Docetaxel (Doc) plays a crucial role in clinical antineoplastic practice. However, it is continuously documented that tumors frequently develop chemoresistance and relapse, which may be related to ...polyploid giant cancer cells (PGCCs). The aim of this study was investigate the formation mechanism and biological behavior of PGCCs induced by Doc. Ovarian cancer cells were treated with Doc, and then the effect of Doc on cellular viability was evaluated by MTT assay and microscopic imaging analysis. The biological properties of PGCCs were further evaluated by Hoechst 33342 staining, cell cycle and DNA content assay, DNA damage response (DDR) signaling detection, beta-galactosidase staining, mitochondrial membrane potential detection, and reverse transcription-quantitative polymerase chain reaction. The results indicated that Doc reduced cellular viability; however, many cells were still alive, and were giant and polyploid. Doc increased the proportion of cells stayed in the G2/M phase and reduced the number of cells. In addition, the expression of gamma-H2A.X was constantly increased after Doc treatment. PGCCs showed senescence-associated beta-galactosidase activity and an increase in the monomeric form of JC-1. The mRNA level of octamer-binding transcription factor 4 (OCT4) and krüppel-like factor 4 (KLF4) was significantly increased in PGCCs. Taken together, our results suggest that Doc induces G2/M cell cycle arrest, inhibits the proliferation and activates persistent DDR signaling to promote the formation of PGCCs. Importantly, PGCCs exhibit a senescence phenotype and express stem cell markers.
Copper-induced death, also termed cuproptosis, is a novel form of programmed cell death and is promising as a new strategy for cancer therapeutics. Elevated copper levels in tumor cells are ...positively associated with high PD-L1 expression. Nonetheless, the prognostic significance of cuproptosis-related immune checkpoint genes (CRICGs) in hepatocellular carcinoma remains to be further clarified. This study aimed to construct the prognostic CRICG signature to predict the immunotherapy response and outcomes of HCC patients. The co-expressed CRICGs were first screened through Pearson correlation analysis. Based on the least absolute shrinkage and selection operator-COX regression analyses, we identified a prognostic 5-CRICGs model, which closely correlates with poor outcomes, cancer development, and immune response to hepatocellular carcinoma. External validation was conducted using the GSE14520 dataset. Lastly, qRT-PCR was performed to determine the expression of the CRICGs in HCC. In summary, we developed and validated a novel prognostic CRICG model based on 5 CRICGs. This prognostic signature could effectively forecast the outcomes and immune response of HCC patients, which may serve as biomarkers for anticancer therapy.
As one of the most frequently used explosives, hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) can cause persistent pollution in the environment, leading to the potential ecological threat crossing the ...generations. In this study, we employed Caenorhabditis elegans to explore the toxic effects of RDX on the parental and offspring worms and the involved signaling pathways. Exposure up to 1000 ng/mL of RDX produced a significant increase in reactive oxygen species (ROS) production, germ cell apoptosis, and decrease in eggs laid. Various mutants were used to demonstrate the RDX-induced apoptosis signaling pathway, and the metabolism of RDX in the nematodes was found related to cytochrome P450 and GST through RNA sequencing. Exposure of parental worms to RDX produced significant reproductive toxicity in F1 and F2, but was recovered in F3 and F4. The transgenerational effects were associated with the decreased expression of met-2, spr-5, and set-2. Our findings revealed the signaling pathways related to the reproductive toxicity caused by RDX in C. elegans and their future generations, which provided the basis for further exploration of the ecological risks of energetic compounds in the environment.
Display omitted
•RDX induces germline apoptosis and DNA damage in C. elegans.•Metabolism of RDX is related to cytochrome P450 and GST.•RDX causes transgenerational reproductive toxicity in C. elegans.•Transgenerational toxicity is influenced by methylation regulation.
Docetaxel (Doc) is a cornerstone of chemotherapy; however, treatment with Doc often and inevitably leads to drug resistance and the formation of polyploid giant cancer cells (PGCCs). In this study, ...we investigated the effect of Doc on non-small cell lung cancer to explore the role of PGCCs in drug resistance and the molecular mechanisms that regulate this resistance. We found that Doc induced G2/M cell cycle arrest and cell death in A549 and NCI-H1299 cells. However, many cells remained alive and became PGCCs by decreasing the expression of key regulatory proteins related to the cell cycle and proliferation. Notably, the PGCCs showed typical features of senescence, especially upregulation of p21 and p-histone H2A.X expression. Moreover, the mRNA level of IL-1β in the senescence-associated secretory phenotype was increased significantly with the development of PGCCs. Inhibition of IL-1β reduced the expression of p-histone H2A.X and promoted polyploidy to enhance the proapoptotic effect of Doc. Taken together, our results suggested that IL-1β was involved in the formation of PGCCs and regulated the senescence of PGCCs, which contributed to drug resistance to Doc. Therefore, targeting IL-1β in PGCCs may be a novel approach to overcome drug resistance.
With the development and application of e-commerce in the process of supply chain integration, the choice of supplier centralized strategy or decentralized mode and how to use supplier financing have ...become significant contents of supply chain management. This study investigates the effect of competition and cooperation on the corporate cash dividend policy under the influence of the supplier relationship strategy and its mediating mechanism based on Chinese data. The motivation of this study is to provide a basis for enterprises to grasp the dynamic evolution process of the economic consequences of supply chain relationships based on big data and adjust the relationship strategy in time to maximize the positive effects of supplier relationships. This study considers supplier concentration and supplier financing as two dimensions to measure the supplier relationship strategy and selects the balanced panel data of Chinese A-share listed companies from 2007 to 2020 as samples by applying the Logit and Tobit model. The results demonstrate that the supplier relationship is negatively correlated with the cash dividends. The intermediary effect found that the competition effect of the supplier relationship aggravates the agency conflict of enterprises and intensifies the degree of financing constraints, and thus acts on the cash dividends of enterprises. This study expands the economic consequences of relational transactions and provides an explanation of dividend policies from the perspective of a supply chain.
blooms are an intractable global environmental problem that pollute water and compromise ecosystem functioning. Closed-lake management practices keep lakes free of sewage and harmful algae invasions ...and have succeeded in controlling local
blooms; however, there is little understanding of how the bacterioplankton communities associated with
have changed. Here, based on metagenomic sequencing, the phyla, genera, functional genes and metabolic functions of the bacterioplankton communities were compared between open lakes (underlying
blooms) and closed lakes (no
blooms). Water properties and zooplankton density were investigated and measured as factors influencing blooms. The results showed that (1) the water quality of closed lakes was improved, and the nitrogen and phosphorus concentrations were significantly reduced. (2) The stability of open vs. closed-managed lakes differed notably at the species and genus levels (
< 0.01), but no significant variations were identified at the phylum and functional genes levels (
> 0.05). (3) The relative abundance of
(Cyanobacteria) increased dramatically in the open lakes (proportions from 1.44 to 41.76%), whereas the relative abundance of several other dominant genera of Cyanobacteria experienced a trade-off and decreased with increasing
relative abundance. (4) The main functions of the bacterioplankton communities were primarily related to dominant genera of Proteobacteria and had no significant relationship with
. Overall, the closed-lake management practices significantly reduced nutrients and prevented
blooms, but the taxonomic and functional structures of bacterioplankton communities remained stable overall.
Chronic cerebral hypoperfusion, a mild ischemic condition, is associated with the cognitive deficits of Alzheimer's disease (AD). Luteolin, a polyphenolic compound found in foods of plant origin, ...belonging to the flavone subclass of flavonoids, has been shown to possess antioxidant, anti-inflammatory and antitumorigenic properties. In the present study, the effects of luteolin on chronic cerebral hypoperfusion-associated neurocognitive pathologies were investigated by using rats with permanent bilateral common carotid artery occlusion, a rat model of chronic cerebral hypoperfusion. As expected, we found that luteolin could attenuate cognitive dysfunction in chronic cerebral hypoperfused rats, as assessed using Morris water maze tests. Daily oral administration of luteolin (50, 100 and 200mg/kg) significantly scavenged oxygen free radicals, enhanced antioxidant potential, decreased the lipid peroxide production and suppressed inflammatory reaction in the cerebral cortex and hippocampus induced by chronic cerebral hypoperfusion. Meanwhile, the results indicated that cerebral hypoperfusion activated nuclear factor-κB (NF-κB), increased the expression of β-site amyloid precursor protein cleaving enzyme (BACE1), as well as elevated amyloid beta (Aβ) levels in the cortex and hippocampus. However, long-term administration of luteolin significantly down-regulated the expression of NF-κB and BACE1, accompanied by diminishing the deposition of Aβ. Our results suggest a potential therapeutic use of luteolin for cerebral hypoperfusion associated cognitive dysfunction in AD.
•Luteolin ameliorated chronic cerebral hypoperfusion-induced cognitive dysfunction.•Luteolin inhibited chronic cerebral hypoperfusion-induced oxidative stress.•Luteolin suppressed chronic cerebral hypoperfusion-induced inflammatory reaction.•Luteolin reduced Aβ levels in hypoperfused rat brain.
The large-scale access of distributed power puts forward higher requirements for the monitoring of the distribution networks, and the topology identification of low-voltage power lines can ...effectively promote the integration of monitoring data and the distribution network information, effectively realizing the rapid identification of faults and ensuring the safety of users. In this paper, the method of graph theory was used to simplify the analysis of low-voltage lines, and the full topology identification strategy was proposed. Based on IEC 61850 SCL topology configuration information, line topology identification within the region was realized, and the correlation between regions was determined by the injection method. According to the configuration information, regional association information, and user’s collection information, the low-voltage station area line topology was divided into known regional topology and unknown regional topology. Aiming for the identification of line topology in the unknown region, according to the similarity of voltage fluctuations over short electrical distances, clustering analysis of user’s voltage data in the unknown region was carried out based on the k-means clustering algorithm. The test results showed that this scheme can realize the identification of topology in the region.
Here we report the prevalence of the suppressed vanM gene cluster as a reservoir of vancomycin resistance genes. Among 1284 clinical isolates of enterococci from four hospitals in Hangzhou, China, 55 ...isolates of Enterococcus faecium and one isolate of Enterococcus faecalis were screened positive for the vanM genotype. Antimicrobial susceptibility testing showed that 55 of the 56 vanM-positive isolates were susceptible to vancomycin and teicoplanin. Most of them (54/56) belonged to the main epidemic lineage CC17, mostly the ST78 type. The vanM gene clusters in the 55 vancomycin-susceptible isolates showed sequence diversity owing to different insertion locations of IS1216E. The vanM transposons could be classified into five types and they all carried two or more IS1216E elements, leading to complete or partial deletions of vanR, vanS, or vanX. Quantitative reverse transcription polymerase chain reaction showed that the expression level of vanM was significantly lower in the vancomycin-susceptible isolates than in the vancomycin-resistant isolate. Considering the prevalence of the vanM genotype and the potential for conversion to a resistant phenotype, vanM might act as an important determinant of glycopeptide resistance in the future. It is essential to strengthen the surveillance of vanM-containing enterococci to control the dissemination of vancomycin resistance.
•The vanM genotype was present at a high rate (4.36%) in clinical enterococci, mostly with silent resistant phenotype.•The suppressed vanM gene clusters were diversity, having defects in vanRS, vanX or vanH caused by IS1216E.•Considering the potential for resistance development, vanM might act as an important glycopeptide resistant gene in future.
The real-time, full-field simulation of the tube hydroforming process is crucial for deformation monitoring and the timely prediction of defects. However, this is rather difficult for finite-element ...simulation due to its time-consuming nature. To overcome this drawback, in this paper, a surrogate model framework was proposed by integrating the finite-element method (FEM) and machine learning (ML), in which the basic methodology involved interrupting the computational workflow of the FEM and reassembling it with ML. Specifically, the displacement field, as the primary unknown quantity to be solved using the FEM, was mapped onto the displacement boundary conditions of the tube component with ML. To this end, the titanium tube material as well as the hydroforming process was investigated, and a fairly accurate FEM model was developed based on the CPB06 yield criterion coupled with a simplified Kim–Tuan hardening model. Numerous FEM simulations were performed by varying the loading conditions to generate the training database for ML. Then, a random forest algorithm was applied and trained to develop the surrogate model, in which the grid search method was employed to obtain the optimal combination of the hyperparameters. Sequentially, the principal strain, the effective strain/stress, as well as the wall thickness was derived according to continuum mechanics theories. Although further improvements were required in certain aspects, the developed FEM-ML surrogate model delivered extraordinary accuracy and instantaneity in reproducing multi-physical fields, especially the displacement field and wall-thickness distribution, manifesting its feasibility in the real-time, full-field simulation and monitoring of deformation states.
