109 research outputs found

    Syntheses and characterizations of the in vivo replicative bypass and mutagenic properties of the minor-groove O2-alkylthymidine lesions.

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    Endogenous metabolism, environmental exposure, and treatment with some chemotherapeutic agents can all give rise to DNA alkylation, which can occur on the phosphate backbone as well as the ring nitrogen or exocyclic nitrogen and oxygen atoms of nucleobases. Previous studies showed that the minor-groove O(2)-alkylated thymidine (O(2)-alkyldT) lesions are poorly repaired and persist in mammalian tissues. In the present study, we synthesized oligodeoxyribonucleotides harboring seven O(2)-alkyldT lesions, with the alkyl group being a Me, Et, nPr, iPr, nBu, iBu or sBu, at a defined site and examined the impact of these lesions on DNA replication in Escherichia coli cells. Our results demonstrated that the replication bypass efficiencies of the O(2)-alkyldT lesions decreased with the chain length of the alkyl group, and these lesions directed promiscuous nucleotide misincorporation in E. coli cells. We also found that deficiency in Pol V, but not Pol II or Pol IV, led to a marked drop in bypass efficiencies for most O(2)-alkyldT lesions. We further showed that both Pol IV and Pol V were essential for the misincorporation of dCMP opposite these minor-groove DNA lesions, whereas only Pol V was indispensable for the T→A transversion introduced by these lesions. Depletion of Pol II, however, did not lead to any detectable alterations in mutation frequencies for any of the O(2)-alkyldT lesions. Thus, our study provided important new knowledge about the cytotoxic and mutagenic properties of the O(2)-alkyldT lesions and revealed the roles of the SOS-induced DNA polymerases in bypassing these lesions in E. coli cells

    Piezoelectric ceramics with hierarchical macro- and micro-pore channels for sensing applications

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    Piezoelectric sensors have attracted increasing attention due to their high sensitivity to forces, pressures and acceleration. The use of porous piezoelectric ceramics with aligned pores formed by freeze casting for sensing application also exhibit advantages due to their combination of a high piezoelectric charge coefficient and low permittivity, which leads to an enhancement in sensor sensitivity compared to dense materials. To fabricate porous materials, the process of direct ink writing (DIW) exhibits superiority in terms of structural design as a result of its ability to provide layer-by-layer and mold-free rapid prototyping. This work provides the first demonstration of the fabrication of lead zirconate titanate (PZT) piezoelectric ceramic scaffolds with sophisticated hierarchical porous structures by simultaneous DIW and freeze casting. The morphology of the porous cells and individual layers of the hierarchical porous PZT ceramic scaffolds were designed by adjusting the rheological properties and optimizing the printing path. The effect of cell structure and number of layers on sensing performance was investigated in detail. Manufactured scaffolds with a sandwich structure exhibited a high output voltage (191 V) under the application of 1 N external force, with a sensitivity of 8.98 V·kPa−1. This work provides a new approach to structural design of piezoelectric sensors to inform future efforts in the fabrication of high-performance piezoelectric ceramics with hierarchical porosity with complex and bespoke geometries.</p

    Oxygen enrichment protects against intestinal damage and gut microbiota disturbance in rats exposed to acute high-altitude hypoxia

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    Acute high-altitude hypoxia can lead to intestinal damage and changes in gut microbiota. Sustained and reliable oxygen enrichment can resist hypoxic damage at high altitude to a certain extent. However, it remains unclear whether oxygen enrichment can protect against gut damage and changes in intestinal flora caused by acute altitude hypoxia. For this study, eighteen male Sprague–Dawley rats were divided into three groups, control (NN), hypobaric hypoxic (HH), and oxygen-enriched (HO). The NN group was raised under normobaric normoxia, whereas the HH group was placed in a hypobaric hypoxic chamber simulating 7,000 m for 3 days. The HO group was exposed to oxygen-enriched air in the same hypobaric hypoxic chamber as the HH group for 12 h daily. Our findings indicate that an acute HH environment caused a fracture of the crypt structure, loss of epithelial cells, and reduction in goblet cells. Additionally, the structure and diversity of bacteria decreased in richness and evenness. The species composition at Phylum and Genus level was characterized by a higher ratio of Firmicutes and Bacteroides and an increased abundance of Lactobacillus with the abundance of Prevotellaceae_NK3B31_group decreased in the HH group. Interestingly, after oxygen enrichment intervention, the intestinal injury was significantly restrained. This was confirmed by an increase in the crypt depth, intact epithelial cell morphology, increased relative density of goblet cells, and higher evenness and richness of the gut microbiota, Bacteroidetes and Prevotellaceae as the main microbiota in the HO group. Finally, functional analysis showed significant differences between the different groups with respect to different metabolic pathways, including Amino acid metabolism, energy metabolism, and metabolism. In conclusion, this study verifies, for the first time, the positive effects of oxygen enrichment on gut structure and microbiota in animals experiencing acute hypobaric hypoxia

    IL-10 plays a central regulatory role in the cytokines induced by hepatitis C virus core protein and polyinosinic acid:polycytodylic acid

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    Hepatitis C virus (HCV) can cause persistent infection and chronic liver disease, and viral factors are involved in HCV persistence. HCV core protein, a highly conserved viral protein, not only elicits an immunoresponse, but it also regulates it. In addition, HCV core protein interacts with toll-like receptors (TLRs) on monocytes, inducing them to produce cytokines. Polyinosinic acid:polycytodylic acid (polyI:C) is a synthetic analogue of double-stranded RNA that binds to TLR3 and can induce secretion of type I IFN from monocytes. Cytokine response against HCV is likely to affect the natural course of infection as well as HCV persistence. However, possible effects of cytokines induced by HCV core protein and polyI:C remain to be investigated. In this study, we isolated CD14+ monocytes from healthy donors, cultured them in the presence of HCV core protein and/or polyI:C, and characterized the induced cytokines, phenotypes and mechanisms. We demonstrated that HCV core protein- and polyI:C-stimulated CD14+ monocytes secreted tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-10, and type I interferon (IFN). Importantly, TNF-α and IL-1β regulated the secretion of IL-10, which then influenced the expression of signal transducer and activator of transcription 1 (STAT1) and interferon regulatory factor 1 (IRF1) and subsequently the production of type I IFN. Interestingly, type I IFN also regulated the production of IL-10, which in turn inhibited the nuclear factor (NF)-κB subunit, reducing TNF-α and IL-1β levels. Therefore, IL-10 appears to play a central role in regulating the production of cytokines induced by HCV core protein and polyI:C

    HCV core protein inhibits polarization and activity of both M1 and M2 macrophages through the TLR2 signaling pathway

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    Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Monocytes and macrophages provide the first line of defense against pathogens, but their roles in HCV infection remains unclear. We have reported that HCV core protein (HCVc) manipulates human blood-derived dendritic cell development. In the present study, we tested whether HCVc affects human blood-derived monocyte differentiating into macrophages. Results showed that HCVc inhibits monocyte differentiation to either M1 or M2 macrophages through TLR2, associated with impaired STATs signaling pathway. Moreover, HCVc inhibits phagocytosis activity of M1 and M2 macrophages, M1 macrophage-induced autologous and allogeneic CD4+ T cell activation, but promotes M2 macrophage-induced autologous and allogeneic CD4+ T cell activation. In conclusion, HCVc inhibits monocyte-derived macrophage polarization via TLR2 signaling, leading to dysfunctions of both M1 and M2 macrophages in chronic HCV infected patients. This may contribute to the mechanism of HCV persistent infection, and suggest that blockade of HCVc might be a novel therapeutic approach to treating HCV infection

    Enhanced understanding of cinnamaldehyde’s therapeutic potential in osteoarthritis through bioinformatics and mechanistic validation of its anti-apoptotic effect

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    IntroductionOsteoarthritis (OA) is a globally prevalent joint disorder affecting approximately 240 million individuals worldwide. Cinnamaldehyde, known for its broad anti-inflammatory and anti-aging effects across various cell types, has not been investigated for its potential impact on apoptosis in OA chondrocytes.MethodsTo explore the effectiveness of cinnamaldehyde in mitigating knee osteoarthritis by reducing chondrocyte apoptosis, bioinformatics analysis was first conducted to identify apoptosis-associated differentially expressed genes (APDEGs). Gene expression datasets GSE55235 and GSE114007 were analyzed using weighted gene co-expression network analysis (WGCNA). Gene modules of interest were cross-referenced with APDEGs to identify those specific to OA. LASSO regression analysis was employed to build a risk model, and this model, along with datasets GSE114007, GSE55457, and GSE12021, was validated using ROC analysis. Cellular experiments and blood analyses from OA patients were performed to evaluate the effects of cinnamaldehyde on apoptosis-related gene expression.ResultsCinnamaldehyde administration was found to rectify the abnormal expression of key apoptosis-related genes in OA patients. Specifically, cinnamaldehyde may affect knee osteoarthritis by regulating apoptosis-related genes such as ZFAND5, BCL6, ELL2, FOSL2, MARCKS, and SGCD. Additionally, three novel apoptotic targets in OA chondrocytes—ZFAND5, ELL2, and SGCD—were identified.DiscussionThese findings provide significant theoretical support for the clinical use of cinnamaldehyde in OA treatment. The discovery of novel apoptotic targets presents new therapeutic possibilities for future OA interventions

    The Impact of Health Risk Perception on Blockchain Traceable Fresh Fruits Purchase Intention in China

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    This paper systematically investigates the impact of consumers&rsquo; health risk perceptions on the purchase intention of blockchain traceable fresh fruits in China. It uses online-survey data collected from four pilot cities that are part of the food traceability system in China. The ordinary least squares (OLS) and the ordered probit model was applied to examine the posited relationships. The results show that consumers&rsquo; health risk perception has a significant positive effect on the purchase intention of blockchain traceable fresh fruits. The stronger consumers&rsquo; health risk perception, the stronger their purchase intention of blockchain traceable fresh fruits. Likewise, heterogeneity exists among gender, age, income, and education in their corresponding effect of consumers&rsquo; health risk perception on blockchain traceable fresh fruit purchase intention. This suggests that male, high-aged, high-income and high-educated groups have a higher health risk perception, and therefore a higher purchase perception for blockchain traceable fresh fruits than female, low-aged, low-income and low-educated, respectively. Furthermore, family structure, consumers&rsquo; traceability cognition and purchase experience of traceable products affect the purchase intention of blockchain traceable fresh fruits. The study has several insights on the broader promotion, acceptance and development of the food traceability system and provides practical cues for policy and practice

    Cytotoxic and mutagenic properties of regioisomeric O

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    Protective Effects of Combined Utilization of Quercetin and Florfenicol on Acute Hepatopancreatic Necrosis Syndrome Infected Litopenaeus vannamei

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    This study aimed to determine the immunity, survival rate, and disease resistance of Litopenaeus vannamei treated using quercetin and florfenicol alone or in combination, after infection with acute hepatopancreatic necrosis syndrome caused by Vibrio parahaemolyticus (VPAHPND). After infection with VPAHPND, different types of feed were given to the shrimp for 5 days, including a control diet (drug-free), florfenicol only diet (15 mg/kg), quercetin only diet (400 mg/kg), a low-dose florfenicol/quercetin combined diet (200 mg/kg quercetin + 7.0 mg/kg florfenicol), a moderate-dose florfenicol/quercetin combined diet (400 mg/kg quercetin + 15 mg/kg florfenicol), and a high-dose florfenicol/quercetin combined diet (800 mg/kg quercetin + 30 mg/kg florfenicol). The cumulative mortality of shrimp was significantly reduced in the drug combination groups compared with either drug used alone (p &lt; 0.05). The density of Vibrio was significantly lower and the immune parameters were significantly increased in the drug combination groups compared with either drug used alone (p &lt; 0.05). Moreover, in the drug combination groups, the hepatopancreas tubules showed better integrity and structure compared with those when either drug was used alone. Therefore, compared with single drug treatment, the florfenicol and quercetin combination enhanced disease resistance, survival, and immune activity of VPAHPND-infected shrimp. When the combination treatment is used, the dosage of florfenicol can be reduced and a better therapeutic effect is obtained
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