Objective: Yiqi Fumai Lyophilized Injection (YQFM), a Chinese medicine injection, has been widely used for the treatment of cardiovascular diseases, especially heart failure (HF). However, bioactive compounds and underlying mechanisms of YQFM in treating HF remain poorly understood. Materials and Methods: Network pharmacology was employed to investigate the bioactive compounds and mechanisms of YQFM. A compound-target network was constructed to screen bioactive compounds based on contribution index calculation. Then, an adriamycin-induced HF rat model was established to evaluate the cardio-protective effects of YQFM by hematoxylin and eosin staining and enzyme-linked immunosorbent assays. Results: Network pharmacology indicated that YQFM may alleviate HF through 36 compounds and 109 targets. Particularly, ginsenosides Rb1, Rg1, Re, Rf, Rb2, Rh1, schisandrin, and ginsenoside Rc were indicated as the top contributors of YQFM in treating HF. YQFM was predicted to act on multiple targets such as vascular endothelial growth factor A, interleukin-2 (IL-2), IL-6, and IL-1β, as well as to regulate signaling pathways such as hypoxia-inducible factor 1, tumor necrosis factor, VEGF, and PI3K-Akt. The pharmacological study suggested that YQFM could attenuate cardiac injury and up-regulate plasma concentrations of VEGFR-1 and NO in HF rats. Ginsenoside Rb1, as the major contributor from network pharmacology analysis, also showed a cardioprotective effect and up-regulation of VEGFR-1 in plasma. Conclusions: Ginsenosides and schisandrin were predicted as the most important contributors to the cardioprotective effect of YQMF. Ginsenoside Rb1 was proved to alleviate HF and increase the plasma concentration of VEGFR-1.

Currently, human health due to corona virus disease 2019 (COVID-19) pandemic has been seriously threatened. The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19. However, the efficacy is compromised by the SARS-CoV-2 evolvement and mutation. Here we report the SARS-CoV-2 S protein receptor-binding domain (RBD) inhibitor licorice-saponin A3 (A3) could widely inhibit RBD of SARS-CoV-2 variants, including Beta, Delta, and Omicron BA.1, XBB and BQ1.1. Furthermore, A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells, with EC50 of 1.016 μM. The mechanism was related to binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis combined with quantum mechanics/molecular mechanics (QM/MM) simulations. Interestingly, phosphoproteomics analysis and multi fluorescent immunohistochemistry (mIHC) respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase (MAPK) pathways and rebalancing the corresponding immune dysregulation. This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.

As a vital and integral component of transportation infrastructure, pavement has a direct and tangible impact on socio-economic sustainability. In recent years, an influx of groundbreaking and state-of-the-art materials, structures, equipment, and detection technologies related to road engineering have continually and progressively emerged, reshaping the landscape of pavement systems. There is a pressing and growing need for a timely summarization of the current research status and a clear identification of future research directions in these advanced and evolving technologies. Therefore, Journal of Road Engineering has undertaken the significant initiative of introducing a comprehensive review paper with the overarching theme of “advanced road materials, structures, equipment, and detection technologies”. This extensive and insightful review meticulously gathers and synthesizes research findings from 39 distinguished scholars, all of whom are affiliated with 19 renowned universities or research institutions specializing in the diverse and multidimensional field of highway engineering. It covers the current state and anticipates future development directions in the four major and interconnected domains of road engineering: advanced road materials, advanced road structures and performance evaluation, advanced road construction equipment and technology, and advanced road detection and assessment technologies.

Abstract Colitis‐associated bowel cancer (CAC) is one of the most common malignancies associated with inflammation. The aim of this study was to observe a new herbal formula “Xiaotan Sanjie Fang” (XTSJF) derived from the addition and subtraction theory of traditional medicine as an alternative to CAC treatment by “Daotan Decoction” and “Xiaojianzhong Decoction”, which are famous traditional Chinese medicine prescriptions for the treatment of inflammatory diseases of the digestive tract. We constructed a DMH/DSS inflammation‐associated colorectal cancer rat model and treated CAC rats with sulfasalazine and different doses of XTSJF. The results showed that the body weight of rats treated with different doses of XTSJF increased, which was still lower than that of normal rats; AFC decreased significantly compared with the model group and the positive control group, and the final dose was superior to the low dose; histological observation revealed that it could maintain the normal structure of colon tissue, while it could inhibit the secretion of VEGF, COX2, and AQP1 and the expression of pro‐inflammatory cytokines IL‐6, IL‐1β, and TNF‐α, promote the expression of caspase‐3 and BAX and inhibit the expression of Bcl‐2. Taken together, these data suggest that XTSJF can inhibit COX‐2/VEGF expression to prevent the development of inflammation‐associated colorectal cancer.

BackgroundStudies have reported that metabolic disturbance exhibits in patients with Alzheimer’s disease (AD). Still, the presence of definitive evidence concerning the genetic effect of metabolites on AD risk remains insufficient. A systematic exploration of the genetic association between blood metabolites and AD would contribute to the identification of new targets for AD screening and prevention.MethodsWe conducted an exploratory two-sample Mendelian randomization (MR) study aiming to preliminarily identify the potential metabolites involved in AD development. A genome-wide association study (GWAS) involving 7,824 participants provided information on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of AD, encompassing 21,982 cases and 41,944 controls of Europeans. The primary two-sample MR analysis utilized the inverse variance weighted (IVW) model while supplementary analyses used Weighted median (WM), MR Egger, Simple mode, and Weighted mode, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. For the further identification of metabolites, replication and meta-analysis with FinnGen data, steiger test, linkage disequilibrium score regression, confounding analysis, and were conducted for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on AD. Besides, an extra replication analysis with EADB data was conducted for final evaluation of the most promising findings.ResultsAfter rigorous genetic variant selection, IVW, complementary analysis, sensitivity analysis, replication and meta-analysis with the FinnGen data, five metabolites (epiandrosterone sulfate, X-12680, pyruvate, docosapentaenoate, and 1-stearoylglycerophosphocholine) were identified as being genetically associated with AD. MVMR analysis disclosed that genetically predicted these four known metabolites can directly influence AD independently of other metabolites. Only epiandrosterone sulfate and X-12680 remained suggestive significant associations with AD after replication analysis with the EADB data.ConclusionBy integrating genomics with metabonomics, this study furnishes evidence substantiating the genetic association of epiandrosterone sulfate and X-12680 with AD. These findings hold significance for the screening, prevention, and treatment strategies for AD.

ObjectiveTo explore the modulations of electroacupuncture in subjective tinnitus (ST) by comparing the difference of functional connectivity (FC) in ST patients and healthy volunteers between the insular (INS) and the whole brain region.MethodsA total of 34 ST patients were selected into electroacupuncture group (EG) and 34 age- and sex-matched normal subjects were recruited into control group (CG). The EG received acupuncture at SI19 (Tinggong), GB11 (Touqiaoyin), TE17 (Yifeng), GV20 (Baihui), GV15 (Yamen), GV14 (Dazhui), SJ13 (Zhongzhu), among which the points of SI19 and GB11 were connected to the electroacupuncture instrument with the density wave of 2/50 Hz, and 3 treatments per week for 10 sessions in total. The severity of tinnitus was evaluated by Tinnitus Handicap Inventory (THI), the hearing status was recorded using pure tone audiometry, and resting-state functional magnetic resonance imaging (rs-fMRI) was performed on the brain before and after treatment, the CG received no intervention yet only rs-fMRI data were collected.ResultsWith the electroacupuncture treatment, the total THI score, average air conduction threshold of patients of EG were significantly lower than before (p

Abstract Apiose is a natural pentose containing an unusual branched-chain structure. Apiosides are bioactive natural products widely present in the plant kingdom. However, little is known on the key apiosylation reaction in the biosynthetic pathways of apiosides. In this work, we discover an apiosyltransferase GuApiGT from Glycyrrhiza uralensis. GuApiGT could efficiently catalyze 2″-O-apiosylation of flavonoid glycosides, and exhibits strict selectivity towards UDP-apiose. We further solve the crystal structure of GuApiGT, determine a key sugar-binding motif (RLGSDH) through structural analysis and theoretical calculations, and obtain mutants with altered sugar selectivity through protein engineering. Moreover, we discover 121 candidate apiosyltransferase genes from Leguminosae plants, and identify the functions of 4 enzymes. Finally, we introduce GuApiGT and its upstream genes into Nicotiana benthamiana, and complete de novo biosynthesis of a series of flavonoid apiosides. This work reports an efficient phenolic apiosyltransferase, and reveals mechanisms for its sugar donor selectivity.

Abstract Acetylation contributes to the bioactivity of numerous medicinally important natural products. However, little is known about the acetylation on sugar moieties. Here we report a saponin acetyltransferase from Astragalus membranaceus. AmAT7-3 is discovered through a stepwise gene mining approach and characterized as the xylose C3′/C4′-O-acetyltransferse of astragaloside IV (1). To elucidate its catalytic mechanism, complex crystal structures of AmAT7-3/1 and AmAT7-3A310G/1 are obtained, which reveal a large active pocket decided by a specific sequence AADAG. Combining with QM/MM computation, the regiospecificity of AmAT7-3 is determined by sugar positioning modulated by surrounding amino acids including #A310 and #L290. Furthermore, a small mutant library is built using semi-rational design, where variants A310G and A310W are found to catalyze specific C3′-O and C4′-O acetylation, respectively. AmAT7-3 and its variants are also employed to acetylate other bioactive saponins. This work expands the understanding of saponin acetyltransferases, and provide efficient catalytic tools for saponin acetylation.

IntroductionWith an incidence rate as high as 46%-58%, hypoglycemia is a common complication of glycemic management among those suffering from type 2 diabetes mellitus(T2DM). According to preclinical research, hypoglycemia episodes may impair cognition by harming neurons. However, there is still controversy regarding the clinical evidence for the relationship between hypoglycemic events and the likelihood of cognitive impairment. Furthermore, little research has been done on the dose-response association between hypoglycemia incidents and the possibility of cognitive impairment. To address these knowledge gaps, the present research intends to update the comprehension of the association among hypoglycemic events and the risk of cognitive impairment and to clarify the correlation between dose and response by incorporating the most recent investigations.Method and analysisThis work has developed a protocol for a systematic review and meta-analysis that will examine, via a well-organized assessment of several databases, the relationship between the incidence of hypoglycemia and the probability of cognitive impairment. Observational studies investigating the connection between hypoglycemia episodes and cognitive impairment will be included. The databases that will be searched are PubMed, Web of Science, the Chinese Biomedical Literature Database (CBM), Cochrane Library, Embase, the China National Knowledge (CNKI), Wan Fang, the Chinese Science and Technology Periodical Database (VIP), and Du Xiu. Literature from the establishment of each database to December 2023 will be included in the search. Two researchers will independently screen the studies that satisfy the requirements for both inclusion and exclusion. A third researcher will be asked to mediate any disputes. The methodological caliber of the studies included will be assessed utilizing the Newcastle-Ottawa Scale (NOS) or the Joanna Briggs Institute (JBI) critical appraisal method. With regard to GRADE, which stands for Grading of Recommendations, Assessment, Development, and Evaluation, the quality of the evidence will be evaluated. ROBIS Tool will be used to evaluate the risk of bias in the development of the systematic review. If the data is accessible, meta-analysis and dose-response curve analysis will be employed by Stata software. However, if the data does not allow for such analysis, a descriptive review will be performed.Discussion and conclusionHypoglycemic episodes may raise the likelihood of cognitive impairment, according to earlier investigations. This study will update the relevant evidence and explore the dose-response connection between hypoglycemic episodes and cognitive impairment. The results of this review will have significant effects on decision-making by individuals with diabetes, healthcare providers, and government policy institutions.Trial registrationProspero registration number: CRD42023432352.

This work aims to analyze the application of IoT in the construction of smart city using entropy method, and explore the validity of IoT in smart city based on the input-output perspective. Based on the SC IoT-oriented EIS model, this work can analyze the development status of 31 Chinese smart cities. From 2011–2020, Shanghai(0.1177–0.1607), Beijing(0.1049–0.1132) ,Guangzhou(0.013–0.1378), Chongqing(0.0708–0.1019) are the four cities with the best status of smart city, the development status of smart city in many central and western regions is still relatively low, such as Taiyuan (0.0151–0.0198), Changchun(0.0202–0.0223),Wuhan(0.0638–0.0331), Xining(0.0102–0.0111),Urumqi(0.0147–0.0167). From the input perspective, the input of capital and labor in IoT has obviously positive correlation with the development of smart city, which have significantly promoted the development of smart city. From the output perspective, IoT has not only promoted the economic development of smart city, but also caused a series of environmental pollution problems. In conclusion, the application of the IoT has promoted the development of smart city, China should further strengthen the investment in IoT technology, so that it can solve the problems of unbalanced development and environmental pollution in urban areas of china

C-Glycosides are important natural products with various bioactivities. In plant biosynthetic pathways, the C-glycosylation step is usually catalyzed by C-glycosyltransferases (CGTs), and most of them prefer to accept uridine 5′-diphosphate glucose (UDP-Glc) as sugar donor. No CGTs favoring UDP-rhamnose (UDP-Rha) as sugar donor has been reported, thus far. Herein, we report the first selective C-rhamnosyltransferase VtCGTc from the medicinal plant Viola tricolor. VtCGTc could efficiently catalyze C-rhamnosylation of 2-hydroxynaringenin 3-C-glucoside, and exhibited high selectivity towards UDP-Rha. Mechanisms for the sugar donor selectivity of VtCGTc were investigated by molecular dynamics (MD) simulations and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) binding free energy calculations. Val144 played a vital role in recognizing UDP-Rha, and the V144T mutant could efficiently utilize UDP-Glc. This work provides a new and efficient approach to prepare flavonoid C-rhamnosides such as violanthin and iso-violanthin.

Abstract An immunosuppressive microenvironment enriched with regulatory CD4+ T lymphocytes (Tregs) facilitates the progression of lung adenocarcinoma (LUAD). This study aims to investigate the cellular mechanism underlying the formation of the immunosuppressive microenvironment in LUAD. LUAD samples (n = 12) and normal lung samples (n = 3) were obtained from patients with different pathological stages of LUAD. Single-cell RNA sequencing was performed to classify cellular components and analyze the transcriptomes, including transcription factors/targets and chemokine ligands/receptors, followed by bioinformatics study such as pseudotime analysis. Myeloid cells and T cells were the most abundant cell types in tumors and normal lung tissues, while tumor-associated macrophage-folate receptor 2 (TAM-FOLR2) and CD4+ nuclear receptor subfamily 4 group A member 3 (NR4A3) exhibited sharp increases in invasive adenocarcinoma (IA). The enrichment of TAM-FOLR2 in IA might result from alveolar resident macrophage-resistin (ARM-RETN) transformation and recruitment of dendritic cells (DCs) and other TAMs, as evidenced by temporal trajectories and differential expression profiles of chemokine ligands/receptors versus those in the early stages of tumors. High expression of CCL17/19/22 was observed in IA as well as in DCs, along with the strong interaction of TAM-FOLR2 with DCs. The results of pseudotime analysis suggested that CD4+NR4A3 might potentially convert to CD4+FOXP3, further supported by the high expression of NR4A3 target genes in CD4+FOXP3 cells. This study provides a single-cell transcriptome atlas from preinvasive to invasive LUAD and reveals a potential ARM-RETN/TAM-FOLR2/DCs/CD4+NR4A3/CD4+FOXP3 trajectory in shaping the immune suppressive microenvironment along the pathogenesis of LUAD.

The bio-engineered ovary is an essential technology for treating female infertility. Especially the development of relevant in vitro models could be a critical step in a drug study. Herein, we develop a semi-opened culturing system (SOCS) strategy that maintains a 3D structure of follicles during the culture. Based on the SOCS, we further developed micro-cavity ovary (MCO) with mouse follicles by the microsphere-templated technique, where sacrificial gelatin microspheres were mixed with photo-crosslinkable gelatin methacryloyl (GelMA) to engineer a micro-cavity niche for follicle growth. The semi-opened MCO could support the follicle growing to the antral stage, secreting hormones, and ovulating cumulus-oocyte complex out of the MCO without extra manipulation. The MCO-ovulated oocyte exhibits a highly similar transcriptome to the in vivo counterpart (correlation of 0.97) and can be fertilized. Moreover, we found that a high ROS level could affect the cumulus expansion, which may result in anovulation disorder. The damage could be rescued by melatonin, but the end of cumulus expansion was 3h earlier than anticipation, validating that MCO has the potential for investigating ovarian toxic agents in vitro. We provide a novel approach for building an in vitro ovarian model to recapitulate ovarian functions and test chemical toxicity, suggesting it has the potential for clinical research in the future.

For a micro-indentation hardness test with non-destructivity, the Nix–Gao model is widely used to describe tested hardness or microhardness variation with an indentation depth induced by indentation size effect, in which tested hardness approaches the macrohardness when the indentation depth is large enough. Based on an analysis of hardness measurements on 10 body-centered cubic steels with diverse microstructure, this paper proposes an analytical relation between microhardness to macrohardness ratio and the indentation depth by explicitly linking characteristic indentation depth (a data-fitting parameter) to grain size and ferrite volume fraction using two different methods. In addition, the normal distribution theory is incorporated to consider the inevitable scatter of identical measurements resulting from material heterogeneity and machining/testing errors. Results show that the proposed model, with 96% reliability, can effectively predict microhardness variation with the indentation depth and its scatter.

The hydro-pneumatic suspension, known for enhancing vehicle ride comfort and stability, finds widespread use in engineering vehicles. Presently, the majority of mining trucks employ hydro-pneumatic suspension with a fixed damping hole, underscoring the critical importance of selecting appropriate damping hole parameters. Initially, an equilibrium mathematical model of the ¼ hydro-pneumatic suspension is established, and the influencing factors of the damping characteristics are analyzed. Subsequently, the simulation model and experimental bench for the hydro-pneumatic suspension are constructed. Sinusoidal signals with different frequencies and amplitudes serve as the excitation signals to analyze the variation trend of the force on the rod with displacement changes. The simulation and experimental results demonstrate a high degree of consistency, validating the rationality and validity of the simulation model. Building upon this foundation, various damping apertures are then selected to study the damping characteristics of the hydro-pneumatic suspension. The research indicates that as the damping aperture increases, the setting time of the hydro-pneumatic suspension system after excitation extends, accompanied by a decrease in the acceleration overshoot. As a result, a comprehensive evaluation index is developed, considering various factors, such as different weight setting times and peak longitudinal accelerations to assess the ride comfort of the suspension. This approach is then employed to determine the optimal damping aperture under both full-load and no-load conditions. The findings of this research offer valuable insights for the development of adaptive variable damping hydraulic suspensions, especially under variable load conditions.

The author retracts the article, ‘Drug Resistance and Molecular Characteristics of Car-bapenem-Resistant OXA-48-Producing Klebsiella pneumoniae Strains in Hainan, China’ [...]

The comprehensive performance of unmanned excavators is crucial for the development and optimization of the field of construction machinery. To effectively improve the unmanned excavator to meet the needs of the market, it is imperative to quantify the evaluation method of the comprehensive performance of unmanned excavators. In this study, an evaluation method combining a fuzzy analytic hierarchy process and multivariate image area analysis method is proposed. Firstly, based on the feature extraction of the signal stability of the unmanned excavators, fifteen evaluation indexes were proposed. Then, the case study is used to obtain the scores corresponding to these indexes. The fuzzy analytic hierarchy process is applied to determine the relative weight of the selected evaluation criteria, in which the uncertain and imprecise judgments of decision makers are converted into fuzzy numbers. At the same time, the braking performance of the three types of unmanned excavators was comprehensively evaluated and ranked using the multivariate image area analysis method as an empirical example. Finally, a weight analysis is performed to check the robustness of the ranking results. The results show that the proposed method is effective and feasible. It provides a reference for the performance improvement and efficiency optimization of unmanned excavators.

Background: Osteosarcoma cells are prone to metastasis, and the mechanism of N6-methyladenosine (m6A) methylation modification in this process is still unclear. Methylation modification of m6A plays an important role in the development of osteosarcoma, which is mainly due to abnormal expression of enzymes related to methylation modification of m6A, which in turn leads to changes in the methylation level of downstream target genes messenger RNA (mRNA) leading to tumor development. Methods: We analyzed the expression levels of m6A methylation modification-related enzyme genes in GSE12865 whole-genome sequencing data. And we used shRNA (short hairpin RNA) lentiviral interference to interfere with METTL3 (Methyltransferase 3) expression in osteosarcoma cells. We studied the cytological function of METTL3 by Cell Counting Kit-8 (CCK8), flow cytometry, migration and other experiments, and the molecular mechanism of METTL3 by RIP (RNA binding protein immunoprecipitation), Western blot and other experiments. Results: We found that METTL3 is abnormally highly expressed in osteosarcoma and interferes with METTL3 expression in osteosarcoma cells to inhibit metastasis, proliferation, and apoptosis of osteosarcoma cells. We subsequently found that METTL3 binds to the mRNA of CBX4 (chromobox homolog 4), a very important regulatory protein in osteosarcoma metastasis, and METTL3 regulates the mRNA and protein expression of CBX4. Further studies revealed that METTL3 inhibited metastasis of osteosarcoma cells by regulating CBX4. METTL3 has been found to be involved in osteosarcoma cells metastasis by CBX4 affecting the protein expression of matrix metalloproteinase 2 (MMP2), MMP9, E-Cadherin and N-Cadherin associated with osteosarcoma cells metastasis. Conclusions: These results suggest that the combined action of METTL3 and CBX4 plays an important role in the regulation of metastasis of osteosarcoma, and therefore, the METTL3-CBX4 axis pathway may be a new potential therapeutic target for osteosarcoma.

Microrobots have shown great potential in many applications, such as non‐invasive surgery, tissue engineering, precision medicine, and environmental remediation. Within the past decade, soft microrobot has become one of the important branches. It is aimed to create soft and deformable microrobots with high bioaffinity, which can perform complex tasks noninvasively in inaccessible small spaces in the body. Herein, the latest research progress of soft microrobots regarding the three cornerstones of this field is reviewed: material, fabrication, and actuation. First, various materials that are used for the fabrication of soft microrobots are summarized, and their characteristics and functions are discussed. Second, various fabrication methods of soft microrobots are introduced, and their applicability to different materials is discussed. Third, the actuation methods of soft microrobots are discussed, as well as their pros, cons, and adaptability. Moreover, the outstanding behaviors of soft microrobots in biomedical and environmental applications are introduced with some typical examples published recently. Finally, current clinical use challenges of soft microrobots are pointed out, and their intelligentization is proposed and discussed for further innovative development.

ObjectiveAlthough intracranial electrical stimulation has emerged as a treatment option for various diseases, its impact on the properties of brain networks remains challenging due to its invasive nature. The combination of intracranial electrical stimulation and whole-brain functional magnetic resonance imaging (fMRI) in patients with refractory epilepsy (RE) makes it possible to study the network properties associated with electrical stimulation. Thus, our study aimed to investigate the brain network characteristics of RE patients with concurrent electrical stimulation and obtain possible clinical biomarkers.MethodsOur study used the GRETNA toolbox, a graph theoretical network analysis toolbox for imaging connectomics, to calculate and analyze the network topological attributes including global measures (small-world parameters and network efficiency) and nodal characteristics. The resting-state fMRI (rs-fMRI) and the fMRI concurrent electrical stimulation (es-fMRI) of RE patients were utilized to make group comparisons with healthy controls to identify the differences in network topology properties. Network properties comparisons before and after electrode implantation in the same patient were used to further analyze stimulus-related changes in network properties. Modular analysis was used to examine connectivity and distribution characteristics in the brain networks of all participants in study.ResultsCompared to healthy controls, the rs-fMRI and the es-fMRI of RE patients exhibited impaired small-world property and reduced network efficiency. Nodal properties, such as nodal clustering coefficient (NCp), betweenness centrality (Bc), and degree centrality (Dc), exhibited differences between RE patients (including rs-fMRI and es-fMRI) and healthy controls. The network connectivity of RE patients (including rs-fMRI and es-fMRI) showed reduced intra-modular connections in subcortical areas and the occipital lobe, as well as decreased inter-modular connections between frontal and subcortical regions, and parieto-occipital regions compared to healthy controls. The brain networks of es-fMRI showed a relatively weaker small-world structure compared to rs-fMRI.ConclusionThe brain networks of RE patients exhibited a reduced small-world property, with a tendency toward random networks. The network connectivity patterns in RE patients exhibited reduced connections between cortical and subcortical regions and enhanced connections among parieto-occipital regions. Electrical stimulation can modulate brain network activity, leading to changes in network connectivity patterns and properties.

The last decade has seen a surge of interest in the field of catalytically propelled micro‐ and nanoswimmers for their potential use in biomedical applications, such as biosensing, biopsy, targeted drug delivery, and on‐the‐fly chemistry. However, to fully utilize these devices, precise control over their motion is essential. Therefore, it is important to thoroughly understand their locomotion mechanisms. Herein, the currently accepted mechanisms for propulsion are discussed, which are self‐electrophoresis, self‐diffusiophoresis, and bubble recoil. Additionally, the concept of using multilocomotive mechanisms as a solution to achieve fully autonomous navigation is explored. Moreover, recent advances in the design of these devices are explored.

Objective: To evaluate the clinical safety and efficacy of Lianhuaqingwen (LHQW) capsules in patients with high-risk common type COVID-19 pneumonia. Methods: A retrospective multicenter study on 383 high-risk common type COVID-19 pneumonia cases was conducted. Patients were categorized as the standard treatment (SDT) group (n=168) and the LHQW+SDT group (n=215). The primary endpoint was the rate of symptom (fever, fatigue, coughing) recovery and the secondary endpoints included the time to symptom recovery, the proportion of patients with improvement in chest CT images, the proportion of patients with clinical cure, the timing and rate of negative conversion of SARS-CoV-2 RNA assay. Results: The recovery rate was significantly higher in the LHQW+SDT group as compared with the SDT group (89.7% vs. 72.0%, P0.05). No serious adverse events were reported. Conclusions: LHQW capsules could be recommended to ameliorate clinical symptoms and reduce the rate of deteriorating to severe cases for high-risk common type COVID-19 pneumonia.

Introduction: Triterpenoids and saponins have a broad range of pharmacological activities. Unlike most legumes which contain mainly oleanane-type scaffold, Astragalus membranaceus contains not only oleanane-type but also cycloartane-type saponins, for which the biosynthetic pathways are unknown. Objectives: This work aims to study the function and catalytic mechanism of oxidosqualene cyclases (OSCs), one of the most important enzymes in triterpenoid biosynthesis, in A. membranaceus. Methods: Two OSC genes, AmOSC2 and AmOSC3, were cloned from A. membranaceus. Their functions were studied by heterologous expression in tobacco and yeast, together with in vivo transient expression and virus-induced gene silencing. Site-directed mutagenesis and molecular docking were used to explain the catalytic mechanism for the conserved motif. Results: AmOSC2 is a β-amyrin synthase which showed higher expression levels in underground parts. It is associated with the production of β-amyrin and soyasaponins (oleanane-type) in vivo. AmOSC3 is a cycloartenol synthase expressed in both aerial and underground parts. It is related to the synthesis of astragalosides (cycloartane-type) in the roots, and to the synthesis of cycloartenol as a plant sterol precursor. From AmOSC2/3, conserved triad motifs VFM/VFN were discovered for β-amyrin/cycloartenol synthases, respectively. The motif is a critical determinant of yield as proved by 10 variants from different OSCs, where the variant containing the conserved motif increased the yield by up to 12.8-fold. Molecular docking and mutagenesis revealed that Val, Phe and Met residues acted together to stabilize the substrate, and the cation-π interactions from Phe played the major role. Conclusion: The study provides insights into the biogenic origin of oleanane-type and cycloartane-type triterpenoids in Astragalus membranaceus. The conserved motif offers new opportunities for OSC engineering.

Abstract The study was mainly to evaluate the changes of left ventricular (LV) myocardial work (MW) in children with CKD stage 5 within 3 months after kidney transplantation (KTx). Forty‐three successful KTx recipients (mean age 10.6 years, 58% male) in childhood and 28 healthy children were enrolled. General clinical characteristics and laboratory parameters were collected. Cardiac structure, function, and LV MW were assessed by echocardiography before and after KTx. The results showed that significantly improvement was observed in LV global MW index (GWI), constructive MW (GCW), and wasted MW (GWW) (p .05). Besides, blood pressure (BP), renal graft function, LV ejection fraction (LVEF), and LV mass index (LVMi) had obviously improved after KTx (p

In order to solve the problems that restrict the efficient development of coalbed methane resources under the conditions of soft and low permeability outburst coal seams in Huainan Mining Area, such as complex coal seam structure, multi-source gas emission, rapid decline of drainage flow, high rock roadway and drilling costs, and low (ultra-low) concentration coalbed methane utilization rate, six key technologies suitable for the coordinated development mode of coal and coalbed methane under the condition of coal seam group mining in Huainan mining area are put forward, namely: coalbed methane extraction technology of ground level staged fracturing wells, shield rapid construction technology of coalbed methane extraction roadways, enhanced extraction technology of underground soft coalbed methane, coalbed methane extraction technology of pressure relief in ground mining area, the construction technology of "replacing roadways with holes", and cascade utilization technology of low concentration coalbed methane. The application of supporting key technologies shows that staged fracturing technology and refined drainage and production technology of roof horizontal wells in broken and soft coal seam have effectively improved the pre pumping production of coalbed methane; The full face hard rock roadheader in deep coal mine roadway greatly improves the roadway excavation efficiency, realizing the automation and less humanization of hard rock excavation; Sand adding of hydraulic fracturing and ultra-high hydraulic slotting have realized pressure relief and permeability enhancement in large areas underground coal mine; Type III and IV surface mining area wells can replace the roof high drainage roadway in the treatment of pressure relief gas in coal seam group mining, and reduce the coalbed methane drainage intensity of other measures; The technology of "replacing roadways with holes" has significantly improved the quality of successful directional drilling at middle and high levels in complex roof; Cascade utilization technology of low concentration coalbed methane has greatly reduced the emission of coalbed methane. The six key technologies have guaranteed the safe production in Huainan mining area, and comprehensively improved the output of coal and coalbed methane and the utilization level of coalbed methane. Six key technologies ensure the safe production in Huainan mining area, and comprehensively improved the output of coal and coalbed methane and the utilization level of coalbed methane. Finally, in view of the problems such as high operation cost, low production, small scope of hydraulic fracturing coal reservoir reconstruction technology for surface horizontal wells, and the risk of breakage of mining wells, and small scale of cascade utilization of ultra-low concentration coalbed methane, the development direction of deep CBM precise geological guidance, super large scale efficient reservoir volume transformation, pumping effect evaluation technology, stable and continuous pumping technology of surface wells in mining areas, underground large area intelligent hydraulic enhanced permeability technology, "one well with multiple uses" collaborative pumping CBM technology, and full concentration CBM comprehensive utilization technology are proposed.

In order to improve the gas pre-drainage efficiency of medium hard coal seam with high gas and low permeability, the applicable conditions, advantages and disadvantages of hydraulic piercing, hydraulic fracturing and hydraulic cutting seam anti-permeability technology were discussed. Based on the principle of ultra-high pressure hydraulic slotting technology, a kind of ultra-high pressure hydraulic slotting device for through-layer drilling is developed, it is mainly composed of diamond hydraulic slotting bit, shallow spiral drill pipe, ultra-high pressure rotary joint, ultra-high pressure clean water pump, high-low pressure converter, ultra-high pressure rubber pipe, etc. The water pressure reaches 60−100 MPa, which can realize the integration of drilling and cutting, and is simple and convenient to use. The device was used to carry out field tests in the pre-drainage boreholes of 11-2 coal seam through the floor roadway of 1361(1) haulage gateway in Dingji coal mine. The coal seam gas pressure was 1.43 MPa, the gas content was 8.05 m3/t, and the gas permeability coefficient was 0.013 m2/ (MPa2·d), the coal seam firmness coefficient is 0.79; 1361(1) transportation roadway floor No.11−No.15 drilling area unit length 227 meters, using high-pressure hydraulic slotting anti-permeability measures, 1361(1) transportation roadway floor No.6—No.10 drilling area unit length 213 meters, anti-permeability measures of low-pressure water punching in coal mine. The results show that the average single-knife slitting time of ultra-high pressure hydraulic slitting drilling is 10.7 min, the single-knife coal output is 0.31 t, the equivalent slitting radius is 1.38 m, the slitting density of the coal hole section is 1 knife/m, and the average cutting rate per hole is The average gas drainage concentration of ultra-high pressure hydraulic slotted holes is 56.97%, which is 2.37 times that of low-pressure punching; The time to reach the standard is about 23 days, which is 74.4% and 54.9% shorter than that of ordinary drilling and hydraulic punching technology respectively. Compared with ordinary drilling and hydraulic punching technology, ultra-high pressure hydraulic slotting technology is more ideal for gas drainage in low permeability medium-hard coal seams.

Non-viral vectors have been developing in gene delivery due to their safety and low immunogenicity. But their transfection effect is usually very low, thus limiting the application. Hence, we designed eight peptides (compounds 1–8). We compared their performances; compound 8 had the best transfection efficacy and biocompatibility. The transfection effect was similar with that of PEI, a most-widely-employed commercial transfection reagent. Atomic force microscope (AFM) images showed that the compound could self-assemble and the self-assembled peptide might encapsulate DNA. Based on these results, we further analyzed the inhibitory result in cancer cells and found that compound 8 could partially fight against Hela cells. Therefore, the compound is promising to pave the way for the development of more effective and less toxic transfection vectors.

Background: The emergence and global spread of carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) are of great concern to health services worldwide. These β-lactamases hydrolyze almost all β-lactams, are plasmid-encoded, and are easily transferable among bacterial species. They are mostly of the KPC types in CR-hvKp. OXA-48-producing hvKP strains have been rarely reported in the literature. Methods: OXA-48-producing hvKP strains were collected from clinical specimens at the First Affiliated Hospital of Hainan Medical University from January 2022 to March 2023. Hypervirulent strains were tested for virulence in a mouse lethality study and underwent whole genome sequencing to identify genomic features. Results: A total of 42 unique OXA-48-bearing K. pneumoniae strains were identified, including three CR-hvKP strains (KP2683-1, NCRE61, and KP2185), which were isolated from bacteremia, pulmonary abscess, and liver abscess separately. The three CR-hvKP strains belonged to two different clones of ST11 KL64 (KP2185 and NCRE61) and ST23 K1 (KP2683-1). The KP2683-1 strain had the highest virulence. Whole genome sequencing analysis indicated that NCRE61 and KP2185 acquired IncFIB-type plasmids with a set of virulence genes (iroBCDN, iucABCD, iutA, rmpA, and rmpA2), while KP2683-1 acquired an IncL-type blaOXA-48-harboring plasmid. Consecutive cultures showed that the blaOXA-48-harboring plasmids were highly stable in the three hvKP strains and could be transmitted to Escherichia coli J53 by conjugation. The drug susceptibility testing results show that Ceftazidime/avibactam is sensitive for OXA-48-producing hvKP. Conclusions: Our study highlighted the two evolutionary pathways of OXA-48-producing hvKP strains and confirmed their virulence through in vivo testing. Ceftazidime/avibactam may be a viable option for treating OXA-48-producing hvKP strains.

Objective Previous studies linking Triglyceride Glucose (TyG) Index to carotid plaque have yielded inconsistent results. Moreover, related studies on the population of Japan are rare. This study aims to provide further results.Design A hospital-based cross-sectional study.Setting The Shin Takeo Hospital.Participants We assessed 1904 Japanese participants (988 men and 916 women) whose mean age was 57±11.9 years, and those participants underwent health check-ups at Shinbuf Hospital at Shin Takeo Hospital from 1 April 2016 to 31 October 2017.Methodology Carotid plaque, triglyceride and fasting glucose and other relevant indicators were collected. We used ultrasonography to evaluate carotid plaque. A multivariable logistic regression model and generalised additive model were used to evaluate the association between the TyG Index and carotid plaque. Subgroup and interaction analyses were validated for the consistency of these correlations.Results Following the adjustment of traditional carotid plaque risk factors, the non-linear relationship between the TyG Index and carotid plaque was investigated. Using a two-piecewise regression model, we calculated the inflection point to be 9.06. The OR and 95% CIs for the inflection points on the left and right sides were 1.70 (1.27 to 2.29) and 0.88 (0.52 to 1.47), respectively. According to the variables tested, the interactions between the TyG Index and all subgroup factors were analysed and significant interactions were not observed.Conclusion In individuals who underwent a comprehensive check-up in Japan, the relationship between the TyG Index and carotid plaque is non-linear. When the TyG Index is less than 9.06, it is associated with carotid plaque.

Parkinson’s disease (PD) is the second most common neurodegenerative disease globally. Levodopa (L-dopa) has been the cornerstone for treating Parkinson’s since the 1960s. However, complications such as “wearing-off” and dyskinesia inevitably appear with disease progression. With the further development of microbiomics in recent years, It has been recognized that gut microbiota plays a crucial role in Parkinson’s disease pathogenesis. However, Little is known about the impact of gut microbiota in PD treatment, especially in levodopa metabolism. This review examines the possible mechanisms of gut microbiota, such as Helicobacter pylori, Enterobacter faecalis, and Clostridium sporogenes, affecting L-dopa absorption. Furthermore, we review the current status of gut microbiota intervention strategies, providing new insights into the treatment of PD.

Abstract Background Previous studies confirmed that ground-glass nodules (GGNs) with certain CT manifestations had a higher probability of malignancy. However, differentiating patchy ground-glass opacities (GGOs) and GGNs has not been discussed solely. This study aimed to investigate the differences between the CT features of benign and malignant patchy GGOs to improve the differential diagnosis. Methods From January 2016 to September 2021, 226 patients with 247 patchy GGOs (103 benign and 144 malignant) confirmed by postoperative pathological examination or follow-up were retrospectively enrolled. Their clinical and CT data were reviewed, and their CT features were compared. A binary logistic regression analysis was performed to reveal the predictors of malignancy. Results Compared to patients with benign patchy GGOs, malignant cases were older (P

It is an urgent demand worldwide to control the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are key targets to discover SARS-CoV-2 inhibitors. After screening 12 Chinese herbal medicines and 125 compounds from licorice, we found that a popular natural product schaftoside inhibited 3CLpro and PLpro with IC50 values of 1.73 ± 0.22 and 3.91 ± 0.19 μmol/L, respectively, and inhibited SARS-CoV-2 virus in Vero E6 cells with EC50 of 11.83 ± 3.23 μmol/L. Hydrogen–deuterium exchange mass spectrometry analysis, quantum mechanics/molecular mechanics calculations, together with site-directed mutagenesis indicated the antiviral activities of schaftoside were related with non-covalent interactions with H41, G143 and R188 of 3CLpro, and K157, E167 and A246 of PLpro. Moreover, proteomics analysis and cytokine assay revealed that schaftoside also regulated immune response and inflammation of the host cells. The anti-inflammatory activities of schaftoside were confirmed on lipopolysaccharide-induced acute lung injury mice. Schaftoside showed good safety and pharmacokinetic property, and could be a promising drug candidate for the prevention and treatment of COVID-19.

Abstract This study aimed to present a comprehensive assessment of anaplastic lymphoma kinase (ALK) rearrangements evaluated by DNA/RNA‐based next‐generation sequencing (NGS) and Ventana immunohistochemistry (IHC) in patients with non‐small‐cell lung cancer (NSCLC) and to evaluate the therapeutic outcomes of ALK tyrosine kinase inhibitor (TKI) treatment. We investigated ALK gene fusions in 14,894 patients with NSCLC using Ventana IHC and NGS, including 12,533 cases detected via DNA‐based NGS and 2,361 cases using RNA‐based NGS. The overall percentage agreement (OPA), positive percentage agreement (PPA), and negative percentage agreement (NPA) were calculated when comparing the results between NGS and IHC. The therapeutic responses to ALK‐TKIs were also evaluated. In total, 3.50% (439/12,533) of specimens were NGS ALK‐positive (NGS‐p) in the DNA‐based NGS cohort and 3.63% (455/12,533) were IHC ALK‐positive (IHC‐p). The OPA of NGS was 99.60%, whereas its PPA and NPA were 92.75 and 99.86%, respectively. In the adenocarcinoma (ADC) subcohort, the PPA was 95.69%. In the RNA‐based NGS cohort, 2.20% (52/2,361) of specimens were NGS‐p and 2.63% (62/2,361) were IHC‐p. The OPA of NGS was 99.49%; its PPA and NPA were 82.26 and 99.96%, respectively. Thirteen patients with discordant results received ALK‐TKI treatment. In the seven NGS‐p/IHC‐negative (IHC‐n) patients, the overall response rate (ORR) was 85.4% (6/7) and the disease control rate (DCR) was 100%. In the six NGS‐negative/IHC‐p patients, the ORR was 66.7% (4/6) and the DCR was 100%. In summary, a high concordance of ALK gene fusion detected via NGS and IHC was observed in this study. DNA‐based NGS had a higher OPA, PPA, and PPA in the ADC subcohort, whereas RNA‐based NGS had a higher NPA. Overall, the results suggest that the combination of NGS and IHC can improve the accuracy of ALK fusion detection; hence, a result determination algorithm for clinical detection of ALK gene fusion was also proposed.

Purpose – The new century has witnessed rapid growth in China's foreign aid. However, there is still yet any consensus about the nature or the consequences of China's foreign aid. In this study, the author reviews the history of China's foreign aid and finds significant changes in China's foreign aid policy in the past seven decades. Design/methodology/approach – The author analyzes China's foreign aid data between 2000 and 2017 from the AidData program with a Tobit model. Findings – This study’s results show both the similarities and differences between China and Western donors. These “Chinese characteristics” in its foreign aid, we argue, illustrate China's dual identity in the new century: both the largest developing country that minds its own economic development and an emerging global power that aspires to elevate its global status and enhance its soft power. Originality/value – This article is, to the author’s knowledge, one of the first comprehensive empirical analysis of China's foreign aid using the data from AidData program. It will enrich our understanding of the nature and consequences of China's foreign aid in the new century.

Abstract Purpose To investigate the expression and prognostic value of c-Jun in hypopharyngeal squamous cell carcinoma (HPSCC). Methods A retrospective study was performed on a cohort of 99 HPSCC patients. The expression of c-Jun and phosphorylated-c-Jun (p-c-Jun) was evaluated via immunohistochemistry (IHC) staining. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan–Meier method and multivariate Cox regression analysis. Results The high expression of c-Jun and p-c-Jun in HPSCC accounted for 60.61% and 16.16%, respectively. High expression of c-Jun was closely associated with cT stage (p = 0.0401), tumor size (p = 0.0276), number of lymph node metastases (p = 0.0205) and pathological differentiation (p = 0.0108). The expression of c-Junhigh (p = 0.0043), p-c-Junhigh (p = 0.0376) and c-Junhigh/p-c-Junhigh were closely associated with poor OS. The Cox proportional multivariate hazard model revealed that lymphovascular invasion and c-Jun expression were independent influencing factors of OS in HPSCC patients. Conclusion Our findings suggest that c-Jun is a reliable prognostic factors in HPSCC patients.

Abstract Background The link between glutathione S-transferase P1 (GSTP1) c.313A > G polymorphism and chemotherapy-related adverse events remains controversial. The goal of this study was to assess how this variant affected the toxicity of anthracycline-/paclitaxel-based chemotherapy in patients with breast cancer. Methods This study retrospectively investigated pharmacogenetic associations of GSTP1 c.313A > G with chemotherapy-related adverse events in 142 breast cancer patients who received anthracycline and/or paclitaxel chemotherapy. Results There were 61 (43.0%), 81 (57.0%), 43 (30.3%), and 99 (69.7%) patients in the T0-T2, T3-T4, N0-N1, and N2-N3 stages, respectively. There were 108 (76.1%) patients in clinical stages I–III and 34 (23.9%) patients in clinical stage IV. The numbers of patients with luminal A, luminal B, HER2 + , and triple-negative breast cancer (TNBC) were 10 (7.0%), 77 (54.2%), 33 (23.2%), and 22 (15.5%), respectively. The numbers of patients who carried GSTP1 c.313A > G A/A, A/G, and G/G genotypes were 94 (66.2%), 45 (31.7%), and 3 (2.1%), respectively. There were no statistically significant differences in the proportion of certain toxicities in patients with A/G, G/G, and A/G + G/G genotypes, except for neutropenia, in which the proportion of patients with A/G + G/G (χ 2 = 6.586, P = 0.035) genotypes was significantly higher than that with the AA genotype. The logistic regression analysis indicated that GSTP1 c.313A > G mutation (A/G + G/G vs. A/A genotype) (adjusted OR 4.273, 95% CI 1.141–16.000, P = 0.031) was an independent variable associated with neutropenia. Conclusions The findings of this study indicate that the GSTP1 c.313A > G mutation is an independent risk factor for neutropenia hematotoxicity in breast cancer patients induced by anthracycline-/paclitaxel-based chemotherapy.