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ABSTRACTBackground Methionine adenosyl transferase II alpha (MAT2A) is the key enzyme to transform methionine into S-adenosylmethionine (SAM), the main methylgroup donor involved in the methylation. The purpose of our study wasto explore whether MAT2A-mediated methionine metabolism affected theexpression of inflammatory cytokines in human gingival fibroblasts(hGFs).Methods Both healthy and inflamed human gingiva were collected. HGFs werecultured and treated with P. gingivalis, with or without MAT2Ainhibitor (PF9366), small interference RNA (siRNA), or extrinsic SAMpretreatment. The levels of inflammatory cytokines were detected byreal-time PCR, western blotting, and ELISA. SAM levels were detectedby ELISA. The nuclear factor-kappa B (NF-κB) and mitogen-activatedprotein kinase (MAPK) pathway was explored by western blotting.Results The expression of MAT2A was increased in the inflamed tissues. P.gingivalis infection promoted the expression of MAT2A and SAM inhGFs. Meanwhile, PF9366 and MAT2A-knockdown significantly decreasedexpression of inflammatory cytokines and SAM production. PF9366inhibited activation of NF-κB/MAPK pathway in P. gingivalis-treatedhGFs.Conclusions MAT2A-mediated methionine metabolism promoted P. gingivalis-inducedinflammation in hGFs. Targeting MAT2A may provide a novel therapeuticmethod for modulating periodontitis.

Triple-negative breast cancer (TNBC) is a challenging subtype with unclear biological mechanisms. Recently, the transcription factor androgen receptor (AR) and its regulation of the DLGAP5 gene have gained attention in TNBC pathogenesis. In this study, we found a positive correlation between high AR expression and TNBC cell proliferation and growth. Furthermore, we confirmed DLGAP5 as a critical downstream regulator of AR with high expression in TNBC tissues. Knockdown of DLGAP5 significantly inhibited TNBC cell proliferation, migration, and invasion. AR was observed to directly bind to the DLGAP5 promoter, enhancing its transcriptional activity and suppressing the activation of the p53 signaling pathway. In vivo experiments further validated that downregulation of AR or DLGAP5 inhibited tumor growth and enhanced CD8+ T cell infiltration. This study highlights the crucial roles of AR and DLGAP5 in TNBC growth and immune cell infiltration. Taken together, AR inhibits the p53 signaling pathway by promoting DLGAP5 expression, thereby impacting CD8+ T cell infiltration in TNBC.

Background: While hepatocellular carcinoma (HCC) represents a highly heterogeneous disease with variable oncogenesis mechanisms and biological features, little is understood about differences in distant metastasis (DM) and prognosis between early-onset and late-onset HCC. This study defined early-onset disease as cancer diagnosed at age younger than 50 years and aimed to present a comprehensive analysis to characterize these disparities based on age. Methods: Information of HCC patients was retrospectively collected from the SEER database and our hospital. Patient demographics, tumor characteristics, and survival were compared between the two groups. A 1:1 propensity score matching (PSM) was adopted to adjust confounding factors. Logistic and cox analysis were utilized to explore risk factors of DM and prognosis, respectively. Besides, the survival differences were assessed by the Kaplan–Meier curve and log-rank test. Results: In total, 19187 HCC patients obtained from the SEER database and 129 HCC patients obtained from our own center were enrolled. Among 19187 patients with HCC, 3376 were identified in the matched cohort, including 1688 early-onset patients and 1688 late-onset patients. Compared with late-onset HCC, early-onset HCC was more likely to occur in female (25.2% vs. 22.9%, P = 0.030), have large tumors (>10.0 cm, 24.1% vs. 14.6%, P = 0.000), harbor poorly differentiated/undifferentiated cancers (17.0% vs. 14.0%, P = 0.003), present advanced clinical stage (T3+T4, 33.7% vs. 28.5%; N1, 9.2% vs. 6.7%; P = 0.000), and develop DM (13.0% vs. 9.5%, P = 0.000). After adjustment for confounders by PSM, we discovered that early-onset HCC remained an independent risk factor for DM. However, combined with Kaplan–Meier curve and cox analysis, early-onset HCC was an independent favorable predictor of survival. We validated these data on an independent cohort from our hospital. Conclusion: In this population-based study, despite developing DM more frequently, early-onset HCC exhibited a superior prognosis than late-onset HCC. Nevertheless, further research is warranted to understand the underlying aetiologic basis for the disparities.

Abstract Objectives The regulatory mechanisms of GCN5 (General control non‐repressed protein5) in the osteogenic differentiation of mesenchymal stem cells (MSCs) in periodontitis are still unclear. The purpose of this review focuses on the regulating roles of GCN5 in bone metabolism and periodontitis, discusses the potential molecular mechanism and provides targets and new ideas for the treatment of periodontitis. Material and Methods The integrative review methodology was used. Data sources include PubMed, Cochrane Library, and additional sources. Results MSCs play an important role in the osteogenesis balance of periodontal tissue. Periodontal ligament stem cells (PDLSCs) from periodontitis patients exhibited defective osteogenic differentiation capacities. Histone acetylation is important in regulating the differentiation of different types of MSCs cells and is closely related to the reduced osteogenic differentiation of PDLSCs. GCN5, one of the first histone acetyltransferase linked to gene transcriptional activation, participates in many biological processes of mesenchymal stem cells. Downregulation of GCN5 expression and lack of GCN5 caused decreased osteogenic differentiation of PDLSCs. Intercellular information exchange may be an important way for MSCs to exert their regulatory and therapeutic functions. Conclusions GCN5 affects the function of cell metabolism‐related genes by regulating the acetylation status of histones or non‐histones, thereby regulating some important progress of MSCs such as PDLSCs' osteogenic differentiation and BMCS osteogenic differentiation.

Abstract Time-averaged shear-wave velocity to 30 m (V S30) is commonly used in ground motion models as a parameter for evaluating site effects. This study used a collection of boreholes in Beijing, Tianjin, Guangxi, Guangdong, and three other municipalities and provinces, which were divided into three regions with reference to the seismic ground motion parameter zonation map of China, to establish V S30 prediction models based on terrain categories. Regional effects were verified by comparing morphometric parameter (topographic slope, surface texture, and local convexity) thresholds and terrain classification maps obtained from global digital elevation model (DEM) data and regional DEM data of the three regions. Additionally, V S30 prediction models for the three regions using both types of terrain classification maps were established and analyzed comparatively to provide credible regional V S30 models for China. Through analysis of the correlations between the measured V S30 values and the predicted V S30 values, calculation of the mean squared error and mean absolute percentage error in each region, and with consideration of the geological characteristics of the boreholes, the V S30 prediction models based on terrain classification maps from regional data were finally applied in developing regional V S30 models for China. Intercomparison of the V S30 prediction models for the three regions indicated that subregional consideration is necessary in terrain classification. Finally, a spatial analysis method adopting inverse distance weighting of the residuals was used to update the initial V S30 models. The developed V S30 models could be used both in developing regional ground motion models and in the construction of earthquake disaster scenarios. Graphical Abstract

This study aimed to conduct a meta-analysis to investigate whether short-term exposure to fine (PM2.5) and coarse (PM10) particulate matter was associated with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) hospitalization, emergency room visit, and outpatient visit at different lag values. PubMed, Embase, and the Cochrane Library were searched for relevant papers published up to March 2021. For studies reporting results per 1-µg/m3 increase in PM2.5, the results were recalculated as per 10-µg/m3 increase. We manually calculated the RRs for these two studies and transferred the RRs to estimate 10 µg/m3 increases in PM2.5. Automation tools were initially used to remove ineligible studies. Two reviewers independently screened the remaining records and retrieved reports. Twenty-six studies (28 datasets; 7,018,419 patients) were included. There was a significant association between PM2.5 and AECOPD events on lag0 (ES = 1.01, 95%CI: 1.01-1.02, p

Abstract Background Liver metastases are a major contributor to the poor immunotherapy response in colorectal cancer patients. However, the distinctions in the immune microenvironment between primary tumors and liver metastases are poorly characterized. The goal of this study was to compare the expression profile of multiple immune cells to further analyze the similarities and differences between the microenvironments of liver metastases and the primary tumor. Methods Tissues from 17 patients with colorectal cancer who underwent resection of primary and liver metastases was analyzed using multispectral immunofluorescence. The expression of multiple immune cells (CD8, Foxp3, CD68, CD163, CD20, CD11c, CD66b, CD56, PD-L1, INF-γ, Ki67 and VEGFR-2) in the tumor center (TC), tumor invasive front (

The rice leaf folder, Cnaphalocrocis medinalis (Lepidoptera: Pyralidae), is a notorious pest of rice in Asia. The larvae and adults of C. medinalis utilize specialized chemosensory systems to adapt to different environmental odors and physiological behaviors. However, the differences in chemosensory genes between the olfactory organs of these two different developmental stages remain unclear. Here, we conducted a transcriptome analysis of larvae heads, male antennae, and female antennae in C. medinalis and identified 131 putative chemosensory genes, including 32 OBPs (8 novel OBPs), 23 CSPs (2 novel CSPs), 55 ORs (17 novel ORs), 19 IRs (5 novel IRs) and 2 SNMPs. Comparisons between larvae and adults of C. medinalis by transcriptome and RT-qPCR analysis revealed that the number and expression of chemosensory genes in larval heads were less than that of adult antennae. Only 17 chemosensory genes (7 OBPs and 10 CSPs) were specifically or preferentially expressed in the larval heads, while a total of 101 chemosensory genes (21 OBPs, 9 CSPs, 51 ORs, 18 IRs, and 2 SNMPs) were specifically or preferentially expressed in adult antennae. Our study found differences in chemosensory gene expression between larvae and adults, suggesting their specialized functions at different developmental stages of C. medinalis. These results provide a theoretical basis for screening chemosensory genes as potential molecular targets and developing novel management strategies to control C. medinalis.

Background: Patients who survive initial esophagogastric variceal bleeding (EVB) are at an increased risk of recurrent bleeding and death; however, a reliable predictive model is lacking. We aimed to develop a model for rebleeding prediction in patients with EVB after modified percutaneous transhepatic variceal embolization (PTVE) with cyanoacrylate. Methods: A total of 122 patients with EVB who underwent PTVE from January 2015 to November 2020 were enrolled. Multivariate logistic analyses were conducted to determine independent risk factors for nomogram construction. The discrimination, calibration, and clinical utility of the nomogram were compared with the Model for End-stage Liver Disease score (MELD) and the Child–Pugh model. Risk stratification was performed according to the nomogram. Results: Rebleeding within 3 months of PTVE occurred in 32 patients (26.2%). Independent rebleeding indicators included prior history of endoscopic therapy, Child–Pugh score, partial splenic embolization, and creatinine level. The nomogram incorporating these four predictors achieved excellent calibration and discriminatory abilities, with a concordance index of 0.85, which was confirmed to be 0.83 through bootstrapping validation. The nomogram demonstrated superior discrimination and clinical applicability than the MELD and Child–Pugh models. As shown in the Kaplan–Meier curves, high-risk patients had a high probability of rebleeding (P ​

In this paper, an incremental nonlinear dynamic inversion (INDI) control scheme is proposed for the attitude tracking of a helicopter with model uncertainties, and actuator delay and saturation constraints. A finite integral compensation based on model reduction is used to compensate the actuator delay, and the proposed scheme can guarantee the semi-globally uniformly ultimately bounded tracking. The overall attitude controller is separated into a rate, an attitude, and a collective pitch controller. The rate and collective pitch controllers combine the proposed method and INDI to enhance the robustness to actuator delay and model uncertainties. Considering the dynamic of physical actuators, pseudo-control hedging (PCH) is introduced both in the rate and attitude controller to improve tracking performance. By using the proposed controller, the helicopter shows good dynamics under the multiple restrictions of the actuators.

CO2 injection technology into coal seams to enhance CH4 recovery (CO2-ECBM), therefore presenting the dual benefit of greenhouse gas emission reduction and clean fossil energy development. In order to gaze into the features of CO2 injection’s influence on reservoir pressure and permeability, the Thermal-Hydraulic-Mechanical coupling mechanism of CO2 injection into the coal seam is considered for investigation. The competitive adsorption, diffusion, and seepage flowing of CO2 and CH4 as well as the dynamic evolution of fracture porosity of coal seams are considered. Fluid physical parameters are obtained by the fitting equation using MATLAB to call EOS software Refprop. Based on the Canadian CO2-ECBM project CSEMP, the numerical simulation targeting shallow low-rank coal is carried out, and the finite element method is used in the software COMSOL Multiphysics. Firstly, the direct recovery (CBM) and CO2-ECBM are compared, and it is confirmed that the injection of CO2 has a significant improvement effect on methane production. Secondly, the influence of injection pressure and temperature is discussed. Increasing the injection pressure can increase the pressure difference in the reservoir in a short time, so as to improve the CH4 production and CO2 storage. However, the increase in gas injection pressure will also lead to the rapid attenuation of near-well reservoir permeability, resulting in the weakening of injection capacity. Also, when the injection temperature increases, the CO2 concentration is relatively reduced, and the replacement effect on CH4 is weakened, resulting in a slight decrease in CBM production and CO2 storage.

On the basis of a conceptual model for an Excavation based Enhanced Geothermal System (EGS-E), which proposed to extract heat from Hot Dry Rock at depth through dominantly adopting shaft, roadways, and caved rock failure techniques but not depending on either wellbore drilling or fracturing stimulation, a novel extensive version of heat extraction is proposed in this paper. Considering its mechanical stability issues, the new scheme contains two fields apart away: the ones are near-field by piping flow to touch the tunnel wall; the others are far-field through filling and driving fluid within the voids of collapsed rock. The former is represented as a tunnel unit being installed hollow linear, which can extract and produce heat precisely according to structural design and accurate operative prediction. The latter is represented as interconnective fissures being induced by stope excavation due to gravitational weight and unloading of a deep-buried squeeze. The EGS-E uses a two-stage heat exchange system of “fluid-rock” and “fluid-fluid.” Then, a 3D transient thermal-hydraulic model is established to demonstrate the heat extraction performance. The temperature field and accumulated heat energy are investigated. The modeling work provides a tentative workflow to simulate an EGS-E system and, most probably for the first time, demonstrated that the deep underground Hot Dry Rock heat mining turns out to be preliminarily studied in a quantitative way.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and a leading cause of cancer-related deaths. Due to late diagnosis, early intrahepatic metastasis and nonresponse to systemic treatments, surgical resection and/or biopsy specimens remain the gold standard for disease staging, grading and clinical decision-making. Since only a small amount of tissue was obtained in a needle biopsy, the conventional tissue biopsy is unable to represent tumor heterogeneity in HCC. For this reason, it is imperative to find a new non-invasive and easily available diagnostic tool to detect HCC at an early stage and to monitor HCC recurrence. The past decade has witnessed considerable evolution in the development of liquid biopsy technologies with the emergence of next-generation sequencing. As a liquid biopsy approach, molecular analysis of cell-free DNA (cfDNA), characterized by noninvasiveness and real-time analysis, may accurately represent the tumor burden and comprehensively reflect genetic profile of HCC. Therefore, cfDNA may be used clinically as a predictive biomarker in early diagnosis, outcome assessment, and even molecular typing. In this review, we provide an update on the recent advances made in clinical applications of cfDNA in HCC.

BackgroundChronic cough is a common complaint which affects a large number of patients worldwide. Increased cough sensitivity is a very important cause of chronic persistent cough. However, there are limited clinical diagnosis and treatment for increased cough sensitivity. Transient receptor potential vanilloid-1 (TRPVl) is a member of the transient receptor potential (TRP) family of channels which is very closely associated with respiratory diseases. However, the mechanism through which TRPV1 that influences downstream events is still poorly understood.ResultsCapsaicin induced increase in cough sensitivity by upregulating the protein level of TRPV1, leading to the secretions of Substance P and neurokinin A which stimulated neurogenic inflammation. However, sinomenine, a component of traditional Chinese medicine, significantly attenuated the capsaicin-induced cough by inhibiting the expression of TRPV1 in guinea pigs. In addition, capsaicin increased the expression of SOX5 which mediated the transcriptional upregulation of TRPV1. However, pretreatment with sinomenine reduced the expression of SOX5.ConclusionThese results indicate that capsaicin induced increase in cough sensitivity by activating neurogenic inflammation, while sinomenine attenuated the increase in cough sensitivity by inhibiting the expressions of SOX5 and TRPV1 in guinea pigs. This finding may provide a novel target for the treatment of aggravated cough sensitivity.

Wet-mix shotcrete has been widely used to support roadways during the excavation of underground mining. In practice, the mix proportion of wet-mix shotcrete plays a key role in later successful application. To obtain an optimal mix proportion, a large number of trial physical experiments should be carried out. Therefore, in this paper, a new ANN–PSO model is proposed to obtain the mix proportion of wet-mix shotcrete quickly, precisely and economically. The artificial neural network (ANN) model was used to establish the objective functions for particle swarm optimization (PSO) optimization, while the PSO was adopted to optimize mix proportions of wet-mix shotcrete to achieve optimal objectives. This hybrid model was applied to optimize mix proportions of wet-mix shotcrete in the Jinchuan mine. The results revealed that the ANN model yielded a mean relative error (MRE) of 2.755% and an R2 of 0.980, indicating an excellent prediction to establish the reasonable objective function. Additionally, PSO spent less than 60 s obtaining an optimal mix proportion of wet-mix shotcrete required by the mine. Consequently, this ANN–PSO model can be used as an efficient design guide to facilitate decision making, prior to the construction phase.

Abstract Resistance to cisplatin (DDP) and dose-related toxicity remain two important obstacles in the treatment of prostate cancer (PCa) patients with DDP-based chemotherapy. We have investigated whether the knockdown of hypoxia-inducible factor-1 alpha (HIF-1α) by siRNA could enhance the antitumor activity of DDP, and aimed to determine the underlying mechanisms. Intravenous injection of attenuated Salmonella carrying a HIF-1α siRNA-expressing plasmid was used to knockdown HIF-1α in a PC-3 xenograft model. The in vitro and in vivo effects of HIF-1α siRNA treatment and/or DPP on PCa cell proliferation, apoptosis, glycolysis, and production of reactive oxygen species (ROS) were assessed by examining molecular markers specific to each process. The results demonstrated that the treatment of tumor-bearing mice with attenuated Salmonella carrying the HIF-1α siRNA plasmid greatly enhanced the antitumor effects of low-dose DDP. Further mechanistic studies demonstrated that knockdown of HIF-1α improved the response of PCa cells to DDP by redirecting aerobic glycolysis toward mitochondrial oxidative phosphorylation, leading to cell death through overproduction of ROS. Our findings indicate that DDP-based chemotherapy combined with targeting the HIF-1α-regulated cancer metabolism pathway might be an ideal strategy to treat PCa.

Carthamus tinctorius L., commonly known as safflower, is an important oilseed crop containing oil bodies. Oil bodies are intracellular organelles in plant cells for storing triacylglycerols (TAGs) and sterol esters. Oleosins are the most important surface proteins of the oil bodies. We predicted and retrieved the sequences of eight putative C. tinctorius oleosin (Ctoleosin) genes from the genome database of safflower. The bioinformatics analyses revealed the size of their open reading frames ranging from 414 to 675 bp, encoding 137 to 224 aa polypeptides with predicted molecular weights of 14.812 to 22.155 kDa, all containing the typical “proline knot” motif. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) determined the spatiotemporal expression pattern of Ctoleosin genes, which gradually increased and peaked during flowering and seed ripening, and decreased thereafter. To validate their role in plant development, we transformed and overexpressed these eight putative Ctoleosin genes in Arabidopsis. Overexpressing Ctoleosins did not affect leaf size, although silique length was altered. Arabidopsis transformed with Ctoleosin3, 4, and 5 grew longer siliques than did the wild-type plants, without altering seed quantity. The 100-grain weight of the transgenic Arabidopsis seeds was slightly more than that of the wild-type seeds. The seed germination rates of the plants overexpressing Ctoleosin4 and 6 were slightly lower as compared with that of the wild-type Arabidopsis, whereas that in the other transgenic lines were higher than that in the wild-type plants. The overexpression of Ctoleosin genes elevated the oil content in the seeds of transgenic Arabidopsis. Our findings not only provide an approach for increasing the oil content, but also for elucidating the intricate mechanisms of oil body synthesis.

High expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) has been detected in a variety of human tumors. However, the association of positive p-STAT3 expression with clinicopathological parameters and the prognosis of colorectal cancer patients remain controversial. To identify the relationship between p-STAT3 expression and clinicopathological parameters and prognosis in patients with colorectal cancer, a systematic review and meta-analysis were performed.We performed a comprehensive literature search from PubMed, EMBASE, and SinoMed through 27 March, 2016. Hazard ratios (HRs) with 95% confidence intervals (CI) were combined to evaluate the association between p-STAT3 expression and overall survival of colorectal cancer patients. Odds ratios (ORs) with 95% CI were combined to evaluate the association between p-STAT3 expression and clinicopathological parameters in patients with colorectal cancer.Seventeen studies including a total of 2,346 colorectal cancer patients were included in this meta-analysis. The combined HR was 1.43 (95% CI: 1.23-1.67, P < 0.001), which suggested a positive relationship between p-STAT3 overexpression and poorer overall survival of colorectal cancer patients. In addition, the results indicated that positive p-STAT3 expression was significantly associated with the presence of lymph node metastasis (OR: 2.43, 95% CI: 1.18-5.01, P = 0.02) but was not associated with TNM stage, tumor differentiation or gender.The meta-analysis results suggest that p-STAT3 overexpression is unfavorable for the prognosis of colorectal cancer patients, and p-STAT3 overexpression is associated with the presence of lymph node metastasis among colorectal cancer patients.

A readily and rapidly accessible triazine dendrimer was manipulated in four steps with 23% overall yield to give a construct displaying four maleimide groups and DOTA. The maleimide groups of the dendrimer are sensitive to hydrolysis under basic conditions. The addition of up to four molecules of water can be observed via mass spectrometry and HPLC. The evolution in the alkene region of the 1H-NMR—the transformation of the maleimide singlet to the appearance of two doublets—is consistent with imide hydrolysis and not the Michael addition. The hydrolysis events that proceeded over hours are sufficiently slower than the desired thiol addition reactions that occur in minutes. The addition of thiols to maleimides can be accomplished in a variety of solvents. The thiols examined derived from cysteine and include the protected amino acid, a protected dipeptide, and native oligopeptides containing either 9 or 18 amino acids. The addition reactions were monitored with HPLC and mass spectrometry in most cases. Complete substitution was observed for small molecule reactants. The model peptides containing nine or eighteen amino acids provided a mixture of products averaging between 3 and 4 substitutions/dendrimer. The functionalization of the chelate group with gadolinium was also accomplished easily.