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Acetaminophen (APAP) overdose is a prevalent cause of clinical pharmacological liver injury worldwide. Artemether (ART), a first-line antimalarial drug, has demonstrated hepatoprotective activity. However, its effect on APAP-induced acute liver injury (AILI) remains unclear. In this study, we investigated whether ART can protect against AILI and examined its underlying mechanisms. In vivo, ART mitigated APAP-induced liver histological changes, including mitochondrial damage, hepatocyte necrosis, hepatocyte apoptosis, and inflammatory infiltration. Additionally, ART reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in APAP-induced mice. ART also activated the Nrf2-HO-1/GPX4 signaling pathway, exerting antioxidant effects in both in vitro and in vivo models of AILI. To confirm Nrf2 as a target of ART in vivo, we pretreated C57BL/6 mice with the Nrf2 inhibitor, ML385. The results indicated that inhibiting Nrf2 diminishes the protective effect of ART against AILI. Overall, our findings suggest that ART's protective effect against AILI is mediated through the Nrf2-related antioxidant pathway.

To address the issues of low anti-clay performance and high adsorption of ordinary superplasticizer in concrete applications, a novel anti-clay polycarboxylate superplasticizer (Abbreviated as KN-G superplasticizer) was developed. Its structure and properties were characterized using techniques such as infrared spectroscopy (IR), nuclear magnetic resonance (NMR), and X-ray diffraction pattern (XRD). The results indicate that the optimal mass ratio for the synthesized KN-G superplasticizer was monomer: sulfonic acid base: initiator quality: chain transfer agent: hydroxypropyl acrylate=0.808:0.129:0.008:0.008: 0.008:0.007:0.048 under specific conditions, including an acid-to-ether molar ratio of 4.0:1, temperature of 35 °C, solid content of 56%, and drop rate of 4 s/drop. The successful grafting of -SO3H functional groups was confirmed by test results of IR and NMR. At a water-to-cement ratio of 0.45, the disage of montmorillonite and KN-G superplasticizer at 3% and 0.5% of the cement mass, respectively, resulted in the fluidity of mortar with low-quality sand reaching 120 mm, demonstrating the effective anti-clay ability of the KN-G superplasticizer.

The existing residual film-recycling machines struggle to efficiently recover and separate film stubble in a single operation. With roller-type film-rolling device unloading difficulties and other problems, in order to improve the recovery efficiency of film stubble and the separation effect while reducing human labor and to improve work efficiency, we designed an automatic hydraulic unloading film stubble-recycling integrated residual film-recycling machine. The angle of the membrane lifting device was determined by theoretical calculations using the method of coupled simulation of EDEM and ANSYS Workbench. We analyzed the amount of resistance as well as the maximum stress and deformation during the working process of the membrane-lifting device and focused on the design of the membrane–soil separating device and membrane-rolling device. The depth of the film shovel, the forward speed of the machine, and the rotational speed of the driving wheel of the jogging chain were selected as the test factors, and the residual film recovery rate was taken as the evaluation index. A three-factor, three-level test was designed by applying the principles of the Box–Behnken experimental design. The results show that when the forward speed is 1.36 m/s, the soil depth is 147.16 mm, and the rotational speed of the driving wheel of the shaking chain is 77.89 r/min, the recovery rate of the residual film is 87.56%, and the relative error between the experimental value and the optimized value is 2.73%. The experimental results can provide a theoretical basis for the design of the residual film-recycling machine.

Aiming at the problems of low soil cover and serious wear and tear of transmission parts in the soil lifting device of potato planters, this paper carries out innovative optimization design of its key parts based on TRIZ theory. The discrete element model of the soil model and the multi-body dynamic model of the soil lifting device are established, the upper scraping and lower scraping soil lifting devices are simulated respectively through the method of DEM-MBD coupling, and the working mechanism of the soil lifting device is further explored. The simulation results show that the lower scraping type lifting device has a large conveying capacity and a stable flow rate at the soil outlet. The results of the soil tank performance comparison test show that: the improved soil lifting device has a simple structure, large conveying capacity, stable flow rate, and fast flow speed and is not easily congested. It meets the standard requirements of dryland potato seedling strip mulching planting technology on mulching parameters and is of great significance for improving dryland food production on the Loess Plateau.

To address the issues of the poor filling and clearing efficiency of spoon–chain potato seed dischargers, an optimization design was implemented in this study. Based on the motion characteristics of potatoes during the filling and transport processes, an inclination angle was set for the seed spoon cavity, and a seed-clearing brush was installed at the top of the seed discharger. A DEM-MBD coupled simulation model of the seed discharger was constructed. The working speed of the driving sprocket, the inclination angle of the seed spoon cavity, and the seed holding height were used as experimental factors, while the single-seed qualification rate, missed seed rate, and over-seeding rate were used as evaluation indices to conduct a quadratic regression orthogonal rotation combination experiment. This determined the optimal technical parameter combination for the best working performance. Based on the results of the DEM-MBD coupled simulation experiments, a response surface optimization test was conducted. The results showed that the optimal working performance was achieved when the working speed of the driving sprocket was 43 rpm, the inclination angle of the seed spoon cavity was 15°, and the seed holding height was 0.2 m. Under these conditions, the single-seed qualification rate was 95.28%, the missed seed rate was 0.92%, and the over-seeding rate was 3.80%. Further soil bin tests confirmed that, under the optimal working parameters, the relative deviations of all test indices from the response surface optimization test results were less than 2%. The research results provide new insights for the optimization design of spoon–chain potato seed-metering devices.

Aiming at the problems of poor passability of a tracked chassis due to small plots, complicated road conditions and steep slopes during mechanized potato harvesting in hilly and mountainous areas. To design a potato combine harvester and take the tracked chassis of the harvester as the research object to study its driving performance under typical road conditions in mountainous areas. Firstly, mechanical analysis and theoretical calculation are carried out on the tracked chassis to obtain the relevant parameters of key components, and secondly, its driving performance is analyzed to obtain the driving limit values of passing performance under different working conditions; RecurDyn software was used to establish the dynamics simulation and analysis model of the whole machine, and the driving limit values of the harvester were determined under five different road conditions through simulation. The results show the following: the driving limit gradient angle is 20° in cross-gradient conditions, 25° in longitudinal up-gradient conditions, 25° in longitudinal down-gradient conditions, the limiting height of the chassis that can be overpassed in obstacle-crossing conditions is 450 mm, and the limiting width of the chassis that can be spanned in trench-crossing conditions is 1200 mm. The simulation results were verified through field tests, and the results of the field tests showed that the harvester met the requirements of stable travelling on longitudinal slopes of 24°, climbed over a 450 mm straight wall and crossed over a 1200 mm trench, which were similar to the simulation results, indicating that the simulation results were accurate and feasible, and met the design requirements for the travelling passage of the crawler potato harvester. This study provides an in-depth understanding of the tracked chassis of the potato combine harvester in hilly mountainous areas, with a view to providing reference for the design of tracked harvesters for other crops in hilly mountainous areas.

IntroductionAccurate detection of potato seedlings is crucial for obtaining information on potato seedlings and ultimately increasing potato yield. This study aims to enhance the detection of potato seedlings in drone-captured images through a novel lightweight model.MethodsWe established a dataset of drone-captured images of potato seedlings and proposed the VBGS-YOLOv8n model, an improved version of YOLOv8n. This model employs a lighter VanillaNet as the backbone network in-stead of the original YOLOv8n model. To address the small target features of potato seedlings, we introduced a weighted bidirectional feature pyramid network to replace the path aggregation network, reducing information loss between network layers, facilitating rapid multi-scale feature fusion, and enhancing detection performance. Additionally, we incorporated GSConv and Slim-neck designs at the Neck section to balance accuracy while reducing model complexity. ResultsThe VBGS-YOLOv8n model, with 1,524,943 parameters and 4.2 billion FLOPs, achieves a precision of 97.1%, a mean average precision of 98.4%, and an inference time of 2.0ms. Comparative tests reveal that VBGS-YOLOv8n strikes a balance between detection accuracy, speed, and model efficiency compared to YOLOv8 and other mainstream networks. Specifically, compared to YOLOv8, the model parameters and FLOPs are reduced by 51.7% and 52.8% respectively, while precision and a mean average precision are improved by 1.4% and 0.8% respectively, and the inference time is reduced by 31.0%.DiscussionComparative tests with mainstream models, including YOLOv7, YOLOv5, RetinaNet, and QueryDet, demonstrate that VBGS-YOLOv8n outperforms these models in terms of detection accuracy, speed, and efficiency. The research highlights the effectiveness of VBGS-YOLOv8n in the efficient detection of potato seedlings in drone remote sensing images, providing a valuable reference for subsequent identification and deployment on mobile devices.

BackgroundBased on pharmacoeconomics, drug availability and actual treatment, optimal treatment regimens for Chinese non-small-cell lung carcinoma (NSCLC) patients over 70 years old are needed.MethodsThis multicenter, single-arm pilot trial enrolled patients with advanced non-squamous NSCLC who refused systemic chemotherapy. Eligible patients received anlotinib (12 mg/day, d1-14, Q3W) until disease progression, intolerant toxicities, or withdrawal from the study. The primary endpoint was progression-free survival (PFS).ResultsForty-nine patients were screened between January 2019 and September 2021, of whom 40 patients were eligible. The median age was 76 years. With a median follow-up period of 16.20 (95% CI: 8.77, 25.10) months, the median PFS was 5.45 months (95% CI: 3.52-9.23) and the median overall survival was 10.32 months (95% CI: 6.44-12.78). Three patients achieved a partial response and 34 had stable disease, with an objective response rate of 7.5% and a disease control rate of 92.5%. Thirty-three (82.5%; 33/40) patients reported treatment-related adverse events (TRAEs) of any grade, and the incidence rate of grade ≥3 TRAEs was 35% (14/40). The most common grade ≥3 TRAEs were hypertension (4/40; 10.0%), hand-foot syndrome (3/40; 7.5%), and proteinuria (2/40; 5.0%).ConclusionAnlotinib treatment was feasible and safe in Chinese elderly patients with advanced non-squamous NSCLC who did not receive any systemic chemotherapy.

The dysregulation of the intestinal epithelial barrier significantly contributes to the inflammatory progression of ulcerative colitis. Recent studies have indicated that lactate, produced by gut bacteria or derived from fermented foods, plays a key role in modulating inflammation via G-protein-coupled receptor 81 (GPR81). In this study, we aimed to investigate the potential role of GPR81 in the progression of colitis and to assess the impact of lactate/GPR81 signaling on intestinal epithelial barrier function. Our findings demonstrated a downregulation of GPR81 protein expression in patients with colitis. Functional verification experiments showed that Gpr81-deficient mice exhibited more severe damage to the intestinal epithelial barrier and increased susceptibility to DSS-induced colitis, characterized by exacerbated oxidative stress, elevated inflammatory cytokine secretion, and impaired expression of tight-junction proteins. Mechanistically, we found that lactate could suppress TNF-α-induced MMP-9 expression and prevent the disruption of tight-junction proteins by inhibiting NF-κB activation through GPR81 in vitro. Furthermore, our study showed that dietary lactate could preserve intestinal epithelial barrier function against DSS-induced damage in a GPR81-dependent manner in vivo. Collectively, these results underscore the crucial involvement of the lactate/GPR81 signaling pathway in maintaining intestinal epithelial barrier function, providing a potential therapeutic strategy for ulcerative colitis.

Abstract Background The Kingdom of Morocco approved BBIBP-CorV (Sinopharm) COVID-19 vaccine for emergency use on 22 January 2021 in a two-dose, three-to-four-week interval schedule. We conducted a retrospective cohort study to determine real-world BBIBP-CorV vaccine effectiveness (VE) against serious or critical hospitalization of individuals RT-PCR-positive for SARS-CoV-2 during the first five months of BBIBP-CorV use in Morocco. Methods The study was conducted among adults 18–99 years old who were tested by RT-PCR for SARS-CoV-2 infection between 1 February and 30 June 2021. RT-PCR results were individually linked with outcomes from the COVID-19 severe or critical hospitalization dataset and with vaccination histories from the national vaccination registration system. Individuals with partial vaccination (

Abstract Schiff base compounds and their metal complexes have become important synthetic organic drugs due to their extensive biological activities, which include anticancer, antibacterial and antiviral effects. In this study, we investigated the cytotoxic and apoptotic effects of VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, on human breast cancer cells and the possible underlying mechanisms. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-test was used to observe the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells induced by VALD-3. Flow cytometry analysis showed that VALD-3 triggered cell cycle arrest and induced apoptosis of breast cancer cells. Western blot analysis revealed that VALD-3 upregulated pro-apoptotic proteins (Bad and Bax), downregulated anti-apoptotic proteins (Bcl-2, Bcl-xl, survivin and XIAP) and increased the expression of cleaved caspase-3, cleaved caspase-8, Cyto-c and cleaved PARP. VALD-3 also regulated the Wnt/β-catenin signaling pathway in breast cancer cells, inhibiting the activation of downstream molecules. By xenografting human breast cancer cells into nude mice, we found that VALD-3 significantly suppressed tumor cell growth while showing low toxicity against major organs. In addition, survival analysis showed that VALD-3 can significantly prolong the survival time of mice (P = 0.036). This study is the first to show that VALD-3 induces apoptosis and cell cycle arrest in human breast cancer cells by suppressing Wnt/β-catenin signaling, indicating that it could be a potential drug for the treatment of breast cancer.

Abstract Long noncoding RNAs are crucial factors for modulating adipogenic differentiation, but only a few have been identified in humans. In the current study, we identified a previously unknown human long noncoding RNA, LYPLAL1-antisense RNA1 (LYPLAL1-AS1), which was dramatically upregulated during the adipogenic differentiation of human adipose-derived mesenchymal stem cells (hAMSCs). Based on 5′ and 3′ rapid amplification of cDNA ends assays, full-length LYPLAL1-AS1 was 523 nt. Knockdown of LYPLAL1-AS1 decreased the adipogenic differentiation of hAMSCs, whereas overexpression of LYPLAL1-AS1 enhanced this process. Desmoplakin (DSP) was identified as a direct target of LYPLAL1-AS1. Knockdown of DSP enhanced adipogenic differentiation and rescued the LYPLAL1-AS1 depletion-induced defect in adipogenic differentiation of hAMSCs. Further experiments showed that LYPLAL1-AS1 modulated DSP protein stability possibly via proteasome degradation, and the Wnt/β-catenin pathway was inhibited during adipogenic differentiation regulated by the LYPLAL1-AS1/DSP complex. Together, our work provides a new mechanism by which long noncoding RNA regulates adipogenic differentiation of human MSCs and suggests that LYPLAL1-AS1 may serve as a novel therapeutic target for preventing and combating diseases related to abnormal adipogenesis, such as obesity.

Background: Cross-linked polyethylene (HXLPE) liners have been used for total hip arthroplasty (THA) to address the problem of osteolysis and revision surgery associated with conventional polyethylene (CPE) liners. This systematic review and meta-analysis investigated the long-term efficacy of HXLPE in preventing revision surgery and radiological osteolysis in comparison to CPE. Materials and Methods: A comprehensive search of PubMed, Embase, and the Cochrane Library from their respective inception to September 2018 was conducted to identify potential candidate articles. Data were pooled using Stata software 14.0. The quality of randomized controlled trials (RCTs) and observational studies was assessed by two different authors using the Cochrane risk-of-bias tool and the Newcastle–Ottawa scale (NOS), respectively. Results: Eight RCTs and six observational studies were included in this review. The pooled results significantly favored HXLPE over CPE in terms of total number of revisions and radiological osteolysis, with a risk reduction of 78% (95% confidence interval [CI] 0.13–0.36; p

Abstract Background Obesity has received increasing attention because of its widespread worldwide occurrence and many threats to health. Human adipose-derived mesenchymal stem cells (hADSCs) are a critical source of adipocytes. Long noncoding RNAs (lncRNAs) play pivotal roles in cell fate determination and differentiation. The objective of the present study was to identify and investigate the function and regulatory mechanism of lncRNAs on adipogenic differentiation of hADSCs. Methods We used lncRNA arrays to identify the prominent differentially expressed lncRNAs before and after hADSC adipogenic differentiation and verified their biological function through antisense oligonucleotide knockdown or lentivirus overexpression. The adipogenic differentiation of hADSCs was assessed by oil red O staining as well as the mRNA and protein levels of adipogenic marker genes through qRT-PCR and western blot. Bioinformatic tool LncPro and immunofluorescence was performed to uncover the interaction between lnc13728 and ZBED3. WNT/β-catenin signaling pathway was evaluated by western blot and immunofluorescence. Results The lncRNA arrays showed that lnc13728 expression was significantly upregulated after hADSC adipogenic differentiation and was correlated positively with the expression of the adipogenesis-related genes in human adipose tissue. Lnc13728 knockdown in hADSCs suppressed the expression of the adipogenesis-related genes at both mRNA and protein level and weakened lipid droplet production. Accordingly, lnc13728 overexpression enhanced hADSC adipogenic differentiation. Beyond that, lnc13728 co-localized with ZBED3 in the cytoplasm and regulated its expression positively. Downregulating ZBED3 had a negative effect on adipogenic differentiation, while the expression of WNT/β-catenin signaling pathway-related proteins was upregulated. Conclusions Lnc13728 promotes hADSC adipogenic differentiation possibly by positively regulating the expression of ZBED3 which plays a role in inhibiting the WNT/β-catenin pathway.

ABSTRACT Global dissemination of K. pneumoniae clones poses health hazards to the public. Genomic epidemiology studies with comprehensive data set further revealed clone divergence, showing a high complexity in evolution. Moreover, clones carrying both acquired virulent and antimicrobial-resistant genes emerged and might replace the carbapenem-resistant clones. Co-occurrence of virulence and resistance is emerging. An unbiased collection of 3,061 clinical K. pneumoniae isolates (January 5, 2013 to July 24, 2018) underwent whole-genome sequencing. Pairwise core-genome single-nucleotide polymorphism (cgSNP) distances identified clone divergence and transmission events. A sum of 2,193 nonduplicated genomes clustered into four phenotypically indistinguishable species complexes. 93% (n = 2,035) were KpI with its largest clonal group (CG) being CG11 (n = 406). Three hundred ninety-three were ST11 and three hundred seventy-four carried blaKPC-2. Noticeably, CG11 is divided into two main subclones based on the capsule synthesis K loci (KL). CG11-KL64 showed a clear hypervirulent plus antimicrobial-resistant (hv+AMR) characteristic. Besides, the phylogenetic structure revealed the clone divergence of CG25, and this is the first report with sufficient CG25 genomes to identify the divergence. The outcomes of the hv+AMR CG25 cluster 1 affected patients were poorer (P < 0.05). Moreover, two episodes of strain transmissions were associated with CG25 cluster 1. Other transmissions were associated with ST20 and ST307. Genomic epidemiology identified clone divergence of CG11 and CG25. The hv+AMR subclones pose greater threats on a global scale. Nosocomial transmissions of the high-risk clones raised our concerns about the evolution and transmission of emerging clones among newborns and critically ill patients. IMPORTANCE The convergence of AMR and acquired virulence posing higher risks to the public is a focusing point. With sufficient genomes and genotypes, we successfully identify the convergence in two subclones, the previously reported CG11-KL64, and the newly reported CG25 cluster 1. The novel finding of the CG25 divergence was not only revealed by the phylogenetic tree but also confirmed by the clinical outcome data and the accessory genome patterns. Moreover, the transmission subclones circulated in two clinically important wards highlights the deficiency of infection control program using conventional methods. Without the assistance of whole-genome sequencing, the transmissions of high-risk clones could not be identified.

Objective: To investigate the effect of transcranial direct current stimulation (tDCS) combined with hyperbaric oxygen therapy (HBOT) in patients with delayed encephalopathy after carbon monoxide poisoning (DEACMP).Design: A parallel-group, open-label randomised controlled study.Setting: Hyperbaric Oxygen Therapy Room of the Second Hospital of Hebei Medical University.Subjects: A total of 40 patients were recruited for the current study. Patients were randomly divided into a treatment group and a control group (20 cases/group).Interventions: Control group: conventional, individualised rehabilitation therapy. Treatment group: conventional, individualised rehabilitation therapy and tDCS.Main Measures: cognitive function of patients, the Barthel Index (BI).Results: After treatment, significantly higher MMSE and BI scores, as well as a greater reduction in P300 latency and an increase in P300 amplitude, were observed in the treatment group compared to the control group (MMSE: 13 ± 7 vs. 9 ± 5; P300 latency: 342 ± 29 vs. 363 ± 17 ms; P300 amplitude: 7.0 ± 3.3 vs. 5.1 ± 2.7 μV; all P < 0.05). In both groups, however, MMSE and BI scores, in addition to P300 amplitude, were significantly improved; in contrast, there was a decrease in P300 latency in both groups after treatment compared to before treatment (all P < 0.05).Conclusion: Combined with HBOT, tDCS can help improve cognitive function and ADL in patients with DEACMP. This combination therapy might be a helpful method to enhance the recovery of patients with DEACMP.

Stability of advanced functional materials subjected to extreme conditions involving ion bombardment, radiation, or reactive chemicals is crucial for diverse applications. Here we demonstrate the excellent stability of wafer-scale thin films of vertically aligned hexagonal BN nanosheets (hBNNS) exposed to high-energy ions and reactive atomic oxygen representative of extreme conditions in space exploration and other applications. The hBNNS are fabricated catalyst-free on wafer-scale silicon, stainless steel, copper and glass panels at a lower temperature of 400 °C by inductively coupled plasma (ICP) assisted chemical vapor deposition (CVD) and subsequently characterized. The resistance of BNNS to high-energy ions was tested by immersing the samples into the plasma plume at the anode of a 150 W Hall Effect Thruster with BNNS films facing Xenon ions, revealing that the etching rate of BNNS is 20 times less than for a single-crystalline silicon wafer. Additionally, using O2/Ar/H2 plasmas to simulate the low Earth orbit (LEO) environment, it is demonstrated that the simulated plasma had very weak influence on the hBNNS surface structure and thickness. These results validate the strong potential of BNNS films for applications as protective, thermally conductive and insulating layers for spacecrafts, electric plasma satellite thrusters and semiconductor optoelectronic devices.

Abstract Objective Although adipocytes are the most abundant stromal cell component in breast cancer tissues, their interaction with breast cancer cells has been less investigated compared to cancer-associated fibroblasts or macrophages. Exosomes are a novel way of cell-cell communication and have been demonstrated to play an important role in various biological processes. However, to our knowledge, only a few studies have reported the effects of adipocyte exosomes on tumor development. Here, utilizing exosomes isolated from in vitro mesenchymal stromal/stem cell (MSC)-differentiated adipocytes, we systematically investigated this issue in a breast cancer model. Material and methods Exosomes were isolated from MSC-differentiated adipocytes and added to breast cancer cells MCF7. Cell proliferation was detected by MTS, and migration was analyzed by wound healing and transwell assay. An in vivo mouse xenograft model was used to evaluate MSC-differentiated adipocyte exosomes’ contribution to tumor growth. Signaling pathway activation was evaluated by western blot and immunofluorescence staining. Results We found MSC-differentiated adipocyte-derived exosomes are actively incorporated by breast cancer cell MCF7 and subsequently promote MCF7 proliferation and migration as well as protect MCF7 from serum derivation or chemotherapeutic drug-induced apoptosis in vitro. In the in vivo mouse xenograft model, depletion of exosomes reduces tumor-promoting effects of adipocytes. Transcriptomic analysis of MSC-differentiated adipocyte exosome-treated MCF7 identified several activated signaling pathways, among which we confirm the Hippo signaling pathway and found a blockade of this pathway leads to a reduced growth-promoting effect of adipocyte exosomes. Conclusion Taken together, our findings provide new insights into the role of adipocyte exosomes in the tumor microenvironment.

ABSTRACT An emerging multidrug-resistant Klebsiella pneumoniae high-risk clone of sequence type 307 (ST307) has been increasingly reported worldwide. Here, we described the genomic characteristics of an IMP-38-producing ST307 K. pneumoniae strain and investigated the prevalence of blaIMP-38 among carbapenem-resistant Klebsiella pneumoniae isolates from a tertiary care hospital in central China. A total of 14 IMP-38-producing ST307 K. pneumoniae strains were identified from 2013 to 2016, with 13 strains isolated from patients with neonatal sepsis in the neonatal ward. PacBio and Illumina whole-genome sequencing analysis performed on a representative IMP-38-producing K. pneumoniae strain, WCGKP294, showed that it contained a circular chromosome and two plasmids. Carbapenemase gene blaIMP-38 is colocated with blaCTX-M-3 in transposon Tn6382 on an IncHI5 plasmid (pWCGKP294-2). WCGKP294 harbors another IncFIB plasmid, pWCGKP294-1, carrying three copies of tandem-repeated IS26-blaSHV-2A-deoR-ygbJ-ygbK-fucA-IS26 composite transposon elements. Phylogenetic analysis placed WCGKP294 in the global ST307 cluster, distant from the U.S. (Texas) and South Africa clusters. Nevertheless, WCGKP294 does not contain the chromosomal fluoroquinolone resistance-associated mutations and IncFIIK/IncFIBK plasmid-associated blaCTX-M-15 gene that are frequently found in other global ST307 strains. IMPORTANCE We described the genome and resistome characterization of a carbapenem-resistant Klebsiella pneumoniae ST307 strain carrying blaIMP-38 in China. This report highlights that the high-risk ST307 clone continues to acquire different antimicrobial resistance genes, posing significant challenges to clinical practice, and should be closely monitored.

Background. Tuberculosis (TB) is usually caused by Mycobacterium tuberculosis, which has the highest mortality rate among infectious diseases. This study is designed to identify the key genes affecting the diagnosis and treatment of TB. Methods. GSE54992, which included 39 peripheral blood mononuclear cell (PBMC) samples, was extracted from the Gene Expression Omnibus database. After the samples were classified into type and time groups by limma package, the differentially expressed genes (DEGs) were analyzed using the Analysis of Variance. Using pheatmap package, hierarchical cluster analysis was performed for the DEGs. Then, the key modules correlated with TB were selected using the WGCNA package. Finally, functional and pathway enrichment analyses were carried out using clusterProfiler package. Results. The DEGs in subclusters 3, 6, 7, and 8 were chosen for further analyses. Based on WGCNA analysis, blue and green modules in type group and pink module in time group were selected as key modules. From the key modules, 9 (including BAX and ARPC1B) hub genes in type group and 6 (including DHX36) hub genes in time group were screened. Through pathway enrichment analysis, the TNF signaling pathway was enriched for the green module. Conclusion. DHX36, BAX, and ARPC1B might be key genes acting in the mechanisms of TB. Besides, the TNF signaling pathway might also be critical for the diagnosis and therapy of the disease.

Abstract Background Colon cancer is a malignancy of the large intestine with high mortality and economic burden. Recent studies reveal a new relationship between blood lipids and the risk of cancer. The presents study aims to investigate the combination of serum lipids with cancer antigens as a novel diagnostic marker for colon cancer. Methods Two hundred of colon cancer patients or healthy subjects were recruited. Serum lipids and cancer antigens such as total cholesterol (TC), high-density lipoprotein (HDL), carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA19–9) were measured. Results There were significantly lower level of serum TC or HDL, and significantly higher level of serum CEA or CA19–9 in patients than in healthy subjects. Serum TC or HDL in patients with advanced colon cancer was significantly lower than the ones with early stage disease. The level of serum TC or HDL in patients after surgical removal of colon cancer was significantly higher compared to the ones before surgery, but serum CEA or CA19–9 after surgery was significantly reduced in comparison with the ones before surgery. Combined TC, HDL, CEA and CA19–9 as a diagnostic marker for colon cancer had the highest positive predictive rate in comparison with individual, two or three of the parameters. Conclusions The combination of serum TC, HDL, CEA and CA19–9 can be used as an effective marker for colon cancer, and offers a novel strategy for clinical diagnosis and monitoring the disease.

Abstract Background Streptococcus pneumoniae, the leading pathogen of bacterial infections in infants and the elderly, is responsible for pneumococcal diseases with severe morbidity and mortality. Emergence of drug-resistant strains presented new challenges for treatment and prevention. Vaccination has proven to be an effective means of preventing pneumococcal infection worldwide. Detailed epidemiological information of antibiotic susceptibilities and serotype distribution will be of great help to the management of pneumococcal infections. Methods A total of 881 S. pneumoniae isolates were collected from patients at 23 teaching hospitals in 17 different cities from 2011 to 2016. The main specimen types included sputum, blood, broncho-alveolar lavage fluid, pharyngeal swabs, and cerebrospinal fluid. Minimum inhibitory concentrations (MICs) were determined using the agar dilution method. Capsular serotypes were identified using latex agglutination and quellung reaction test. Molecular epidemiology was investigated using multilocus sequence typing. Results S. pneumoniae isolates were highly resistant to macrolides, tetracycline, and trimethoprim/sulfamethoxazole. The rate of resistance to penicillin was 51.6% (oral breakpoint). However, levofloxacin and moxifloxacin maintained excellent antimicrobial activity and all of the isolated strains were susceptible to vancomycin. Twenty-two serotypes were identified among the 881 isolates. Prevalent serotypes were 19F (25.7%), 19A (14.0%), 15 (6.8%), 6B (3.6%), 6A (3.0%), and 17 (2.8%). The overall vaccine coverage rates for 7- and 13-valent pneumococcal conjugate vaccines were 37.5% and 58.3%, respectively. Vaccine coverage rates in young children and economically underdeveloped regions were higher than those in older adults and developed regions. Vaccine-covered serotypes demonstrated higher resistance compared with uncovered serotypes. Molecular epidemiological typing demonstrated that S. pneumoniae showed significant clonal dissemination and that ST271 (120, 28.3%), ST320 (73, 17.2%) and ST81 (27, 6.6%) were the major STs. Conclusions High resistance to clinical routine antibiotics was observed for all 881 S. pneumoniae strains. Drug resistance varied among different serotypes and age groups. Prevalent serotypes among the isolates were 19F, 19A, 15, 6B, 6A, and 17. Community-acquired strains should also be included in future studies to gain a better understanding of the prevalence and resistance of S. pneumoniae in China.

Abstract Background In tumor microenvironment, a continuous cross-talk between cancer cells and other cellular components is required to sustain tumor progression. Accumulating evidence suggests that exosomes, a novel way of cell communication, play an important role in such cross-talk. Exosomes could facilitate the direct intercellular transfer of proteins, lipids, and miRNA/mRNA/DNAs between cells. Since mesenchymal stem cells (MSCs) can be attracted to tumor sites and become an important component of the tumor microenvironment, there is an urgent need to reveal the effect of tumor exosomes on MSCs and to further explore the underlying molecular mechanisms. Methods Exosomes were harvested from lung cancer cell line A549 and added to MSCs. Secretion of inflammation-associated cytokines in exosome-treated MSCs were analyzed by RT-PCR and ELISA. The growth-promoting effect of exosome-treated MSCs on lung tumor cells was evaluated by in vivo mouse xenograft model. Signaling pathway involved in exosomes-treated MSCs was detected by PCR array of human toll-like receptor signaling pathway, RT-PCR, and Western blot. Results Data showed that lung tumor cell A549-derived exosomes could induce a pro-inflammatory phenotype in MSCs named P-MSCs, which have significantly elevated secretion of IL-6, IL-8, and MCP-1. P-MSCs possess a greatly enhanced ability in promoting lung tumor growth in mouse xenograft model. Analysis of the signaling pathways in P-MSCs revealed a fast triggering of NF-κB. Genetic ablation of Toll-like receptor 2 (TLR2) by siRNA and TLR2-neutralizing antibody could block NF-κB activation by exosomes. We further found that Hsp70 present on the surface of lung tumor exosomes contributed to the induction of P-MSCs by A549 exosomes. Conclusions Our studies suggest a novel mechanism by which lung tumor cell-derived exosomes induce pro-inflammatory activity of MSCs which in turn get tumor supportive characteristics.

C/EBPα is a critical transcriptional regulator of adipogenesis. How C/EBPα transcription is itself regulated is poorly understood, however, and remains a key question that needs to be addressed for a complete understanding of adipogenic development. Here, we identify a lncRNA, ADINR (adipogenic differentiation induced noncoding RNA), transcribed from a position ∼450 bp upstream of the C/EBPα gene, that orchestrates C/EBPα transcription in vivo. Depletion of ADINR leads to a severe adipogenic defect that is rescued by overexpression of C/EBPα. Moreover, we reveal that ADINR RNA specifically binds to PA1 and recruits MLL3/4 histone methyl-transferase complexes so as to increase H3K4me3 and decrease H3K27me3 histone modification in the C/EBPα locus during adipogenesis. These results show that ADINR plays important roles in regulating the differentiation of human mesenchymal stem cells into adipocytes by modulating C/EBPα in cis.

Inspired by the significant bioactivity of ergosterol peroxide, we designed and synthesized four fluorescent coumarin and ergosterol peroxide conjugates 8a−d through the combination of ergosterol peroxide with 7-N,N-diethylamino coumarins fluorophore. The cytotoxicity of synthesized conjugates against three human cancer cells (HepG2, SK-Hep1, and MCF-7) was evaluated. The results of fluorescent imaging showed that the synthesized conjugates 8a−d localized and enriched mainly in mitochondria, leading to significantly enhanced cytotoxicity over ergosterol peroxide. Furthermore, the results of biological functions of 8d showed that it could suppress cell colony formation, invasion, and migration; induce G2/M phase arrest of HepG2 cells, and increase the intracellular ROS level.

A recent paper in this journal, presented a novel method by topical application of growth factors in stimulating diabetic cutaneous wound healing that caught our attention. We believe that the experimental method in the article is efficient and creative, but it also has some controversies and shortcomings to be discussed. We noted that the authors used “Tegaderm” as a semiocclusive dressing film and stated that it exerted a “splinting effect” on the wound margins and controlled contraction. Indeed, the “Tegaderm” itself can serve as a dressing film to isolate the wound bed with outside environments while the “splinting effect” is mainly achieved by adding silicone splints around the wound. Considering the unique properties of silicone splints and “Tegaderm,” our experimental group propose an alternative method named “combined-suturing” technique that is not only suturing the silicone splints but also securing the “Tegaderm” around the wound. The specific reasons and operative procedures are explained in detail in this letter.

Background: EBV-miR-BARTs exhibit significant relevance in epithelial tumors, particularly in EBVassociated gastric and nasopharyngeal cancers. However, their specific mechanisms in the initiation and progression of gastric cancer remain insufficiently explored. Material and Methods: Initially, EBV-miRNA-BART6-5p and its target gene SMAD4 expression were assessed in EBV-associated gastric cancer tissues and cell lines. Subsequent transfection induced overexpression of EBV-miRNA-BART6-5p in AGS and MKN-45, and downregulation in EBVpositive cells (SUN-719). The subsequent evaluation aimed to observe their impact on gastric cancer cell proliferation, migration, and glycolytic processes, with the TGF-ß/SMAD4 signaling pathway value clarified using a TGF-ß inhibitor. Results: EBV-miRNA-BART6-5p exhibits pronounced upregulation in EBV-associated gastric cancer tissues and EBV-positive cells, while its target gene SMAD4 demonstrates downregulated expression. Upregulation of it can promote the proliferation and migration of gastric cancer cells. Additionally, We found EBV-miRNA-BART6-5p promotes glycolysis of gastric cancer cells. Inhibition of the TGF-ß/SMAD4 signaling pathway resulted in suppressed proliferation and migration of gastric cancer cells, concomitant with a diminished glycolytic capacity. Conclusion: In this study, we found that EBV-miRNA-BART6-5p can target SMAD4, effectively increasing glycolysis in gastric cancer cells by regulating the TGF-ß/SMAD4 signaling pathway, thereby enhancing the proliferation and metastasis of gastric cancer cells. Our findings may offer new insights into the metabolic aspects of gastric cancer. [ABSTRACT FROM AUTHOR]

Multicentric Castleman disease (MCD) is a heterogeneous, life-threatening disease. A subgroup of HIV-negative and HHV-8-negative MCD is defined as idiopathic MCD (iMCD) with a poor prognosis. Here we report an unusual case of a 47-year-old male patient with iMCD who experienced multiple treatment regimens such as chemotherapy, immunomodulatory therapy, and targeted therapy, all of which were considered ineffective. Subsequently, he was started on bortezomib in combination with dexamethasone for six cycles and he was in complete remission. The patient has survived nearly 13 years to date – the longest survival of any iMCD patient treated with bortezomib in combination with dexamethasone. Bortezomib combined with dexamethasone may be an effective salvage strategy for severe and refractory iMCD. [ABSTRACT FROM AUTHOR]

Background: The aim was to explore the value of combined detection of PCT, CRP, and FIB in differentiating severe pneumonia from viral infection and bacterial infection. Methods: A total of 100 patients with severe pneumonia admitted to Hebei General Hospital from August 2020 to November 2021 were selected as the research objects, including 50 patients with viral pneumonia (as the viral group, n = 50) and 50 patients with bacterial pneumonia (as the bacterial group, n = 50). At the same time, the clinical data of 50 healthy people in the hospital were selected as the healthy group (n = 50). All the subjects in the three groups were tested for PCT, CRP, and FIB. The difference of each index level among the three groups was compared. The diagnostic efficacy of each index for pneumonia was analyzed by drawing receiver operating characteristic curves, and the independent predictors of pneumonia were determined by logistic regression model. Results: There were no statistically significant differences in gender, age, course of disease, body mass index (BMI), and other general data among the three groups (p > 0.05). Compared with the healthy group, the levels of serum PCT, CRP, and FIB in the viral group and the bacterial group were significantly increased, and the levels of serum PCT, CRP, and FIB in the bacterial group were significantly higher than those in the viral group, and the differences were statistically significant (p < 0.05). The positive rates of FIB, CRP, and PCT in bacterial group and viral group were increased in turn, and the differences were statistically significant (p < 0.05), and the positive rates of combined detection in the two groups were significantly higher than the positive rates of single index detection (p < 0.05). Taking etiological examination as the gold standard, the sensitivity (92.59%) and specificity (90.17%) of the three combined detection methods were significantly higher than those of PCT, CRP, and FIB alone. Kappa test showed that the results of the combined detection and etiological examination were in good agreement (Kappa value = 0.847, p < 0.05). ROC curve analysis showed that the AUC of combined prediction of the three was 0.964, which was higher than that of single detection of 0.859, 0.832, and 0.871. Logistic regression analysis showed that serum PCT, CRP, and FIB were independent predictors of bacterial pneumonia, and the differences were statistically significant (p < 0.05). Pearson's correlation analysis showed that FIB level in the bacterial group was positively correlated with PCT and CRP. PCT was positively correlated with CRP. Conclusions: Compared with viral pneumonia, the levels of serum PCT, CRP, and FIB in patients with bacterial pneumonia are higher. Biochemical indexes can be used as independent predictors for the diagnosis of bacterial pneumonia, and have high diagnostic value. The combined detection of the three has the highest diagnostic efficiency, which is conducive to the clinical differential diagnosis of the early types of pneumonia infection. [ABSTRACT FROM AUTHOR]

Introduction: Golden pompano (Trachinotus ovatus) is economically significant important for offshore cage aquaculture in China and Southeast Asian countries. Lack of high-quality genomic data and accurate gene annotations greatly restricts its genetic breeding progress. Objectives: To decode the mechanisms of sex determination and rapid growth in golden pompano and facilitate the sex- and growth-aimed genetic breeding. Methods: Genome assemblies of male and female golden pompano were generated using Illumina, PacBio, BioNano, genetic maps and Hi-C sequencing data. Genomic comparisons, whole genome re-sequencing of 202 F1 individuals, QTL mapping and gonadal transcriptomes were used to analyze the sex determining region, sex chromosome evolution, SNP loci, and growth candidate genes. Zebrafish model was used to investigate the functions of growth candidate gene. Results: Female (644.45 Mb) and male (652.12 Mb) genomes of golden pompano were assembled and annotated at the chromosome level. Both genomes are highly conserved and no new or highly differentiated sex chromosomes occur. A 3.5 Mb sex determining region on LG15 was identified, where Hsd17b1, Micall2 and Lmx1a were putative candidates for sex determination. Three SNP loci significantly linked to growth were pinpointed, and a growth-linked gene gpsstr1 was identified by locus BSNP1369 (G → C, 17489695, Chr23). Loss of sstr1a (homologue of gpsstr1) in zebrafish caused growth retardation. Conclusion: This study provides insights into sex chromosome evolution, sex determination and rapid growth of golden pompano.

The antitumor activities of natural paclitaxel (PTX), semisynthetic docetaxel, and cabazitaxel are highly dependent on their C-13 side chains. Therefore, using natural ergosterol peroxide (EP, 1) as the lead compound, two EP-PTX hybrids (EP-A2 and EP-B2) were prepared and their antitumor activities were evaluated against 4 kinds of human MCF-7, HepG2, HCT-116, and A549 cell lines in vitro. The results showed that both EP-A2 and EP-B2 inhibited the growth of all four kinds of tested tumor cell lines. For paclitaxelresistant MCF-7 cells, both EP-A2 and EP-B2 showed significant inhibitory activity with relatively low IC50 values (9.39 μM and 8.60 μM, respectively). In addition, EP-B2 inhibited the growth of the HepG2 cells (IC50=7.82 μM) more successfully than EP. Preliminary studies of the mechanism suggest that EP-B2 could arrest the G1 phase transition in HepG2 cells. In addition, EPB2 showed an obvious apoptosis-inducing effect in HepG2 cells, as detected by the Annexin V/PI binding assay and the Western blot assay. Hybrid EP-B2 has the potential to become a novel antitumor drug through further study of the mechanism of action and its structural modifications. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. Methods RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. Results PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. Conclusions PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

Abstract Background Breast cancer has the highest incidence rate of cancer worldwide, and brain metastases (BrM) are among the most malignant cases. While some patients have benefited from immune checkpoint inhibitors (ICIs), the complex anatomical structure of the brain and the heterogeneity of metastatic tumors have made it difficult to characterize the tumor immune microenvironment (TME) of metastatic tumors. Methods To address this, we used single‐cell RNA sequencing (scRNA‐seq) to analyze immune cells in the cerebrospinal fluid (CSF) of BrM patients with breast cancer, thereby providing a comprehensive view of the immune microenvironment landscape of BrM. Results Based on canonical marker genes, we identified nine cell types, and further identified their subtypes through differential expression gene (DEG) analysis. We compared the changes in cells and functions in the immune microenvironment of patients with different prognoses. Our analysis revealed a series of genes that promote tumor immune function (CCR5, LYZ, IGKC, MS4A1, etc.) and inhibit tumor immune function (SCGB2A2, CD24, etc.). Conclusions The scRNA‐seq in CSF provides a noninvasive method to describe the TME of breast cancer patients and guide immunotherapy.

ABSTRACTThe most crucial variables that influence the characteristics and quality of cotton fibers during the cotton growth and ginning processes are temperature and moisture regains. Here the cotton fiber samples were generated with pre-treatment using a synergistic strategy of moisture regains and low temperatures, the morphology and structure of the fibers with different pre-treatments were analyzed by using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray Photoelectron Spectrometer (XPS), X-ray diffraction (XRD), and Carbon-13 Nuclear Magnetic Resonance Spectrometry (13C NMR). Further, the mechanical properties of the cotton fibers were evaluated using LLY-06E tensile. The results shown that, with 3 days of freezing in -18℃, the linear density variation of the cotton fiber samples reached maximum, and the surface of the fibers showed noticeable fractures, local holes, and folded damage. Moreover, the low temperature and high moisture regain caused the internal water molecules of the cotton fibers interact in complex ways, altering the intermolecular forces but without changing the chemical composition. This research expands the temperature field of cotton fibers, particularly in the ginning process, by investigating the damage to the mechanical characteristics of cotton fibers caused by the combined effect of low temperature and moisture regain.

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Objective: To observe the morphological characteristics of posterior scleral staphyloma (PSS) with or without macular retinoschisis (MRS) using optical coherence tomography (OCT). Additionally, the incidence and severity of other pathologic myopic maculopathy associated with posterior scleral staphyloma was also evaluated. Methods: General information and OCT imaging data from 440 patients with posterior scleral staphyloma (PSS) and the PSS curvature > 20×10−3 μm–1 were collected. These patients visited the Department of Ophthalmology at the First Affiliated Hospital of Harbin Medical University from January 2013 to June 2021. The obtained OCT images of PSS were analyzed using the Image J software to measure the curvature along the Bruch's membrane. The measured curvature was divided into four levels using the quartile method. The classification of macular retinoschisis (MRS) was based on the anatomical structure of the retina and the location of macular retinoschisis. Patients with PSS accompanied by MRS were assigned to the MRS group, while PSS patients without MRS were assigned to the non-MRS group. Additionally, typical OCT changes in other pathologic myopic maculopathy diseases, such as myopic choroidal neovascularization (mCNV), myopic traction maculopathy (MTM), and myopic foveoschisis (MF), were recorded and evaluated. Results: A total of 615 eyes (328 right eyes, 287 left eyes) from 440 patients (80 males and 360 females) were recruited in this study. The MRS group consisted of 159 patients (36.1%) with 190 eyes (30.9%), while the non-MRS group consisted of 281 patients (63.9%) with 425 eyes (69.1%). Both groups had a significantly higher proportion of female patients compared to male patients, and the right eye was more commonly affected than the left eye. In the MRS group, the prevalence of MRS increased progressively with the severity of PSS. Among the common posterior pole diseases, epiretinal membrane had the highest prevalence (33.2%), while lamellar macular hole had the lowest prevalence (5.3%). In the non-MRS group, the proportion of PSS in each group decreased progressively (except for an equal prevalence in the third and fourth levels) with increasing severity of PSS. Among the common posterior pole diseases, choroidal neovascularization had the highest prevalence (41.4%), while lamellar macular hole had the lowest prevalence (6.5%). When comparing the two groups, there were no significant differences in age, gender, and eye distribution. The MRS group had a higher prevalence of macular schisis, retinal detachment, and dome-shaped macula (17.9%, 14.2%, 14.8%) compared to the non-MRS group (11.3%, 9.2%, 9.6%). The non-MRS group had a significantly higher prevalence of choroidal neovascularization (41.4%) compared to the MRS group (12.6%), while there were no significant differences in the prevalence of epiretinal membrane and lamellar macular hole between the two groups. Conclusion: The prevalence of MRS increased progressively with the severity of PSS, and the MRS occurrence was positively correlated with PSS, which indicated that PSS may lead to MRS, while the proportion of PSS in each group decreases gradually with the severity of PSS in the non-MRS group decreased progressively (except for an equal prevalence in the third and fourth levels). In the MRS group, outer macular retinoschisiss were most relevant to posterior scleral staphyloma, and the prevalence of macular holes and retinal detachments was higher in the MRS group compared to the non-MRS group, indicating that MRS may further turn into complications such as macular holes and retinal detachments, which can significantly affect vision or lead to blindness. The prevalence of choroidal neovascularization (CNV) was significantly higher in the non-MRS group compared to the MRS group, suggesting that PSS with lower severity is more prone to develop into CNV. Dome-shaped macula (DSM) seems to play a protective role in the development of pathologic myopia, and abnormal changes in posterior scleral staphyloma curvature may be an important factor affecting the development and shape of DSM.

Toxoplasma gondii (T. gondii) is a highly successful global parasite, infecting about one-third of the world's population and significantly affecting human life and the economy. However, current drugs for toxoplasmosis treatment have considerable side effects, and there is no specific drug to meet current needs. This study aims to evaluate the anti-T. gondii activity of broxaldine (BRO) in vitro and in vivo and explore its mechanism of action. Our results showed that compared to the control group, the invasion rate of tachyzoites in the 4 μg/mL BRO group was only 14.31%, and the proliferation rate of tachyzoites in host cells was only 1.23%. Furthermore, BRO disrupted the lytic cycle of T. gondii and reduced the size and number of cysts in vitro. A mouse model of acute toxoplasmosis reported a 41.5% survival rate after BRO treatment, with reduced parasite load in tissues and blood. The subcellular structure of T. gondii was observed, including disintegration of T. gondii, mitochondrial swelling, increased liposomes, and the presence of autophagic lysosomes. Further investigation revealed enhanced autophagy, increased neutral lipids, and decreased mitochondrial membrane potential in T. gondii treated with BRO. The results also showed a significant decrease in ATP levels. Overall, BRO demonstrates good anti-T. gondii activity in vitro and in vivo; therefore, it has the potential to be used as a lead compound for anti-T. gondii treatment.

This study aims to explore the effect of the Rubus extract on the TLR4/NF-κB signaling pathway in alcoholic liver fibrosis rats. The alcoholic liver rat model was established by continuous ethanol gavage administration. Rats were divided randomly into six groups (i.e., blank control, model, 0.05g/kg Rubus extract, 0.125g/kg Rubus extract, 0.259 g/kg Rubus extract and positive control groups). Liver tissue and blood were collected after treatment for four weeks. The pathological changes in the liver were observed by HE and Masson staining methods. The hyaluronic acid (HA), TNF-a and IL-6 levels were determined by ELISA kits. The TLR4 and p-p65 protein expression levels in liver were detected by Western blot. The liver lesion degree was significantly decreased in the Rubus extract group, and a high concentration of the Rubus extract indicated a significant improvement. The TNF-a, HA and IL-6 levels in the Rubus extract and positive control groups were significantly lower than those of the model group (P<0.05). The TLR4 and pp65 protein expression levels were also significantly decreased in the Rubus extract and positive control groups (P< 0.05) with a concentration dependence of Rubus extract. The Rubus extract could delay the development of alcoholic liver fibrosis through inhibiting the TLR4/NF-κB pathway activity. [ABSTRACT FROM AUTHOR]

To investigate the synergistic effect of Rosa roxbunghii Tratt. polysaccharide（RRTP）and Rosa roxbunghii Tratt. insoluble dietary fiber（RTIDF）on hypoglycemic function. In this study, RRTP and RTIDF were extracted, isolated and purified, the antioxidant and hypoglycemic activities of polysaccharides were measured by in vitro experiment and the relationship between hypoglycemic function and intestinal microbial community structure in mice was analyzed in vivo intervention experiment of Type Ⅱ diabetes in mice. The results were as follows: (1) RRTP had a good free radical scavenging ability in vitro, and could significantly inhibit α-glucosidase and α-amylase activities with IC50 values of 0.293 and 4.251 mg·mL-1, respectively. RTIDF only showed certain inhibitory activity on α-amylase activity. (2) After the intervention of the extracts in the model mice, the tendency of the obese mice to continue to lose weight was reversed. Compared with CK group (physiological saline), the blood glucose level of RTIDF and RRTP+RTIDF mice were significantly down-regulated, and the activity of CAT enzyme in serum was significantly enhanced. RRTP+RTIDF group was superior to RTIDF group. (3) The extract intervention could reduce the inflammatory factors in the liver, relieve the degree of cell swelling, increase the number of absorbing cells in the cecum, and restore the intestinal wall mucosal layer. (4) Further analysis of intestinal microbial community showed that RTIDF+RRTP could reduce the proportion of Bacteroidetes and Firmicutes, increase the abundance of beneficial bacteria such as Acetobacter, but RTIDF had more significant regulation effect on the population. Therefore, based on in vitro hypoglycemic simulation and in vivo intervention results, RRTP and RTIDF have a certain synergistic effect on glucose intervention in diabetic mice, it may be used together as an intervention to improve Type Ⅱ diabetes.

Abstract Multi-enzyme complexes designed based on scaffold proteins are a current topic in molecular enzyme engineering. They have been gradually applied to increase the production of enzyme cascades, thereby achieving effective biosynthetic pathways. This paper reviews the recent progress in the design strategy and application of multi-enzyme complexes. First, the metabolic channels in the multi-enzyme complex have been introduced, and the construction strategies of the multi-enzyme complex emerging in recent years have been summarized. Then, the discovered enzyme cascades related to scaffold proteins are discussed, emphasizing on the influence of the linker on the fusion enzyme (fusion protein) and its possible mechanism. This review is expected to provide a more theoretical basis for the modification of multi-enzyme complexes and broaden their applications in synthetic biology.