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Abstract Background A 3.0-mm ultrathin bronchoscope (UTB) with a 1.7-mm working channel provides better accessibility to peripheral bronchi. A 4.0-mm thin bronchoscope with a larger 2.0-mm working channel facilitates the use of a guide sheath (GS), ensuring repeated sampling from the same location. The 1.1-mm ultrathin cryoprobe has a smaller diameter, overcoming the limitation of the size of biopsy instruments used with UTB. In this study, we compared the endobronchial ultrasound localization rate and diagnostic yield of peripheral lung lesions by cryobiopsy using UTB and thin bronchoscopy combined with GS. Methods We retrospectively evaluated 133 patients with peripheral pulmonary lesions with a diameter less than 30 mm who underwent bronchoscopy with either thin bronchoscope or UTB from May 2019 to May 2023. A 3.0-mm UTB combined with rEBUS was used in the UTB group, whereas a 4.0-mm thin bronchoscope combined with rEBUS and GS was used for the thin bronchoscope group. A 1.1-mm ultrathin cryoprobe was used for cryobiopsy in the two groups. Results Among the 133 patients, peripheral pulmonary nodules in 85 subjects were visualized using r-EBUS. The ultrasound localization rate was significantly higher in the UTB group than in the thin bronchoscope group (96.0% vs. 44.6%, respectively; P

Abstract Background Patients with mucopolysaccharidosis (MPS) often face delayed diagnoses, limited treatment options and high healthcare costs, that may significantly affect patients' quality of life. The objective of this study was to understand medical service utilization related to diagnosis and treatment, economic burden during diagnosis period, and health-related quality of life among MPS patients in China. Methods A series of patients diagnosed with MPS registered in the national patient organization were recruited for a cross-sectional survey from May to July 2019. Information were collected from patients or their parents via phone interview, including demographic data, utilization of services related to diagnosis and treatment, total cost during the period of MPS diagnosis and health-related quality of life (HRQoL). HRQoL was assessed by PedsQL 4.0 Generic Core Scale (PedsQL) and 36-item short-form health survey (SF-36) depending on the age of patients with MPS and compared with the general Chinese population. Results A total of 180 MPS patients (50, 67, 15, 46, 1 and 1 for type I, II, III, IV, VI and VII), with a mean age of 9.54 years and 137 (76.11%) males, were included in analysis. The mean age at first visit to a medical doctor for MPS related symptoms was 3.65 ± 2.58 years old, while only 12 patients (6.67%) were diagnosed on their first visit. The mean diagnostic delay, which is defined as the time between the first visit to a medical doctor for MPS related symptoms and the final diagnosis, was 9.42 months, with no significant difference between types. The average number of misdiagnosis was 4.56. Before the confirmed diagnosis, the patients made an average of 6.31 visits and visited 4.3 hospitals. During diagnosis period, the mean of ¥81,086.72 direct medical costs accounted for 63.75% of the total cost. Only 32.78% of the patients had ever received specific treatments. The mean scores of PedsQL and SF-36 of patients were significantly lower than the Chinese norms. Household annual income per person, specific treatment use and MPS subtype were significantly associated HRQoL of patients. Conclusion The results highlight challenges faced by MPS patients in terms of diagnosis, access to specific treatments, economic burden and low HRQoL. There is an urgent need to improve early detection and diagnosis, create fair and consistent mechanisms to increase access to specialized treatment and reduce the economic burden of MPS patients in China.

Objectives: Mycobacterium abscessus complex (MABC) is the most common rapidly growing Mycobacterium species in structural pulmonary diseases and can be life-threatening. This study aimed to assess the clinical characteristics and drug-susceptibility statuses of different M. abscessus (MAB) subspecies in the Zhejiang Province. Methods: DNA sequencing was used to differentiate clinical MABC subspecies isolates. The Clinical and Laboratory Standards Institute guidelines were used to determine in vitro susceptibility of imipenem-relebactam (IMP-REL), omadacycline, and other conventional antibiotics. Patient clinical characteristics were collected and analysed. Results: In total, 139 M. abscessus, 39 Mycobacterium massiliense, and 1 Mycobacterium bolletii isolates were collected, accounting for 77.7%, 21.8%, and 0.5% of the MABC isolates, respectively. Patients with M. abscessus pulmonary disease (M.ab-PD) had higher proportions of older adults, tuberculosis history, chronic pulmonary disease, and malignancy than those with M. massiliense pulmonary disease (M.ma-PD). Patients with M.ab-PD had higher rates of bilateral middle- and lower-lobe involvement than patients with M.ma-PD. Both subspecies showed high resistance rates to doxycycline and moxifloxacin, and clarithromycin-induced resistance was more common in M.ab than in M.ma. IMP-REL resulted in a twofold reduction in the minimum inhibitory concentration (MIC) value compared with imipenem alone among MAB; furthermore, the MIC was lower in M.ab than in M.ma. Omadacycline and tigecycline had comparable in vitro susceptibility, and the MIC showed no statistically significant difference between M.ab and M.ma. Conclusions: M.ab is the most prevalent MABC subspecies in the Zhejiang Province. Patients with M.ab-PD have complex underlying diseases and broader lobar lesions. IMP-REL and omadacycline are promising antibiotics for MABC infection treatment.

Abstract Abnormalities in ether lipid metabolism as well as the formation of neutrophil extracellular traps have recently been recognized as detrimental factors affecting tumorigenesis and progression. However, the role of abnormal ether lipid metabolism in colorectal cancer (CRC) evolution has not been reported. Here we show that the lipid metabolism-related gene enoyl-CoA δ-isomerase 2 (ECI2) plays a tumor-suppressor role in CRC and is negatively associated with poor prognosis in CRC patients. We mechanistically demonstrate that ECI2 reduces ether lipid-mediated Interleukin 8 (IL-8) expression leading to decreased neutrophil recruitment and neutrophil extracellular traps formation for colorectal cancer suppression. In particular, ECI2 inhibits ether lipid production in CRC cells by inhibiting the peroxisomal localization of alkylglycerone phosphate synthase (AGPS), the rate-limiting enzyme for ether lipid synthesis. These findings not only deepen our understanding of the role of metabolic reprogramming and neutrophil interactions in the progression of CRC, but also provide ideas for identifying potential diagnostic markers and therapeutic targets for CRC.

Background: The obesity paradox in patients with coronary artery disease is well established, but the role of the metabolic syndrome associated with obesity is not well studied. Our study aims to evaluate the in-hospital outcomes of percutaneous coronary intervention (PCI) in metabolically healthy individuals with obesity (MHO) and metabolically unhealthy (MUHO) individuals with obesity over 65 years of age with acute coronary syndrome (ACS) between 2016 and 2020. Methods: This was a retrospective and observational study. Patients were identified through utilizing the National Inpatient Sample (NIS) Database (2016–2020) and ICD-10 codes. By employing a t-test and Pearson's Chi-square test, we assessed and contrasted the initial attributes, concurrent conditions, and results pertaining to all-cause mortality (ACM), cardiogenic shock (CS), length of stay (LOS), and hospitalization expense. Moreover, propensity score matching was conducted in a 1:1 ratio with respect to age, gender, and race. We also utilized multivariable logistic regression to compare MHO and MUHO in terms of the impact on all-cause mortality. Results: Out of a total of 135,395 patients identified, 2995 patients with MUHO were matched with 2995 MHO patients. Patients in the MUHO group had a higher prevalence of chronic pulmonary disease (24.9 % vs. 19.5 %), peripheral vascular disease (9.3 % vs. 6.7 %), hypothyroidism (16 % vs. 11.5 %), prior myocardial infarction (15.9 % vs. 6.2 %), and prior stroke (7.5 % vs. 2.8 %). Patients in the MHO group had a higher ACM (12.4 % vs. 2.8 %, p

BackgroundAlthough the emerging NGS-based assays, metagenomic next-generation sequencing (mNGS) and targeted next-generation sequencing (tNGS), have been extensively utilized for the identification of pathogens in pulmonary infections, there have been limited studies systematically evaluating differences in the efficacy of mNGS and multiplex PCR-based tNGS in bronchoalveolar lavage fluid (BALF) specimens.MethodsIn this study, 85 suspected infectious BALF specimens were collected. Parallel mNGS and tNGS workflows to each sample were performed; then, we comparatively compared their consistency in detecting pathogens. The differential results for clinically key pathogens were confirmed using PCR.ResultsThe microbial detection rates of BALF specimens by the mNGS and tNGS workflows were 95.18% (79/83) and 92.77% (77/83), respectively, with no significant difference. mNGS identified 55 different microorganisms, whereas tNGS detected 49 pathogens. The comparative analysis of mNGS and tNGS revealed that 86.75% (72/83) of the specimens were complete or partial concordance. Particularly, mNGS and tNGS differed significantly in detection rates for some of the human herpesviruses only, including Human gammaherpesvirus 4 (P

Abstract In this paper, we prove that for certain class of initial data, the corresponding solutions to the 3-D viscous primitive equations blow up in finite time. Specifically, we find a special solution to simplify the 3-D systems, assuming that the pressure function p ( x , y , t ) $p(x,y,t)$ is a concave function. We also consider the equations on the line x = 0 $x=0$ , y = 0 $y=0$ .

Abstract Background Multiple myeloma (MM) is the second most common refractory hematologic cancer. Searching for new targets and prognostic markers for MM is significant. Methods GSE39754, GSE6477 and GSE24080 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in MM versus healthy people from GSE39754 and GSE6477 were screened using limma package, and MM-related module genes were chosen with the use of Weighted gene co-expression network analysis (WGCNA), and the two were intersected using ggVennDiagram for obtaining MM-related DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out. Then, protein–protein interactions (PPI) analysis in String database was used to obtain hub genes, while prognosis was analyzed by survival package in GSE24080. Receiver operating characteristic (ROC) curve was adopted for evaluating diagnostic value of hub genes. Besides, univariable/multivariable Cox regression were employed to screen independent prognostic biomarkers. Gene set enrichment analysis (GSEA) was used to find possible mechanism. Finally, western-blotting and reverse transcription-polymerase chain reaction (RT-PCR) verify TYROBP expression within MM and healthy people. We performed cell adhesion and transwell assays for investigating TYROBP function in MM cell adhesion and migration. Results Through differential analyses, 92 MM-related DEGs were obtained. 10 hub genes were identified by PPI and CytoHubba. Their diagnostic and prognostic significance was analyzed. Down-regulation of genes like TYROBP, ELANE, MNDA, and MPO related to dismal MM prognosis. Upon univariable/multivariable Cox regression, TYROBP independently predicted MM prognosis. GSEA pathway was enriched, indicating that TYROBP expression affected MM development via cell adhesion molecular pathway. Upon Western-blotting and RT-PCR assays, TYROBP expression among MM patients decreased relative to healthy donors. Cell adhesion and transwell migration assays revealed increased MM cell adhesion and decreased migration upon TYROBP up-regulation. Conclusion In summary, TYROBP is a potential prognostic marker for MM.

AbstractBackground The effect of microwave ablation (MWA) for the renal cell carcinoma (RCC) in Von Hippel-Lindau (VHL) disease is unclear.Objective To assess the safety, Technique efficacy, renal function and oncological outcome of MWA for RCC in VHL patients.Methods Consecutive patients with RCCs in VHL disease treated by MWA were retrospectively collected from November 2009 to October 2020. The technical efficacy rate and complications were assessed. The outcomes of pre- and post-ablative eGFR were compared. The local recurrent-free survival (LRFS), renal-cancer-free survival (RCFS), cancer-specific survival (CSS), overall survival (OS) and complications were presented.Results A total of 10 patients (mean age, 39.0 years ± 10.7 [SD]; 3 women) with 28 RCCs (mean tumor size, 3.0 cm ± 0.34; mean tumor volume, 20.7 mL ± 43.3) treated with MWA were included. Th median follow-up time was 52 months(IQR:27-80). The overall technical efficacy rate was 100% with no major complications occurred. No significant statistical difference between pre-ablative and postablative creatinine level (102.0 µmol/L ± 30.4 vs 112.3 µmol/L ± 38.7, p = 0.06), but the pre-ablative eGFR level was significantly higher than the post-ablative eGFR (78.0 mL/(min*1.73m2) ± 28.6 vs 72 mL/(min*1.73m2) ± 31.4, p = 0.04), with the mean decrease of 5.86 ml/(min*1.73m2). The local recurrent-free survival(LRFS) and renal-cancer-free survival (RCFS) were 100% and 60%, respectively. The cancer specifical survival (CSS) and overall survival (OS) were 95.5% and 100%, respectively.Conclusion Microwave ablation is a safe and feasible method for the treatment of RCC in VHL disease, preserving renal function and yielding satisfactory oncological outcomes.

BackgroundTumor microenvironment (TME) represents the key factor inducing leukemia development. As stromal cells within the leukemia microenvironment, Bone Marrow Mesenchymal Stem Cells (BM-MSCs) can trigger leukemia progression under certain conditions. As a critical transcription factor, nuclear factor erythroid related factor 2 (Nrf2) can modulate antioxidant response and antioxidant enzyme gene expression, and prevent various oxidative changes. We previously identified a novel mechanism by which Nrf2 promotes leukemia resistance, providing a potential therapeutic target for the treatment of drug-resistant/refractory leukemias. However, the role of Nrf2 in BM-MSCs from B-cell acute lymphoblastic leukemia (B-ALL) patients has not been clearly reported. The present work focused on investigating the effect of Nrf2 overexpression within MSCs on leukemia cell invasion, extramedullary infiltration and proliferation as well as its downstream pathway.MethodsThrough clinical sample detection, in vitro cell experiments and in vivo animal experiments, the role of Nrf2 within MSCs within adult B-ALL cell migration and invasion and its potential molecular mechanism was explored through transcriptome sequencing analysis, RT-PCR, Western blot, cell migration, cell invasion, lentivirus transfection and other experiments.ResultsNrf2 was highly expressed in BM-MSCs from patients with B-ALL as well as in BM-MSCs co-cultured with leukemia cells. Overexpression of Nrf2 within MSCs significantly promoted leukemia cell migration, invasion and proliferation. The extramedullary organ infiltration rate in B-ALL model mice receiving the combined infusion of both cell types dramatically increased relative to that of leukemia cells alone, accompanied by the significantly shortened survival time. Mechanism study found that Nrf2 overexpression within MSCs promoted PI3K-AKT/ERK1/2 phosphorylation in the downstream pathway by activating SDF-1/CXCR4 axis, ultimately leading to extramedullary infiltration of leukemia cells.ConclusionHigh Nrf2 expression with in MSCs enhances leukemia cell invasion and migration, which then accelerates infiltration in leukemic extramedullary organs. Targeting Nrf2 or inhibiting its downstream signal molecules may be the effective interventions for B-ALL patients treatment.

BackgroundBile acids (BAs), products of gut microbiota metabolism, have long been implicated in atherosclerotic disease pathogenesis. Characterizing the serum bile acid profile and exploring its potential role in carotid atherosclerosis (CAS) development are crucial tasks.MethodsIn this study, we recruited 73 patients with CAS as the disease group and 77 healthy individuals as the control group. We systematically measured the serum concentrations of 15 bile acids using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression were applied to analyze the impact of bile acids on the disease and select the key BAs. The possible molecular mechanism was elucidated by network pharmacology.Results(1) The BA profile of patients with CAS significantly differed. (2) Multifactorial logistic regression analysis identified elevated levels of GCDCA (OR: 1.01, P < 0.001), DCA (OR: 1.01, P = 0.005), and TDCA (OR: 1.05, P = 0.002) as independent risk factors for CAS development. Conversely, GCA (OR: 0.99, P = 0.020), LCA (OR: 0.83, P = 0.002), and GUDCA (OR: 0.99, P = 0.003) were associated with protective effects against the disease. GCA, DCA, LCA, and TDCA were identified as the four key BAs. (3) TNF, FXR, GPBAR1, ESR1 and ACE were predicted to be targets of BAs against AS. These four BAs potentially impact AS progression by triggering signaling pathways, including cAMP, PPAR, and PI3K-AKT pathways, via their targets.ConclusionThis study offers valuable insights into potential therapeutic strategies for atherosclerosis that target bile acids.

Miura origami's reconfigurable characteristic and structural asymmetry, combined with electromagnetic (EM) wave manipulation, crashed a unique spark. However, the complexity of the three‐dimensional (3D) origami structure after folding makes it challenging to study the phase regulation mechanism. Here, we propose a reconfigurable phase gradient metasurface based on Miura origami and derive the underlying mechanism of phase modulation in detail under linearly and circularly polarized (LP and CP) incidence. We adopt the one‐dimensional (1D) gradient design along the x direction to verify the idea. The phase calculation formulas are given under LP and CP incidence through the Jones matrix's derivation. The beam deflector angles corresponding to LP and CP waves are identical in the planar state. As the folding angle increases, the phase evolution rules corresponding to the LP and CP waves are discrepant, leading to differential beam steering. Finally, the origami sample is processed for verification, and the experimental data are consistent with the simulation and theoretically calculated values. We believe this work can help analyze the EM behavior of complex 3D origami structures and lay a foundation for designing a multifunctional EM origami metasurface.

ABSTRACT Background The aim was to identify the nutritional indexes, construct a prognostic model, and develop a nomogram for predicting individual survival probability in pan‐cancers. Methods Nutritional indicators, clinicopathological characteristics, and previous major treatment details of the patients were collected. The enrolled patients were randomly divided into training and validation cohorts. Least absolute shrinkage and selection operator (Lasso) regression cross‐validation was used to determine the variables to include in the cox regression model. The training cohort was used to build the prediction model, and the validation cohort was used to further verify the discrimination, calibration, and clinical effectiveness of the model. Results A total of 2020 patients were included. The median OS was 56.50 months (95% CI, 50.36–62.65 months). In the training cohort of 1425 patients, through Lasso regression cross‐validation, 13 characteristics were included in the model. Cox proportional hazards model was developed and visualized as a nomogram. The C‐indexes of the model for predicting 1‐, 3‐, 5‐, and 10‐year OS were 0.848, 0.826, 0.814, and 0.799 in the training cohort and 0.851, 0.819, 0.814, and 0.801 in the validation cohort. The model showed great calibration in the two cohorts. Patients with a score of less than 274.29 had a better prognosis (training cohort: HR, 6.932; 95% CI, 5.723–8.397; log‐rank p

IntroductionCaregivers of children with autism spectrum disorder (ASD) in China often experience alienation due to societal stigma. While this alienation detrimentally impacts their mental well-being, family resilience serves as a protective factor. Previous research has predominantly examined the social support derived from social activities but has neglected to delve into the specific patterns of these activities. The primary objective of this study was twofold: firstly, to gain insights into the various social activities engaged in by caregivers of children with autism in China, and secondly, to ascertain the influence of these social activities on alienation and family resilience.MethodsBetween June and August 2023, a cross-sectional survey was carried out across multiple cities in Jilin Province, aiming to gather data from a total of 205 Chinese caregivers of children with autism. Data collection was conducted through the utilization of a structured questionnaire. The assessment of social activity involved the completion of 12 questionnaires, while alienation was evaluated using the Generalized Alienation Scale (GSAS), and family resilience was gauged through the Chinese version of the Family Resilience Scale (FaRE). The classification of social activities was conducted through latent class analysis (LCA), while the impact of these social activities on alienation and family resilience was examined using linear regression analysis.ResultsThe findings revealed that social activities can be categorized into five types (Low, Self-Recreation, Communication, Web Surfing, High). Communication social activities were found to reduce family resilience(β=.332, p

The remaining useful life (RUL) of complex equipment is an important criterion to ensure stable operation. In recent years, deep learning-based methods for predicting the RUL of complex equipment have attracted wide attention. However, it is only able to obtain the potential information in the Euclidean space, which hinders their ability to capture the deeply degradation information. Thus, graph neural networks have gradually entered the researchers’ field of vision. Despite the fact that graph neural networks are able to accomplish the task of RUL for complex equipment, there are still limitations that restrict the prediction performance in practical engineering. To address this challenge, an improved adaptive war strategy optimization algorithm assisted-adaptive multi-head graph attention mechanism network (IWSO-LMGAT) is proposed. For one thing, a learnable attention mechanism is proposed to adjust the weights of different heads dynamical and improve the limitation of GAT in obtaining deep degradation information. In addition, since hyperparameters are essential elements affecting the predicted result, inspired by the “no-free lunch” principle, an improved mathematical expression is described to avoid the issue such as precocity, fall into local optimums for WSO so that the optimal hyperparameters of the LMGAT could be obtained. The effectiveness and advancement of IWSO-LMGAT are validated on the CMAPSS dataset, and experimental results show that the proposed method could provide competitive forecasted results compared to traditional methods, that is, R2 = 0.9939, RMSE = 4.3638, and MAPE = 0.0137; this illustrates the IWSO-LMGAT’s potential for the RUL prediction of complex equipment.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease characterized by irreversible scarring of the lung parenchyma. Despite various interventions aimed at mitigating several different molecular aspects of the disease, only two drugs with limited clinical efficacy have so far been approved for IPF therapy. Objective We investigated the therapeutic efficacy of amifostine, a detoxifying drug clinically used for radiation-caused cytotoxicity, in bleomycin-induced murine pulmonary fibrosis. Methods C57BL6/J mice were intratracheally instilled with 3 U/kg of bleomycin. Three doses of amifostine (WR-2721, 200 mg/kg) were administered intraperitoneally on days 1, 3, and 5 after the bleomycin challenge. Bronchoalveolar lavage fluid (BALF) was collected on day 7 and day 21 for the assessment of lung inflammation, metabolites, and fibrotic injury. Human fibroblasts were treated in vitro with transforming growth factor beta 1 (TGF-β1), followed by amifostine (WR-1065, 1–4 µg/mL) treatment. The effects of TGF-β1 and amifostine on the mitochondrial production of reactive oxygen species (ROS) were assessed by live cell imaging of MitoSOX. Cellular metabolism was assessed by the extracellular acidification rate (ECAR), the oxygen consumption rate (OCR), and the concentrations of various energy-related metabolites as measured by mass spectrum (MS). Western blot analysis was performed to investigate the effect of amifostine on sirtuin 1 (SIRT1) and adenosine monophosphate activated kinase (AMPK). Results Three doses of amifostine significantly attenuated lung inflammation and pulmonary fibrosis. Pretreatment and post-treatment of human fibroblast cells with amifostine blocked TGF-β1-induced mitochondrial ROS production and mitochondrial dysfunction in human fibroblast cells. Further, treatment of fibroblasts with TGF-β1 shifted energy metabolism away from mitochondrial oxidative phosphorylation (OXPHOS) and towards glycolysis, as observed by an altered metabolite profile including a decreased ratio of NAD + /NADH and increased lactate concentration. Treatment with amifostine significantly restored energy metabolism and activated SIRT1, which in turn activated AMPK. The activation of AMPK was required to mediate the effects of amifostine on mitochondrial homeostasis and pulmonary fibrosis. This study provides evidence that repurposing of the clinically used drug amifostine may have therapeutic applications for IPF treatment. Conclusion Amifostine inhibits bleomycin-induced pulmonary fibrosis by restoring mitochondrial function and cellular metabolism.

Abstract Objective The purpose of this study is to reduce the spread of the vanA gene by curing the vanA-harboring plasmid of vancomycin-resistant using the CRISPR-Cas9 system. Methods Two specific spacer sequence (sgRNAs) specific was designed to target the vanA gene and cloned into plasmid CRISPR-Cas9. The role of the CRISPR-Cas system in the plasmid elimination of drug-resistance genes was verified by chemically transformation and conjugation delivery methods. Moreover, the elimination efficiency in strains was evaluated by plate counting, PCR, and quantitative real-time PCR (qPCR). Susceptibility testing was performed by broth microdilution assay and by Etest strips (bioMérieux, France) to detect changes in bacterial drug resistance phenotype after drug resistance plasmid clearance. Results In the study, we constructed a specific prokaryotic CRISPR-Cas9 system plasmid targeting cleavage of the vanA gene. PCR and qPCR results indicated that recombinant pCas9-sgRNA plasmid can efficiently clear vanA-harboring plasmids. There was no significant correlation between sgRNA lengths and curing efficiency. In addition, the drug susceptibility test results showed that the bacterial resistance to vancomycin was significantly reduced after the vanA-containing drug-resistant plasmid was specifically cleaved by the CRISPR-Cas system. The CRISPR-Cas9 system can block the horizontal transfer of the conjugated plasmid pUC19-vanA. Conclusion In conclusion, our study demonstrated that CRISPR-Cas9 achieved plasmid clearance and reduced antimicrobial resistance. The CRISPR-Cas9 system could block the horizontal transfer of plasmid carrying vanA. This strategy provided a great potential to counteract the ever-worsening spread of the vanA gene among bacterial pathogens and laid the foundation for subsequent research using the CRISPR-Cas9 system as adjuvant antibiotic therapy.

Abstract Radar target detection with fewer echo pulses in non-Gaussian clutter background is a challenging problem. In this instance, the conventional detectors using coherent accumulation are not very satisfactory. In contrast, the matrix detector based on Riemannian manifolds has shown potential on this issue since the covariance matrix of radar echo data during one coherent processing interval(CPI) has a smooth manifold structure. The Affine Invariant (AI) Riemannian distance between the cell under test (CUT) and the reference cells has been used as a statistic to achieve improved detection performance. This paper uses the Bures–Wasserstein (BW) distance and Generalized Bures–Wasserstein (GBW) distance on Riemannian manifolds as test statistics of matrix detectors, and propose relevant target detection method. Maximizing the GBW distance is formulated as an optimization problem and is solved by the Riemannian trust-region (RTR) method to achieve enhanced discrimination for target detection. Our evaluation of simulated data and measured data show that the matrix detector based on GBW distance leads to a significant performance gain over existing methods.

Introduction: Osteoporosis is the most common bone disorder where the hyperactive osteoclasts represent the leading role during the pathogenesis. Targeting hyperactive osteoclasts is currently the primary therapeutic strategy. However, concerns about the long-term efficacy and side effects of current frontline treatments persist. Alternative therapeutic agents are still needed. Objectives: Obacunone (OB) is a small molecule with a broad spectrum of biological activities, particularly antioxidant and anti-inflammatory effects. This study aims to examine OB’s therapeutic potential on osteoporosis and explore the rudimentary mechanisms. Methods: Osteoclast formation and osteoclastic resorption assays were carried out to examine OB’s inhibitory effects in vitro, followed by the in-vivo studies of OB’s therapeutic effects on ovariectomy-induced osteoporotic preclinical model. To further study the underlying mechanisms, mRNA sequencing and analysis were used to investigate the changes of downstream pathways. The molecular targets of OB were predicted, and in-silico docking analysis was performed. Ligand-target binding was verified by surface plasmon resonance (SPR) assay and Western Blotting assay. Results: The results indicated that OB suppressed the formation of osteoclast and its resorptive function in vitro. Mechanistically, OB interacts with macrophage migration inhibitory factor (MIF) which attenuates receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL)-induced signaling pathways, including reactive oxygen species (ROS), NF-κB pathway, and mitogen-activated protein kinases (MAPKs). These effects eventually caused the diminished expression level of the master transcriptional factor of osteoclastogenesis, nuclear factor of activated T cells 1 (NFATc1), and its downstream osteoclast-specific proteins. Furthermore, our data revealed that OB alleviated estrogen deficiency-induced osteoporosis by targeting MIF and thus inhibiting hyperactive osteoclasts in vivo. Conclusion: These results together implicated that OB may represent as a therapeutic candidate for bone disorders caused by osteoclasts, such as osteoporosis.

Abstract Mounting evidence indicate that cuproptosis, a novel form of programmed cell death, contributes to cancer development and progression. However, a comprehensive analysis regarding the expressions, functions, and regulatory network of cuproptosis-related genes is still lacking. In the present work, cuproptosis-related genes, upstream miRNAs and lncRNAs, and clinical data of breast cancer from TCGA database were analyzed by R language including Cox regression analysis, correlation calculation, ROC curve construction, and survival evaluation, and were further verified by public-available databases. Chemosensitivity and immune infiltration were also evaluated by online tools. SLC31A1 was significantly increased in breast cancer samples than those in normal tissues. SLC31A1 was negatively related to a favorable outcome in breast cancer, and the AUC value increased with the prolongation of follow-up time. LINC01614 and miR-204-5p were potential upstream regulators of SLC31A1. Moreover, SLC31A1 was significantly positively correlated with different immune cells infiltration, immune cell biomarkers, and immune checkpoints in breast cancer. SLC31A1 was a potential cuproptosis-related gene in breast cancer, which was significantly upregulated and was able to predict diagnosis, prognosis, chemosensitivity, and immune infiltration. LINC01640/miR-204-5p/SLC31A1 might be a significant and promising axis during cuproptosis in breast cancer.

Heavy metal contamination has been regarded as an environmental variable that affects the efficiency of pest biological control, but the parasitic fitness of parasitoids under heavy metal stress is poorly understood. Herein, the effect of Cd exposure through the host pupa of Hyphantria cunea on the parasitic fitness of Chouioia cunea was investigated, and the mechanism by which Cd exposure affects the interaction between H. cunea and C. cunea from the perspective of innate immunity in host insect and the oxidative status in the parasitoid offspring was explored. Our results indicated that Cd can be transferred from the H. cunea pupae to the parasitoid offspring, and the transfer coefficient reflected biological amplification. There were no significant differences in the rates of parasitism success and offspring emergence between the untreated and Cd-treated groups. However, after parasitizing Cd-accumulated pupae, the parasitic fitness of offspring wasps (e.g., the number, individual size and life span) decreased significantly. Under Cd exposure, the cellular and humoral immunity of H. cunea pupae decreased significantly. Compared with the untreated group, the H2O2 content of parasitoid offspring in the Cd-treated group was significantly increased. Cd exposure significantly inhibited superoxide dismutase activity in parasitoid offspring, but the contents of ascorbic acid and glutathione were significantly increased by Cd stress. Taken together, these results indicate that Cd exposure reduces the cyclic utilization efficiency of C. cunea on H. cunea pupae. The oxidative status of parasitoid offspring triggered by Cd exposure could be responsible for the reduced parasitic fitness of C. cunea on Cd-accumulated H. cunea pupae.

Abstract The WUSCHEL-related homeobox (WOX) family members are plant-specific transcriptional factors, which function in meristem maintenance, embryogenesis, lateral organ development, as well as abiotic stress tolerance. In this study, 14 MsWOX transcription factors were identified and comprehensively analyzed in the cultivated alfalfa cv. Zhongmu No.1. Overall, 14 putative MsWOX members containing conserved structural regions were clustered into three clades according to phylogenetic analysis. Specific expression patterns of MsWOXs in different tissues at different levels indicated that the MsWOX genes play various roles in alfalfa. MsWUS, MsWOX3, MsWOX9, and MsWOX13-1 from the three subclades were localized in the nucleus, among which, MsWUS and MsWOX13-1 exhibited strong self-activations in yeast. In addition, various cis-acting elements related to hormone responses, plant growth, and stress responses were identified in the 3.0 kb promoter regions of MsWOXs. Expression detection of separated shoots and roots under hormones including auxin, cytokinin, GA, and ABA, as well as drought and cold stresses, showed that MsWOX genes respond to different hormones and abiotic stress treatments. Furthermore, transcript abundance of MsWOX3, and MsWOX13-2 were significantly increased after rhizobia inoculation. This study presented comprehensive data on MsWOX transcription factors and provided valuable insights into further studies of their roles in developmental processes and abiotic stress responses in alfalfa.

ABSTRACT: Objectives: Faropenem has antituberculosis activity in vitro but its utility in treating patients with tuberculosis (TB) is unclear. Methods: We conducted an open-label, randomized trial in China, involving newly diagnosed, drug-susceptible pulmonary TB. The control group was treated with the standard 6-month regimen. The experimental group replaced ethambutol with faropenem for 2 months. The primary outcome was the treatment success rate after 6 months of treatment. Noninferiority was confirmed if the lower limit of a 95% one-sided confidence interval (CI) of the difference was greater than −10%. Results: A total of 227 patients eligible for the study were enrolled in the trial group and the control group in a ratio of 1:1. Baseline characteristics of participants were similar in both groups. In the modified intention-to-treat population, 88.18% of patients in the faropenem group achieved treatment success, and 85.98% of those in the control group were successfully treated, with a difference of 2.2% (95% CI, −6.73-11.13). In the per-protocol population, treatment success was 96.04% in the faropenem group and 95.83% in the control group, with a difference of 2.1% (95% CI, −5.31-5.72). The faropenem group showed noninferiority to the control group in the 6-month treatment success rates. The faropenem group had significantly fewer adverse events (P

We aimed to determine the molecular characteristics of carbapenem-resistant Pseudomonas aeruginosa strains 18081308 and 18083286, which were isolated from the urine and the sputum of two Chinese patients, respectively. Additionally, we conducted a comparative analysis between Tn6411 carrying blaIMP-1 in strain 18083286 and transposons from the same family available in GenBank. Bacterial genome sequencing was carried out on strains 18081308 and 18083286 to obtain their whole genome sequence. Average nucleotide identity (ANI) was used for their precise species identification. Serotyping and multilocus sequence typing were performed. Furthermore, the acquired drug resistance genes of these strains were identified. The carbapenem-resistant P. aeruginosa strains isolated in the present study were of sequence type ST865 and serotype O6. They all carried the same resistance genes (aacC2, tmrB, and blaIMP-1). Tn6411, a Tn7-like transposon carrying blaIMP-1, was found in strain 18083286 by single molecule real time (SMRT) sequencing. We also identified the presence of this transposon sequence in other chromosomes of P. aeruginosa and plasmids carried by Acinetobacter spp. in GenBank, indicating the necessity for heightening attention to the potential transferability of this transposon.

In this paper, we present a two-step Newton-based matrix-splitting iteration method for solving the generalize absolute value equation. This method can produce a number of two-step Newton-based relaxation iteration algorithms with the right matrix-splitting options. In particular, some specific sufficient conditions are presented, when A is an H+-matrix. Finally, numerical results indicate that the two-step Newton-based relaxation iteration techniques are effective for solving the generalized absolute value equation.

Abstract Background Inflammatory bone resorption is a prominent risk factor for implantation failure. Simvastatin (SIM) has anti‐inflammatory effects independent of cholesterol lowering and reduces osteoclastogenesis by decreasing both the number and activity of osteoclasts. However, the specific mechanism of inflammatory bone loss alleviation by SIM remains to be elucidated. We hypothesized that SIM relieves inflammatory bone loss by modulating autophagy and suppressing the NOD‐like receptor family pyrin domain‐containing protein 3 (NLRP3) signaling pathway. Methods and results RAW264.7 cells were stimulated by lipopolysaccharide (LPS) after being pretreated with various concentrations of SIM. Osteoclast (OC) differentiation, formation and activity were evaluated by tartrate‐resistant acid phosphatase staining, F‐actin ring staining and bone resorption pit assays, respectively. We observed autophagosomes by transmission electron microscopy. Then NLRP3 inhibitor MCC950 was used to further explore the corresponding molecular mechanism underlying anti‑inflammatory bone resorption, the expression of autophagy‐related proteins and NLRP3 signaling pathway factors in pre‐OCs were evaluated by western blot analysis, and the expression of OC‑specific molecules was analyzed using reverse transcription‑quantitative polymerase chain reaction. The results showed that SIM decreased the expression of tumor necrosis factor‐α, whereas increased Interleukin‐10. In addition, SIM inhibited LPS‐induced OC differentiation, formation, bone resorption activity, the level of autophagosomes, and OC‑specific markers. Furthermore, SIM significantly suppressed autophagy by downregulating LC3II, Beclin1, ATG7, and NLRP3‐related proteins expression while upregulating P62 under inflammatory conditions. Conclusions SIM may reduce autophagy secretion to attenuate LPS‐induced osteoclastogenesis and the NLRP3 signaling pathway participates in this process, thus providing theoretical basis for the application of this drug in peri‐implantitis.

To investigate the impact of the ethanoic fractions of Periploca forrestii Schltr. (P. forrestii) in ameliorating the liver injury caused by fluoride ingestion and to explore the potential mechanisms. Initially, an in vitro fluorosis cell model was constructed using the human normal liver cell line (L-02) induced by fluoride. Cell viability was assessed using the CCK-8 assay kit. The lactate dehydrogenase (LDH) assay kit was utilized to measure LDH content in the cell supernatant, while the malonic dialdehyde (MDA) assay kit was employed to determine MDA levels within the cells. Subsequently, a fluorosis rat model was established, and LDH content in the cell supernatant was measured using the LDH assay kit. Various parameters, including MDA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and reactive oxygen species (ROS) content within the cells, were detected using appropriate assay kits. Additionally, cell apoptosis rate was determined using the Annexin V-FITC/PI cell apoptosis assay kit. The protein expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Cleaved Caspase-3, Caspase-9, and Cleaved Caspase-9 were analyzed through Western blotting. Compared to the model group, the ethanolic fraction D of P.forrestii (Fr.D) increased cell viability (P

BackgroundThe eHealth Literacy Scale (eHEALS) was introduced in China in 2013 as one of the most important electronic health literacy measurement instruments. After a decade of development in China, it has received widespread attention, although its theoretical underpinnings have been challenged, thus demanding more robust research evidence of factorial validity and multigroup measurement properties. ObjectiveThis study aimed to evaluate the Chinese version of the eHEALS in terms of its measurement properties. MethodsA cross-sectional survey was conducted in a university setting in China. Item statistics were checked for response distributions and floor and ceiling effects. Internal consistency reliability was confirmed with Cronbach α, split-half reliability, Cronbach α if an item was deleted, and item-total correlation. A total of 5 representative eHEALS factor structures were examined and contrasted using confirmatory factor analysis. The study used the item-level content validity index (I-CVI) and the average of the I-CVI scores of all items on the scale to assess the content validity of the dominance model. Furthermore, the validated dominance model was subsequently used to evaluate the relevance and representation of elements in the instrument and to assess measurement invariance across genders. ResultsA total of 972 respondents were identified, with a Cronbach α of .92, split-half reliability of 0.88, and item-total score correlation coefficients ranging from 0.715 to 0.781. Cronbach α if an item was deleted showed that all items should be retained. Acceptable content validity was supported by I-CVIs ≥0.80. The confirmatory factor analysis confirmed that the 3-factor model was acceptable. The measurement model met all relevant fit indices: average variance extracted from 0.663 to 0.680, composite reliability from 0.810 to 0.857, chi-square divided by the df of 4.768, root mean square error of approximation of 0.062, standardized root mean squared residual of 0.020, comparative fit index (CFI) of 0.987, and Tucker-Lewis index of 0.979. In addition, the scale demonstrated error variance invariance (Δnormed fit index=−0.016, Δincremental fit index=−0.012, ΔTucker-Lewis index=0.005, Δcomparative fit index=−0.012, Δrelative fit index=0.005, and Δroot mean square error of approximation=0.005). ConclusionsA 3-factor model of the Chinese version of the eHEALS fits best, and our findings provide evidence for the strict measurement invariance of the instrument regarding gender.

Fresh leaves of Echa 1 were fixed by roller, steam/hot air and light-wave, and the effects of the three fixation methods on the chemical characteristics of straight-shaped green teas (GTs) were studied by widely targeted metabolomic analysis. 1001 non-volatile substances was identified, from which 97 differential metabolites were selected by the criteria of variable importance in projection (VIP) > 1, p 1. Correlation analysis indicated that 14 taste-active metabolites were the major contributors to the taste differences between differently processed GTs. High-temperature fixation induces protein oxidation or degradation, γ-glutamyl peptide transpeptidation, degradation of flavonoid glycosides and epimerization of cis-catechins, resulting in the accumulation of amino acids, peptides, flavonoids and trans-catechins, which have flavor characteristics such as umami, sweetness, kokumi, bitterness and astringency, thereby affecting the overall taste of GTs. These findings provided a scientific basis for the directional processing technology of high-quality green tea.

BackgroundWohlfahrtiimonas chitiniclastica is an emerging fly-borne zoonotic pathogen, which causes infections in immunocompromised patients and some animals. Herein, we reported a W. chitiniclastica BM-Y from a dead zebra in China.MethodsThe complete genome sequencing of BM-Y showed that this isolate carried one chromosome and one novel type of blaVEB–1-carrying plasmid. Detailed genetic dissection was applied to this plasmid to display the genetic environment of blaVEB–1.ResultsThree novel insertion sequence (IS) elements, namely ISWoch1, ISWoch2, and ISWoch3, were found in this plasmid. aadB, aacA1, and gcuG were located downstream of blaVEB–1, composing a gene cassette array blaVEB–1–aadB–aacA1–gcuG bracketed by an intact ISWoch1 and a truncated one, which was named the blaVEB–1 region. The 5′-RACE experiments revealed that the transcription start site of the blaVEB–1 region was located in the intact ISWoch1 and this IS provided a strong promoter for the blaVEB–1 region.ConclusionThe spread of the blaVEB–1-carrying plasmid might enhance the ability of W. chitiniclastica to survive under drug selection pressure and aggravate the difficulty in treating infections caused by blaVEB–1-carrying W. chitiniclastica. To the best of our knowledge, this is the first report of the genetic characterization of a novel blaVEB–1-carrying plasmid with new ISs from W. chitiniclastica.

As one of the five major engineering plastics, polyamide brings many benefits to humans in the fields of transportation, clothing, entertainment, health, and more. However, as the production of polyamide increases year by year, the pollution problems it causes are becoming increasingly severe. This article reviews the current recycling and treatment processes of polyamide, such as chemical, mechanical, and energy recovery, and degradation methods such as thermal oxidation, photooxidation, enzyme degradation, etc. Starting from the synthesis mechanism of polyamide, it discusses the advantages and disadvantages of different treatment methods of polyamide to obtain more environmentally friendly and economical treatment schemes. Finding enzymes that can degrade high-molecular-weight polyamides, exploring the recovery of polyamides under mild conditions, synthesizing environmentally degradable polyamides through copolymerization or molecular design, and finally preparing degradable bio-based polyamides may be the destination of polyamide.

Hyperglycemia in pregnancy (HIP) is linked to fetoplacental endothelial dysfunction, which might be a result of hyperglycemia. Hyperglycemia is associated with cell senescence; however, the role and mechanism of high glucose and cell senescence in HIP endothelial cell failure are largely unknown. Our study discovered that human umbilical vein endothelial cells (HUVECs) obtained from HIP pregnant women exhibit excessive senescence, with significantly elevated expression of senescence markers senescence-associated beta-galactosidase (SA-β-gal), p16, p21, and p53. Subsequently, we found that exposing primary HUVECs and cell lines to high glucose resulted in an increase in the synthesis of these senescence indicators, similar to what had been observed in pregnant women with HIP. A replicate senescence model and stress-induced premature senescence (SIPS) model showed higher amounts of vascular damage indicators, including von Willebrand factor (vWF), chemotactic C-C motif chemokine ligand 2 (CCL2), intercellular adhesion molecule 1 (ICAM-1), along with the anti-apoptotic protein BCL2. However, lower expressions of the pro-apoptotic component BAX, in addition to defective proliferation and tubulogenesis, were seen. Further studies indicated that hyperglycemia can not only induce these alterations in HUVECs but also exacerbate the aforementioned changes in both aging HUVECs. The experiments outlined above have also been validated in pregnant women with HIP. Collectively, these data suggest that exposure to high glucose accelerates cell senescence-mediated vein endothelial cell dysfunction, including excessive inflammation, cell adhesion, impaired angiogenesis, and cell proliferation possibly contributing to pregnancy complications and adverse pregnancy outcomes.

Introduction:Cynanchum auriculatum (CA) is usually used to treat digestive disorders, such as anorexia, enteritis, dysentery, and indigestion. Functional dyspepsia (FD) is characterized by a group of symptoms associated with the gastroduodenal region. Recent pharmacological studies have demonstrated the efficacy of CA for treating FD. However, the pharmacokinetics (PK) and tissue distribution of CA in physiological and FD states is still unclear. The present study aimed to clarify the differences in PK parameters and tissue distribution of the four major active components of CA (baishouwu benzophenone, deacylmet-aplexigenin, qingyangshengenin, and syringic acid) under both physiological and FD states.Methods: For this, normal and FD rats were orally administered 10 mg/kg CA extract. Then, plasma and tissue (heart, liver, spleen, lung, kidney, brain, stomach, and small intestine) samples were obtained. The four active components of CA in rat plasma and tissues were quantified by developing and validating a fast and reliable ultra–high–performance liquid chromatography–mass spectrometry method.Results: The area under the plasma concentration–time curve from time zero to time t (AUC0-t) of baishouwu benzophenone was significantly lower in the FD group than in the normal group (p < 0.01). The FD group had significantly lower (p < 0.001) apparent volume of distribution and plasma clearance of qing-yangshengenin and significantly higher (p < 0.05) AUC0-t of deacylmetaplexigenin and qingyangshengenin. The four active components were rapidly distributed into various tissues, and the main target organs of CA activity were the stomach and small intestine. In addition, baishouwu benzophenone, deacylmetaplexigenin, and qingyangshengenin could cross the blood-brain barrier, indicating that the brain may be another target organ in the treatment of FD.Discussion: These results indicate that the pathological state of FD alters the PK behavior and tissue distribution characteristics of baishouwu benzophenone, deacylmetaplexigenin, qingyangshengenin, and syringic acid in the CA extract, providing an experimental basis for the role of CA in FD treatment.

IntroductionChina experienced a record surge of coronavirus disease 2019 cases in December 2022, during the pandemic.MethodsWe conducted a randomized, parallel-controlled prospective cohort study to evaluate efficacy and antibody duration after a fourth-dose booster with Ad5-nCoV or inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine.ResultsA total of 191 participants aged ≥18 years who had completed a three-dose regimen of the inactivated SARS-CoV-2 vaccine 6 months earlier were recruited to receive the intramuscular Ad5-nCoV booster or the inactivated SARS-CoV-2 vaccine. The Ad5-nCoV group had significantly higher antibody levels compared with the inactivated vaccine group at 6 months after the fourth vaccination dose. After the pandemic, the breakthrough infection rate for the Ad5-nCoV and the inactivated vaccine groups was 77.89% and 78.13%, respectively. Survival curve analysis (p = 0.872) and multivariable logistic regression analysis (p = 0.956) showed no statistically significant differences in breakthrough infection between the two groups.DiscussionCompared with a homologous fourth dose, a heterologous fourth dose of Ad5-nCoV elicited a higher immunogenic response in healthy adults who had been immunized with three doses of inactivated vaccine. Nevertheless, the efficacy of the two vaccine types was equivalent after the pandemic.

ABSTRACT Vibrio parahaemolyticus is a marine bacterium coming from estuarine environments, where the migratory birds can easily be colonized by V. parahaemolyticus. Migratory birds may be important reservoirs of V. parahaemolyticus by growth and re-entry into the environment. To further explore the spreading mechanism of V. parahaemolyticus among marine life, human beings, and migratory birds, we aimed to investigate the characteristics of the genetic diversity, antimicrobial resistance, virulence genes, and a potentially informative gene marker of V. parahaemolyticus isolated from migratory birds in China. This study recovered 124 (14.55%) V. parahaemolyticus isolates from 852 fecal and environmental (water) samples. All of the 124 strains were classified into 85 known sequence types (STs), of which ST-2738 was most frequently identified. Analysis of the population structure using whole-genome variation of the 124 isolates illustrated that they grouped into 27 different clonal groups (CGs) belonging to the previously defined geographical populations VppX and VppAsia. Even though these genomes have high diversity, an extra copy of tRNA-Gly was presented in all migratory bird-carried V. parahaemolyticus isolates, which could be used as a potentially informative marker of the V. parahaemolyticus strains derived from birds. Antibiotic sensitivity experiments revealed that 47 (37.10%) isolates were resistant to ampicillin. Five isolates harbored the plasmid-mediated quinolone resistance (PMQR) gene qnrD, which has not previously been identified in this species. The investigation of antibiotic resistance provides the basic knowledge to further evaluate the risk of enrichment and reintroduction of pathogenic V. parahaemolyticus strains in migratory birds. IMPORTANCE The presence of V. parahaemolyticus in migratory birds' fecal samples implies that the human pathogenic V. parahaemolyticus strains may also potentially infect birds and thus pose a risk for zoonotic infection and food safety associated with re-entry into the environment. Our study firstly highlights the extra copy of tRNA as a potentially informative marker for identifying the bird-carried V. parahaemolyticus strains. Also, we firstly identify the plasmid-mediated quinolone resistance (PMQR) gene qnrD in V. parahaemolyticus. To further evaluate the risk of enrichment and reintroduction of pathogenic strains carried by migratory birds, we suggest conducting estuarine environmental surveillance to monitor the antibiotic resistance and virulence factors of bird-carried V. parahaemolyticus isolates.

Key points Comparative genomics and transcriptomics revealed that B. velezensis encodes a series of lignocellulosic enzymes capable of degrading polysaccharides. Arabinoxylan degradation mainly occurs after 48 h of B. velezensis CL-4 fermentation, followed by the partial degradation of cellulose, pectin and starch. Exogenous cellulase could significantly improve the fermentation quality of corn germ meal.

Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced lung cancer growth, wound-healing, migration, and invasion versus controls (P

This paper aims to investigate a group of Chinese students’ intercultural encounters studying in two articulation programmes in one British university and analyses the barriers that seem to exist between them, home and other international students. This research is qualitative in nature. Thematic analysis of sixteen Chinese students’ interviews and reflective narratives were adopted. A core finding is that the power of the ‘Chinese circle’ provides this group with a comfortable zone but also presents a barrier to engaging in intercultural communication and developing more intercultural identities. Contributing factors to this pull of the Chinese circle include changing attitudes to English and Chinese language, negative intercultural experiences, and a lack of awareness of intercultural identity. It is suggested that universities should diversify their international recruitment, enhance intercultural education and training provided for all international students before and during their studies abroad.

ABSTRACT Importance Coronary artery dilation may occur in febrile children with and without Kawasaki disease (KD). Objective We explored the application of unsupervised learning algorithms in the detection of novel patterns of coronary artery phenotypes in febrile children with and without KD. Methods A total of 239 febrile children (59 non‐KD and 180 KD patients), were recruited. Unsupervised hierarchical clustering analysis of phenotypic data including age, hemoglobin, white cell count, platelet count, C‐reactive protein, erythrocyte sedimentation rate, albumin, alanine aminotransferase, aspartate aminotransferase, and coronary artery z scores were performed. Results Using a cutoff z score of 2.5, the specificity was 98.3% and the sensitivity was 22.1% for differentiating non‐KD from KD patients. Clustering analysis identified three phenogroups that differed in a clinical, laboratory, and echocardiographic parameters. Compared with phenogroup I, phenogroup III had the highest prevalence of KD (91%), worse inflammatory markers, more deranged liver function, higher coronary artery z scores, and lower hematocrit and albumin levels. Abnormal blood parameters in febrile children with z scores of coronary artery segments

Context Aidi injection (ADI), a traditional Chinese medicine antitumor injection, is usually combined with doxorubicin (DOX) for the treatment of malignant tumours. The cardiotoxicity of DOX is ameliorated by ADI in the clinic. However, the relevant mechanism is unknown.Objective To investigate the effects of ADI on DOX-induced cardiotoxicity and its mechanism.Materials and methods ICR mice were randomly divided into six groups: control, ADI-L, ADI-H, DOX, DOX + ADI-L and DOX + ADI-H. DOX (i.p., 0.03 mg/10 g) was administered in the presence or absence of ADI (i.p., 0.1 or 0.2 mL/10 g) for two weeks. Heart pathology and levels of AST, LDH, CK, CK-MB and BNP were assessed. H9c2 cells were treated with DOX in the presence or absence of ADI (1, 4, 10%). Cell viability, caspase-3 activity, nuclear morphology, and CBR1 expression were then evaluated. DOX and doxorubicinol (DOXol) concentrations in heart, liver, kidneys, serum, and cells were analysed by UPLC-MS/MS.Results High-dose ADI significantly reduced DOX-induced pathological changes and the levels of AST, LDH, CK, CK-MB and BNP to normal. Combined treatment with ADI (1, 4, 10%) improved the cell viability, and IC50 increased from 68.51 μM (DOX alone) to 83.47, 176.9, and 310.8 μM, reduced caspase-3 activity by 39.17, 43.96, and 61.82%, respectively. High-dose ADI inhibited the expression of CBR1 protein by 32.3%, reduced DOXol levels in heart, serum and H9c2 cells by 59.8, 72.5 and 48.99%, respectively.Discussion and Conclusions ADI reduces DOX-induced cardiotoxicity by inhibiting CBR1 expression, which provides a scientific basis for the rational use of ADI.

Abstract Bone metabolic homeostasis is largely dependent on the dynamic balance between osteoblasts and osteoclasts. MicroRNAs (miRNAs) play critical roles in regulating bone metabolism. In this study, we explored the role of a new miRNA (miR-148a) in osteoporosis. We compared the bone phenotype between miR-148a knockout (KO) mice and the wild-type (WT) littermates. We found miR-148a KO mice exhibited an increased bone mass phenotype and decreased osteoclastogenesis compared to the WT group. In vitro, miR-148a overexpression promoted osteoclastogenesis and bone resorption function. Mechanistically, NRP1 was identified as a novel direct target of miR-148a, and NRP1 silencing reversed the effect of miR-148a knockout. In OVX and calvarial osteolysis models, miR-148a KO protects mice against excessive bone resorption, while miR-148a agomiR/AAV-shNRP1 accelerates pathologic bone loss. Finally, the miR-148a level was found to be positively correlated with β-CTX in postmenopausal osteoporosis (PMOP) serum specimens. In summary, our findings revealed that miR-148a genetic deletion ameliorates bone loss under physiological and pathological conditions by targeting NRP1. In osteoclast-related bone metabolic diseases such as PMOP, miR-148a may be an attractive therapeutic target in the future.

In order to explore the differences of flavor characteristics among different cultivars (strains) of large-leaf yellow tea, the main tea tree varieties (strains) in Hubei Province were used as materials to process large-leaf yellow tea. The differences in sensory quality, taste and aroma components were analyzed, and chemometrics analysis was used to explore the relationship between taste-characteristic attributes and chemical compositions. The results showed that large-leaf yellow tea of B6-1 and 07-7-44 strains had the best total sensory scores with long-lasting roasting aroma and sweet floral fragrance, the large-leaf yellow tea of D12 and B6-1 strains had the higher contents of non-ester catechins and amino acids, while large-leaf yellow tea of D12, B6-1 and 07-7-44 strains had the lower ratio of tea polyphenols/amino acids, showed the characteristics of mellow and sweet aftertaste. Correlation analysis showed that taste score and total sensory score were significantly positively correlated with the contents of water extracts, amino acids and soluble sugars (P

The present study investigated the anti-diabetic activity and potential mechanisms of sea cucumber gonad hydrolysates (SCGH) in a rat model of type II diabetes induced by streptozotocin (STZ) combined with high-fat diet (HFD). Results showed that SCGH significantly reduced water intake, fasting blood glucose level and glycated hemoglobin level. Moreover, the oral glucose tolerance, insulin resistance and plasma lipid level in diabetic rats were also alleviated. Furthermore, histological analysis showed that SCGH effectively protected the tissue structure of liver. In addition, mechanism studies showed that SCGH improved glucose metabolism via activating the IRS/Akt signaling pathway, and promoted lipid metabolism via activating the AMPK signaling pathway. In summary, these findings suggested that SCGH have potential anti-diabetic effects by improving insulin resistance and lipid metabolism disorders.

AIM: To study the clinical features, microbial spectrum, associated factors and prognosis of endogenous endophthalmitis (EE) in a group of Chinese patients. METHODS: The medical records from 32 eyes of 29 patients diagnosed with EE in Peking Union Medical College Hospital from January 2009 to October 2019 were reviewed. RESULTS: The initial visual acuity (VA) of 30 eyes in this study was worse than 20/400. Twenty-three eyes were diagnosed with fungal endophthalmitis and nine with bacterial endophthalmitis. The most common fungal and bacterial isolates were Candida and Klebsiella pneumoniae, respectively. Several rare fungi and bacteria species were also isolated from our patients, including Cryptococcus, Paecilomyces, Brucella, and Bacillus licheniformis. The leading risk factor for EE was diabetes. The most common extraocular infection locus was genitourinary tract. Vitrectomy was performed on twenty-nine eyes. Eight eyes achieved final VA of 20/400 or better. EE caused by Candida had a better prognosis. CONCLUSION: The visual outcome of EE is based on pathogens and prompt intervention. Early vitrectomy and antimicrobial treatment are beneficial for EE.

In order to explore the correlation between mineral elements content and quality ingredients of flat green tea, ten representative flat green tea samples from five production areas (Dawu County, Hubei Province, Pan'an County, Zhejiang Province, She County, Anhui Province, Meitan County, Guizhou Province and Emeishan City, Sichuan Province) were collected. The content of nine mineral elements (Mg, K, Ca, P, Al, Mn, Fe, Zn, B) and five quality ingredients (water extracts, tea polyphenols, free amino acids, total soluble sugars, caffeine) were determined. Results showed that the mineral elements influenced each other and existed with synergistic or antagonistic effects. The water extracts content was significantly negatively correlated with the B content (P

Abstract Background The production and processing of animal-based products generates many collagen-rich by-products, which have received attention both for exploitation to increase their added value and to reduce their negative environmental impact. The collagen-rich by-products can be hydrolyzed by collagenases for further utilization. Therefore, collagenases are of benefit for efficient collagen materials processing. An alternative and safe way to produce secreted collagenases is needed. Results Two collagenases from Hathewaya histolytica, ColG and ColH, were successfully secreted by the yeast Saccharomyces cerevisiae. Compared with the native signal peptide of collagenase, the α-factor leader is more efficient in guiding collagenase secretion. Collagenase secretion was significantly increased in YPD medium by supplementing with calcium and zinc ions. Recombinant collagenase titers reached 68 U/mL and 55 U/mL for ColG and ColH, respectively. Collagenase expression imposed metabolic perturbations on yeast cells; substrate consumption, metabolites production and intracellular cofactor levels changed in engineered strains. Both recombinant collagenases from yeast could hydrolyze soluble and insoluble collagen materials. Recombinant ColG and ColH showed a synergistic effect on efficient collagen digestion. Conclusions Sufficient calcium and zinc ions are essential for active collagenase production by yeast. Collagenase secretion was increased by optimization of expression cassettes. Collagenase expression imposed metabolic burden and cofactor perturbations on yeast cells, which could be improved through metabolic engineering. Our work provides a useful way to produce collagenases for collagen resource utilization. Graphical Abstract

Diabetic nephropathy (DN) is one of the most serious complications of diabetes. The purpose of the present study was to investigate the renoprotective effects of sea cucumber hydrolysates (SCH) produced using enzyme mixture of papain and protamex in diabetic rats and further to explore the underlying anti-oxidation mechanisms of peptides. Results showed that the activities of GSH-px and SOD were markedly increased by 16.97 % and 52.97 % respectively after SCH administration. Moreover, SCH increased the protein expression of NQO1, Akt, Nrf2 in kidney tissue of diabetic rats. Furthermore, 13 novel peptides were identified and further synthesized. Molecular docking analysis revealed that these peptides such as WWGP and APGY might directly bind to Keap1 through hydrogen bond, π-π bond or π-donor hydrogen bond, and thus modulate Akt/Nrf2 pathway. In summary, these findings suggested that SCH ameliorated oxidative stress by triggering Akt/Nrf2 signaling pathway, indicating that SCH may possess anti-diabetic nephropathy effects.

Biological control is widely used for integrated pest management. However, there are many abiotic factors that can affect the biocontrol efficiency. In this study, we investigated the susceptibility of Hyphantria cunea larvae to Beauveria bassiana under Cd stress, and the corresponding mechanism was analyzed around innate immunity and energy metabolism. The results showed that mortality of H. cunea larvae treated with Cd and B. bassiana was significantly higher than those treated with B. bassiana alone, and the combined lethal effect exhibited a synergistic effect. Compared with the single fungal treatment group, the total hemocyte count in the combined Cd and fungal treatment group decreased significantly, accompanied by a decrease in phagocytosis, encapsulation, and melanization activity. The expression levels of three phagocytosis-related genes, one encapsulation-promoting gene, and one melanization-regulating gene were significantly lower in the combined treatment group than those in the single fungal treatment group. Furthermore, pathogen recognition ability, signal transduction level, and immune effector expression level were weaker in the combined treatment group than those in the single fungal treatment group. The expression levels of 14 key metabolites and 7 key regulatory genes in glycolysis and tricarboxylic acid cycle pathways were significantly lower in the combined treatment group than those in the single fungal treatment group. Taken together, the weakness of innate immunity and energy metabolism in response to pathogen infection resulted in an increased susceptibility of H. cunea larvae to B. bassiana under Cd pre-exposure. Microbial insecticide is a preferred strategy for pest control in heavy metal-polluted areas. Availability of data and material: All the data that support the findings of this study are available in the manuscript.

PurposeTo explore fecal immune-related proteins that can be used for colorectal cancer (CRC) diagnosis.Patients and methodsThree independent cohorts were used in present study. In the discovery cohort, which included 14 CRC patients and 6 healthy controls (HCs), label-free proteomics was applied to identify immune-related proteins in stool that could be used for CRC diagnosis. Exploring potential links between gut microbes and immune-related proteins by 16S rRNA sequencing. The abundance of fecal immune-associated proteins was verified by ELISA in two independent validation cohorts and a biomarker panel was constructed that could be used for CRC diagnosis. The validation cohort I included 192 CRC patients and 151 HCs from 6 different hospitals. The validation cohort II included 141 CRC patients, 82 colorectal adenoma (CRA) patients, and 87 HCs from another hospital. Finally, the expression of biomarkers in cancer tissues was verified by immunohistochemistry (IHC).ResultsIn the discovery study, 436 plausible fecal proteins were identified. And among 67 differential fecal proteins (|log2 fold change| > 1, P< 0.01) that could be used for CRC diagnosis, 16 immune-related proteins with diagnostic value were identified. The 16S rRNA sequencing results showed a positive correlation between immune-related proteins and the abundance of oncogenic bacteria. In the validation cohort I, a biomarker panel consisting of five fecal immune-related proteins (CAT, LTF, MMP9, RBP4, and SERPINA3) was constructed based on the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression. The biomarker panel was found to be superior to hemoglobin in the diagnosis of CRC in both validation cohort I and validation cohort II. The IHC result showed that protein expression levels of these five immune-related proteins were significantly higher in CRC tissue than in normal colorectal tissue.ConclusionA novel biomarker panel consisting of fecal immune-related proteins can be used for the diagnosis of CRC.