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Abstract Objectives This study evaluated the impact of self-management interventions based on the COM-B model on peri-implant conditions in older adults with periodontitis. Materials and methods The patients were randomly divided into two groups: Group 1 (control group) received only an oral health education (OHE) pamphlet. Group 2 (test group) performed a self-management intervention based on the COM-B model. Each patient was examined for the most inflammatory implant. The measurement parameters included self-efficacy, self-management ability, and clinical indicators such as probing depth (PD), bleeding on probing (BOP), modified gingival index (mGI), modified plaque index (mPI), and peri-implant mucositis severity score (PMSS). The data was collected at baseline, 4, 8, and 12 weeks. Results 42 patients underwent testing for 3 months. After 12 weeks, the improvement of self-efficacy, self-management ability, and the reduction of BOP, mPI, and PMSS in the test group was significantly higher than in the control group. Conclusion The study suggests that self-management interventions based on the COM-B model can enhance the self-management ability of older adults with periodontitis and reduce peri-implant inflammation. This method is more effective than distributing OHE pamphlets. Trial registration The randomized controlled clinical trial was registered on Chinese Clinical Trial Registry (No. ChiCTR2400082660, Date: 03/04/2024).

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition in children, underscoring the urgent need for non-invasive markers for early detection in this population.MethodsWe utilized survey data from the National Health and Nutrition Examination Survey (NHANES) 2017–2020 regarding liver ultrasound transient elastography (LUTE) for the diagnosis of NAFLD (dependent variable), and used multiple logistic regression models to explore the association between weight-adjusted waist circumference index (WWI) and the prevalence of NAFLD in US adolescents. Smoothing curves and threshold effect analyses were used to assess the non-linear association between the independent variables and the dependent variable. Subgroup analysis was conducted to pinpoint particularly susceptible subgroups within our study cohort of 1,711 participants.ResultsOur findings indicated a positive correlation between WWI and NAFLD scores. Adjusting for all covariates revealed a significant association between increased WWI and the presence of NAFLD, with an odds ratio of 3.37 (95% CI: 2.74, 4.15). This association proved stronger than those observed with waist circumference, body mass index, and NAFLD. Stratifying WWI into quartiles showed a clear and strong positive correlation (P for trend < 0.0001). The results of smoothing curves and threshold effect analysis showed a non-linear relationship between WWI and NAFLD (LLR < 0.001). Notably, for WWI values below 10.65, a significant correlation was observed (OR = 5.25, 95% CI: 3.77,7.31). Additionally, our subgroup analysis revealed that WWI and NAFLD were associated more positively among male participants aged 16 years and older.ConclusionWWI is positively correlated with NAFLD in American adolescents and offers a straightforward and cost-effective method for identifying hepatic steatosis. The findings highlight the importance of focusing on individuals with a WWI below 10.65, where the risk of NAFLD increases. Priority should be given to the male adolescent population aged 16 and above.

BackgroundThe progression of chronic hepatitis B (CHB) to liver fibrosis and even cirrhosis is often unknown to patients, but noninvasive markers capable of effectively identifying advanced liver fibrosis remains absent.ObjectiveBased on the results of liver biopsy, we aimed to construct a new nomogram to validate the stage of liver fibrosis in CHB patients by the basic information of CHB patients and routine laboratory tests.MethodsPatients with CHB diagnosed for the first time in the First Affiliated Hospital of Anhui Medical University from 2010 to 2018 were selected, and their basic information, laboratory tests and liver biopsy information were collected. Eventually, 974 patients were enrolled in the study, while all patients were randomized into a training cohort (n = 732) and an internal validation cohort (n = 242) according to a 3:1 ratio. In the training cohort, least absolute shrinkage and selection operator (Lasso) regression were used for predictor variable screening, and binary logistic regression analysis was used to build the diagnostic model, which was ultimately presented as a nomogram. The predictive accuracy of the nomograms was analyzed by running operating characteristic curve (ROC) to calculate area under curve (AUC), and the calibration was evaluated. Decision curve analysis (DCA) was used to determine patient benefit. In addition, we validated the built models with internal as well as external cohort (n = 771), respectively.ResultsUltimately, the training cohort, the internal validation cohort, and the external validation cohort contained sample sizes of 188, 53, and 149, respectively, for advanced liver fibrosis. Gender, albumin (Alb), globulin (Glb), platelets (PLT), alkaline phosphatase (AKP), glutamyl transpeptidase (GGT), and prothrombin time (PT) were screened as independent predictors. Compared with the aminotransferase-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), and King’s score, the model in the training cohort (AUC = 0.834, 95% CI 0.800–0.868, p < 0.05) and internal validation cohort (AUC = 0.804, 95% CI 0.742–0.866, p < 0.05) showed the best discrimination and the best predictive performance. In addition, DCA showed that the clinical benefit of the nomogram was superior to the APRI, FIB-4 and King’s scores in all cohorts.ConclusionThis study constructed a validated nomogram model with predictors screened from clinical variables which could be easily used for the diagnosis of advanced liver fibrosis in CHB patients.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a prevalent condition that often goes unrecognized in the population, and many risk factors for this disease are not well understood. Glyphosate (GLY) is one of the most commonly used herbicides worldwide, and exposure to this chemical in the environment is significant. However, studies exploring the association between GLY exposure and NAFLD remain limited. Therefore, the aim of this study was to assess the association between urinary glyphosate (uGLY) level and fatty liver index (FLI) using data from the National Health and Nutrition Examination Survey (NHANES), which includes uGLY measurements. Methods The log function of uGLY was converted and expressed as Loge(uGLY) with the constant “e” as the base and used for subsequent analysis. The association between Loge(uGLY) (the independent variable) level and FLI (the dependent variable) was assessed by multiple linear regression analysis. Smoothing curve fitting and a generalized additive model were used to assess if there was a nonlinear association between the independent and the dependent variables. A subgroup analysis was used to find susceptible individuals of the association between the independent variable and the dependent variable. Results A final total of 2238 participants were included in this study. Participants were categorized into two groups (< -1.011 and ≥ -1.011 ng/ml) based on the median value of Loge(uGLY). A total of 1125 participants had Loge(uGLY) levels ≥ -1.011 ng/ml and higher FLI. The result of multiple linear regression analysis showed a positive association between Loge(uGLY) and FLI (Beta coefficient = 2.16, 95% CI: 0.71, 3.61). Smoothing curve fitting and threshold effect analysis indicated a linear association between Loge(uGLY) and FLI [likelihood ratio(LLR) = 0.364]. Subgroup analyses showed that the positive association between Loge(uGLY) and FLI was more pronounced in participants who were female, aged between 40 and 60 years, had borderline diabetes history, and without hypertension history. In addition, participants of races/ethnicities other than (Mexican American, White and Black) were particularly sensitive to the positive association between Loge(uGLY) and FLI. Conclusions A positive linear association was found between Loge(uGLY) level and FLI. Participants who were female, 40 to 60 years old, and of ethnic backgrounds other than Mexican American, White, and Black, deserve more attention.

The seamless asphalt plug expansion joint integrates a traditional asphalt plug joint (APJ) with an overlying continuous asphalt concrete layer, preventing block failure of the asphalt plug joint and enhancing driving comfort. However, typical damages such as fatigue cracking, rutting, and permanent deformation often occur in the upper asphalt layer. This is attributed to the inadequate stiffness of the lower joint plug mastic, particularly under high temperatures and heavy loads. To extend the service life of asphalt plug expansion joints under such conditions and enhance their durability, efforts were made to bolster the performance of the lower asphalt plug joint mixture and improve anti-rutting performance. This study involved: (1) Qualifying APJ mixture requirements under high temperature and heavy load by focusing on two critical material properties: good rutting resistance and permanent deformation resistance. High temperature rheological properties of these binders were examined through temperature scanning tests and multi-stress creep recovery tests (MSCR). (2) Exploring the impact of binder-aggregate ratios and specimen molding methods (standard compaction, paving vibration and pre-mixing) on the bonding strength and rutting resistance of the APJ mixture. This analysis was conducted using pull-off tests and dynamic stability tests. (3) Development of a novel APJ featuring dowel bars to enhance vertical deflection resistance and joint horizontal movement. Comprehensive laboratory tests showcased the modified joint structure's resilience after numerous test cycles, demonstrating exceptional resistance to bending and vertical deformation. The significant findings from this research provide valuable insights for optimal material selection, appropriate joint design, and installation guidelines for seamless asphalt plug expansion joints.

Slope failures in nature and engineering are typically three-dimensional (3D). The rotational failure mechanism derived from the variational limit equilibrium (LE) method shows superior performance in the stability analysis of the 3D slope. In contrast to the traditional LE methods, it avoids arbitrary kinematical and statical assumptions. Stability charts obtained by the variational LE method are used to derive explicit expression equations of the safety factor, also known as the stability equations, for both 3D reinforced and unreinforced slopes. These equations are highly accurate and can provide a convenient means to assess slope stability in practical engineering. An example of a convex reinforced slope with a turning arc is illustrated in this study to investigate the effect of the 3D effects on the required reinforcement length for design. The results indicate that the 2D method underestimates the required reinforcement length when dealing with a 3D reinforced slope problem. Furthermore, a forensic analysis of the Yeager Airport reinforced slope is conducted within the framework of the variational LE method. The required strength for stability is found to be significantly less than the allowable strength of reinforcements without considering the decrease in soil shear strength. However, the required strength greatly exceeds the allowable strength when the decrease in soil shear strength is considered. The results verify that the decrease in shear strength of the weak layer is responsible for the collapse.

Abstract. Background:. The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking. Methods:. We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases. Results:. We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control. Conclusions:. REDH is accessible at http://www.redhdatabase.com/. This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

Abstract Background Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD‐L1 translocation in various tumor cells. Methods C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD‐L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD‐L1‐related pathways after being treated with PPIs. The related gene expression is performed by qRT‐PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD‐L1 in the tissue samples by immunohistochemistry. Results We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD‐L1 on cell membrane at clinically relevant concentrations. Furthermore, pre‐treatment with PPIs appeared to synergize the efficiency of anti‐PD‐L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD‐L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3β, then leading to PD‐L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD‐L1 was negated following GSK3β knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD‐L1 expression in esophageal cancer patients. Conclusion We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD‐L1 by inducing GSK3β phosphorylation and facilitate primary tumor progression and metastasis.

Abstract Aim The purpose of this study was to explore the association of weight-adjusted-waist index (WWI) with non-alcoholic fatty liver disease (NAFLD) and liver fibrosis. Methods A cross-sectional study including 6587 participants was conducted in the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression was used to validate the association of WWI with NAFLD and liver fibrosis, and smoothed curve fitting and threshold effect models were used to validate non-linear relationships. Subgroup analyses were used to verify the stability of the relationship between the independent and dependent variables in different populations. Results There was a positive association of WWI with NAFLD and liver fibrosis. In the model adjusted for all covariates, the effect values of WWI with NAFLD and liver fibrosis were (OR = 3.44, 95% CI: 3.09–3.82) and (OR = 2.40, 95% CI: 2.05–2.79), respectively. This positive correlation became more significant as WWI increased when WWI was presented in quartiles (P for trend

This article studies a nonlinear model predictive control (NMPC) scheme for the trajectory tracking efficiency of a quadcopter UAV. A cost function is first proposed that incorporates weighted increments of control forces in each direction, followed by a weighted summation. Furthermore, a contraction constraint for the cost function is introduced based on the numerical convergence of the system for the sampling period of the UAV control force. Then, an NMPC scheme based on improved continuous/generalized minimum residuals (C/GMRES) is proposed to obtain acceptable control performance and reduce computational complexity. The proposed control scheme achieves efficient and smooth tracking control of the UAV while guaranteeing the closed-loop stability of the system. Finally, simulation results are presented to illustrate the effectiveness and superior performance of the proposed NMPC control scheme.

Abstract Background To explore the relationship between blood manganese and liver stiffness in the United States among participants with chronic obstructive pulmonary disease (COPD). Methods All data were obtained from the 2017–2018 National Health and Nutrition Examination Survey database (NHANES). A total of 4690 participants were included in the study. All participants included complete information on COPD, liver stiffness, and blood manganese. Liver stiffness (kPa) was measured from “Examination Date” and blood manganese (ug/L) was obtained from “Laboratory Data”. A multiple linear regression model was used to assess the correlation between blood manganese and liver stiffness. Results Among the 4690 participants, blood manganese was lower in the COPD group but liver stiffness was higher (p

Abstract Albeit the majority of eukaryotic genomes can be pervasively transcribed to a diverse population of lncRNAs and various subtypes of lncRNA are discovered. However, the genome‐wide study of miRNA‐derived lncRNAs is still lacking. Here, it is reported that over 800 miRNA gene‐originated lncRNAs (molncRNAs) are generated from miRNA loci. One of them, molnc‐301b from miR‐301b and miR‐130b, functions as an “RNA decoy” to facilitate dissociation of the chromatin remodeling protein SMARCA5 from chromatin and thereby sequester transcription and mRNA translation. Specifically, molnc‐301b attenuates erythropoiesis by mitigating the transcription of erythropoietic and translation‐associated genes, such as GATA1 and FOS. In addition, a useful and powerful CRISPR screen platform to characterize the biological functions of molncRNAs at large‐scale and single‐cell levels is established and 29 functional molncRNAs in hematopoietic cells are identified. Collectively, the focus is on miRNA‐derived lncRNAs, deciphering their landscape during normal hematopoiesis, and comprehensively evaluating their potential roles.

The second messenger cAMP modulates a wide range of important biological processes. Here, the authors developed a fluorescent indicator termed G-Flamp1, which can accurately report levels of cAMP in living cells.

Natural regeneration plays an important role in species diversity and evolution. Exploring the causes of variation in regeneration dynamics can provide key insights into the factors affecting regeneration. However, the relationship between the regeneration of Larix principis-rupprechtii and environmental factors in North China has remained unexplored. In this study, 14 plots were established based on the three extents of regenerated plant numbers in Shanxi Province. Redundancy analysis determined that environmental factors (topography, stand structure, soil property, and litter) affected natural regeneration. Structural equation modeling identified the most important direct and indirect factors that affected L. principis-rupprechtii natural regeneration. Litter thickness, canopy density, and adult tree diameter at breast height were positively correlated with natural regeneration. Aspect and total nitrogen volume were negatively associated with natural regeneration. Additionally, there was no significant correlation between natural regeneration and other environmental factors (altitude, slope, adult tree height, stand density, soil water content, SOC, total P, available N, available P, or soil enzyme). Further artificial intervention measures should be considered to promote plantation regeneration. These findings provide an effective basis for future forest restorations and sustainable management.

RNA-binding proteins (RBPs) are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes. The transcriptional regulatory ability of RBPs was indicated by the identification of chromatin-enriched RBPs (Che-RBPs). One of these proteins, KH-type splicing regulatory protein (KHSRP), is a multifunctional RBP that has been implicated in mRNA decay, alternative splicing, and miRNA biogenesis and plays an essential role in myeloid differentiation by facilitating the maturation of miR-129. In this study, we revealed that KHSRP regulates monocytic differentiation by regulating gene transcription and RNA splicing. KHSRP-occupied specific genomic sites in promoter and enhancer regions to regulate the expression of several hematopoietic genes through transcriptional activation and bound to pre-mRNA intronic regions to modulate alternative splicing during monocytic differentiation. Of note, KHSRP had co-regulatory effects at both the transcriptional and posttranscriptional levels on MOGOH and ADARB1. Taken together, our analyses revealed the dual DNA- and RNA-binding activities of KHSRP and have provided a paradigm to guide the analysis of other functional Che-RBPs in different biological systems.

COVID-19 is caused by severe acute respiratory SARS-CoV-2. Regardless of the availability of treatment strategies for COVID-19, effective therapy will remain essential. A promising approach to tackle the SARS-CoV-2 could be small interfering (si) RNAs. Here we designed the small hairpin RNA (named as shRNA688) for targeting the prepared 813 bp Est of the S protein genes (Delta). The conserved and mutated regions of the S protein genes from the genomes of the SARS-CoV-2 variants in the public database were analyzed. A 813 bp fragment encoding the most part of the RBD and partial downstream RBD of the S protein was cloned into the upstream red florescent protein gene (RFP) as a fusing gene in the pCMV-S-Protein RBD-Est-RFP plasmid for expressing a potential target for RNAi. The double stranded of the DNA encoding for shRNA688 was constructed in the downstream human H1 promoter of the plasmid in which CMV promoter drives enhanced green fluorescent protein (EGFP) marker gene expression. These two kinds of the constructed plasmids were co-transfected into HEK293T via Lipofectamine 2000. The degradation of the transcripts of the SARS-CoV-2 S protein fusing gene expressed in the transfected HEK293T treated by RNAi was analyzed by RT-qPCR with a specific probe of the targeted SARS-CoV-2 S protein gene transcripts. Our results showed that shRNA688 targeting the conserved region of the S protein genes could effectively reduce the transcripts of the S protein genes. This study provides a cell model and technical support for the research and development of the broad-spectrum small nucleic acid RNAi drugs against SARS-CoV-2 or the RNAi drugs for the other hazard viruses which cause human diseases.

This work addresses the issue of multi-agent system (MAS) formation control under external disturbances and a directed communication topology. Firstly, a new disturbance observer is proposed to effectively reconstruct and compensate for external disturbances within a short period of time. Then, the integral terminal sliding mode technology is introduced to devise a novel distributed formation control protocol, ultimately realizing the stability of the MAS within a fixed time. Moreover, by means of rigorous Lyapunov theory analyses, a faster formation convergence rate and more accurate consensus accuracies are achieved in the proposed fixed-time strategy with variable exponent form. Finally, the formation tracking control scheme is applied to a multi-wheeled mobile robot (WMR) system. The experimental results strongly support the fine effectiveness of the control scheme designed in this work.

BackgroundMetabolism is an ordered series of biological processes that occur in an organism. Altered cellular metabolism is often closely associated with the development of cancer. The aim of this research was to construct a model by multiple metabolism-related molecules to diagnose and assess the prognosis of patients.MethodWGCNA analysis was used to screen out differential genes. GO, KEGG are used to explore potential pathways and mechanisms. The lasso regression model was used to filter out the best indicators to construct the model. Single-sample GSEA (ssGSEA) assess immune cells abundance, immune terms in different Metabolism Index (MBI) groups. Human tissues and cells were used to verify the expression of key genes.ResultWGCNA clustering grouped genes into 5 modules, of which 90 genes from the MEbrown module were selected for subsequent analysis. GO analysis was found that BP mainly has mitotic nuclear division, while KEGG pathway is enriched to Cell cycle, Cellular senescence. Mutation analysis revealed that the frequency of TP53 mutations was much higher in samples from the high MBI group than in the low MBI group. Immunoassay revealed that patients with higher MBI have higher macrophage and Regulatory T cells (Treg) abundance, while NK cells were lowly expressed in the high MBI group. RT-qPCR and immunohistochemistry (IHC) revealed that the hub genes expression is higher in cancer tissues. The expression in hepatocellular carcinoma cells was also much higher than that in normal hepatocytes.ConclusionIn conclusion, a metabolism-related model was constructed that can be used to estimate the prognosis of hepatocellular carcinoma, and the clinical treatment of different hepatocellular carcinoma patients with medications was guided.

This study aimed to design a three-dimensional (3D) guide plate using computer-aided design and a 3D printing system for precise implantation of microimplants for orthodontic treatment and investigate the accuracy and feasibility of a 3D guide plate in clinical practice. A total of 30 microimplants were placed in 15 patients in the Department of Stomatology, Affiliated Hospital of Jiangnan University. Before surgery, DICOM data from cone-beam computed tomography (CBCT) scans and STereoLithography data from the 3D model scan were imported to 3Shape Dental System. Data fitting and matching were performed, and 3D guide plates were designed primarily focusing on the thickness of guide plates, amount of concave compensation, and dimensions of the ring. Assist implantation method was used to place the microimplants, and postoperative CBCT images were used to evaluate the position and implantation angle. The feasibility of placing microimplants and precise implantation guided by the 3D guide plate. CBCT data before and after the placement of microimplants were compared. Regarding the secure positioning of microimplants based on CBCT data, 26 implants were categorized as Grade i, four as Grade ii, and none as Grade iii. No loosening of microimplants 1 and 3 months after surgery was reported. The implantation of microimplants is more accurate under the guidance of a 3D guide plate. This technology can achieve accurate implant positioning, thus ensuring safety, stability, and improved success rates after implantation.

To improve the performance of an ice bucket, the data obtained using a mathematical model of the ice-making process are compared with the experimental data using the system parameters of the tested flake ice producer. Three concepts—the ice-layer drying time ratio (Kdry), deicing time ratio (Kdei), and water-distribution icing ratio (b)—are introduced as theoretical and data support for improving the structure of the water-distribution pan of the ice bucket and setting a reasonable amount of water distribution. Based on the structure of the water-distribution pan, an area model of the ice bucket is developed for improving the ice-bucket area. The results revealed that when the ice-making period of the tested flake ice maker is 20–40 s and the average temperature of the ice layer is regulated to −3°C, the Kdry exceeds 0.02–0.06. When the ice-making period is 20–40 s and the minimum ice-layer thickness is set to 0.5 mm, the Kdry is less than 0.32–0.53. The ice-layer thickness can reach 98%–99% of the maximum ice-layer thickness when the b is 3.8–5.6. The obtained Kdry, Kdei, and b can be used to optimize the structure of the water-distribution pans, amounts of water distribution, and ice-making bucket performances of other flake ice makers.

BackgroundPrevention and treatment of liver fibrosis at an early stage is of great prognostic importance, whereas changes in liver stiffness are often overlooked in patients before the onset of obvious clinical symptoms. Recognition of liver fibrosis at an early stage is therefore essential.ObjectiveAn XGBoost machine learning model was constructed to predict participants' liver stiffness measures (LSM) from general characteristic information, blood test metrics and insulin resistance-related indexes, and to compare the fit efficacy of different datasets for LSM.MethodsAll data were obtained from the National Health and Nutrition Examination Survey (NHANES) for the time interval January 2017 to March 2020. Participants' general characteristics, Liver Ultrasound Transient Elastography (LUTE) information, indicators of blood tests and insulin resistance-related indexes were collected, including homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR). Three datasets were generated based on the above information, respectively named dataset A (without the insulin resistance-related indexes as predictor variables), dataset B (with METS-IR as a predictor variable) and dataset C (with HOMA-IR as a predictor variable). XGBoost regression was used in the three datasets to construct machine learning models to predict LSM in participants. A random split was used to divide all participants included in the study into training and validation cohorts in a 3:1 ratio, and models were developed in the training cohort and validated with the validation cohort.ResultsA total of 3,564 participants were included in this study, 2,376 in the training cohort and 1,188 in the validation cohort, and all information was not statistically significantly different between the two cohorts (p > 0.05). In the training cohort, datasets A and B both had better predictive efficacy than dataset C for participants' LSM, with dataset B having the best fitting efficacy [±1.96 standard error (SD), (-1.49,1.48) kPa], which was similarly validated in the validation cohort [±1.96 SD, (-1.56,1.56) kPa].ConclusionsXGBoost machine learning models built from general characteristic information and clinically accessible blood test indicators are practicable for predicting LSM in participants, and a dataset that included METS-IR as a predictor variable would improve the accuracy and stability of the models.

Background: Previous studies have shown that Leukocyte cell-derived chemotaxin2 (LECT2) is associated with the development of HCC. However, there are still no studies with a comprehensive analysis of the role of LECT2 in hepatocellular carcinoma (HCC).Methods: TCGA data sets were used to analyze the expression of LECT2 in HCC. In addition, the prognostic value of LECT2 in HCC was also investigated. DriverDBv3 was used to analyze the Mutation, CNV, and methylation profiles of LECT2. And, validated by immunohistochemistry in 72 HCC samples. The prognostic value of LECT2 and the correlation with clinicopathological features were analyzed. The GO/KEGG enrichment analysis of LECT2 co-expression and gene set enrichment analysis (GSEA) was performed using the R software package. The PPI interaction network was constructed by Search Tool for the Retrieval of Interacting Genes (STRING) database. Immune infiltration was estimated by the XCELL, TIMER, QUANTISEQ, MCPCOUNTER, EPIC, CIBERSORT abs and CIBERSORT algorithms, and Spearman was used to analyzing their correlation with LECT2. Moreover, we analyzed the correlation of LECT2 expression with immune checkpoint molecules and HLA genes. Finally, we analyzed the IC50 values of six chemotherapeutic drugs by the pRRophetic package.Results: Reduced LECT2 expression levels found in HCC patients. Moreover, decreased levels of LECT2 were associated with poor overall survival, disease-free survival, disease-specific survival, and progression-free survival. Besides, methylation was significantly associated with LECT2 expression. The functional enrichment analysis revealed that LECT2 may affect HCC progression through various pathways such as JAK/STAT signaling pathway, cell cycle, and pathways in cancer. Additionally, the results showed that LECT2 expression was negatively correlated with immune infiltration of B cells, Neutrophil, Monocyte, Cancer-associated fibroblast, and Myeloid dendritic cell, and positively correlated with T cell CD8+ naive, Endothelial cell, and Hematopoietic stem cell. LECT2 expression was negatively correlated with multiple immune checkpoint molecules and HLA genes. Chemosensitivity analysis showed that chemosensitivity was lower in the LECT2 high expression group. We validated the prognostic value of LECT2 and analysis of clinicopathological features showed a lower TNM stage in the group with high expression of LECT2.Conclusion: Low expression of LECT2 in HCC is closely associated with poor prognosis, LECT2 may have potential clinical applications due to its unique immunological effects.

Abstract. Objective:. Emetine, an isoquinoline alkaloid that is enriched at high concentrations in the lung, has shown potent in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to better understand the effectiveness of low-dose emetine for patients with coronavirus disease 2019 (COVID-19). Methods:. In this real-world study, 63 patients with mild or common COVID-19 were recruited from Wuhan Fangcang Shelter Hospital and five COVID-19-designated hospitals in Anhui Province, China from February to March 2020. Thirty-nine patients from Wuhan Fangcang Shelter Hospital were assigned to a pragmatic randomized controlled clinical trial, and 24 patients from the 5 COVID-19-designated hospitals in Anhui Province underwent a real-world study. The medication course of emetine was less than 10 days. The main symptoms and adverse reactions of all patients were observed and recorded. The primary outcome measure was the time required for a negative SARS-CoV-2 RNA result or the negative result rate on day 10. Secondary outcomes included axillary temperature, transcutaneous oxygen saturation, and respiratory frequency recovery. The study was approved by the Ethics Committee of The First Affiliated Hospital of Anhui Medical University on February 20, 2019 (approval No. PJ2020-03-19) and was registered with the Chinese Clinical Trial Registry on February 20, 2019 (registration number: ChiCTR2000030022). Results:. The oxygen saturation values were higher in the treatment group than in the control group on the first day after enrollment for patients treated at Fangcang Shelter Hospital. The axillary body temperature, respiratory rate, and oxygen saturation among patients in Fangcang Shelter Hospital were related to the time effect but not to the intervention measures. The respiratory rate and oxygen saturation of patients in the Anhui designated hospitals were related to the intervention measures but not to the time effect. The axillary body temperature of patients in Anhui designated hospitals was related to the time effect but not to the intervention measures. Conclusion:. Our preliminary study shows that low-dose emetine combined with basic conventional antiviral drugs improves clinical symptoms in patients with mild and common COVID-19 without apparent adverse effects, suggesting that moderately increased doses of emetine may have good potential for treatment and prevention of COVID-19.

BackgroundThe Omicron SARS-CoV-2 variant has spread quickly worldwide due to its effects on virus transmission and vaccine effectiveness. Interferon(IFN) has been shown to have a protective effect against SARS-CoV because of its broad antiviral activity. This study aimed to analyze the treatment effects of IFN α-2b spray in virus clearance of the Omicron SARS-CoV-2 variant.MethodsWe examined the effectiveness and safety of IFN α-2b spray in Shanghai, China, with participants infected with the Omicron SARS-CoV-2 variant in an open, prospective cohort study from April 16th to May 5th, 2022.ResultsA total of 871 confirmed patients were enrolled in this study. Four hundred and thirteen patients were allocated to the IFN α-2b spray group, and 458 patients were allocated to the control group. The viral shedding time was significantly different between experimental group and control group (11.90 vs.12.58, P 3 days group (13.56, 95%CI: 7.00-22.25, P

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that greatly threatens public health. This study aimed to examine a convenient early-warning biomarker of fatal outcomes in patients with SFTS to reduce mortality.MethodsA retrospective cohort study was performed, and patients with confirmed SFTS were enrolled in the top two hospitals in Anhui Province, China from 1 May 2016 to 31 October 2019. The clinical symptoms, laboratory indicators, and treatment data of patients with SFTS were evaluated. All patients with SFTS were followed up till 28 days from the start of admission. The laboratory indicators that could be used to predict the fatal outcome were identified.ResultsA total of 228 patients with SFTS were enrolled, 177 patients were enrolled in the survival group, and 51 patients in the death group. The median age of all 228 patients with SFTS was 63 years. Five laboratory indicators (SFTSV viral load, neutrophil to lymphocyte ratio (NLR), aspartate transaminase (AST)/alanine aminotransferase (ALT), ALT, and blood urea nitrogen (BUN)) were identified as the predicting factors of the fatal outcome of patients with SFTS. The area under the receiver operating characteristic (ROC) curve (AUC) of SFTSV viral load was the highest (0.919), then NLR (0.849), followed by AST/ALT (0.758), AST (0.738), and BUN (0.709). The efficacy of SFTVS viral load and NLR in predicting fatal outcomes was significantly higher than AST/ALT, AST, and BUN. The Kaplan–Meier survival curves show that the case fatality rate was significantly increased in patients whose SFTSV viral load was higher than 500,000 or NLR higher than 2.0. Gamma-globulin treatment showed a significant difference between the survival group and the death group, and the duration of gamma-globulin that had been proposed should not be

The antiviral response of natural killer (NK) cells and CD8+ T cells is weak in patients with chronic hepatitis B (CHB) infection. However, the specific characteristics of these cells and the association between NK cells and CD8+ T cell dysfunction is not well known. In this study, higher galectin-9 (Gal-9) expression was observed in circulating NK cells from CHB patients than from healthy controls and was found to contribute to NK cell dysfunction. In addition, circulating CD8+ T cells showed obvious dysfunction and overexpressed TIM-3, the natural receptor of Gal-9, during active CHB infection. Gal-9+ and Gal-9- NK cells from active CHB patients were sorted and cocultured with autologous CD8+ T cells. The proportion of tetramer+CD8+ T cells and the cytokines production of CD8+ T cells were lower after cocultivation with Gal-9+ than with Gal-9- NK cells. We showed that in vitro depletion of NK cells increased circulating hepatitis B virus (HBV)-specific CD8+ T cell responses in patients with active CHB infection. Because Gal-9 is increased in the serum of CHB patients, CD8+ T cells were sorted and cultured with exogenous Gal-9, resulting in lower IFN-γ, TNF-α, CD107a, and granzyme B levels, decreased expression of the activation receptor CD69, increased expression of TIM-3, and a high percentage of early apoptotic CD8+ T cells. Blocking Gal-9 or TIM-3 in vitro in a culture of peripheral blood mononuclear cells (PBMCs) stimulated with HBV peptide from active CHB patients restored CD8+ T cell function. However, blocking Gal-9 in vitro after removal of NK cells from PBMCs did not rescue CD8+ T cells exhaustion. Furthermore, NK and CD8+ T cells from active CHB patients were sorted and cocultured in vitro, and the exhaustion of CD8+ T cells were alleviated after blocking Gal-9 or TIM-3. In summary, overexpression of Gal-9 on NK cells, which interacts with TIM-3+CD8+ T cells and likely contributes to antiviral CD8+ T cell dysfunction, may be a potential target for the treatment of CHB patients.

The objective of this project was to explore the distribution and related factors of blood lead and the association between blood lead and hepatitis B core antibody (HBcAb). All the data were from the U.S. National Health and Nutrition Examination Survey (NHANES). In total, 15,097 (aged 20–80 years) participants were included. Participants without a history of blood transfusion were more likely to be exposed to lower levels of blood lead [−2.30 (−3.13, −1.47) for HBcAb (–) and −2.23 (−4.54, 0.08) for HBcAb (+)]. The odds ratio (OR) of HBcAb (+) increased with blood lead and the result was 1.09 (1.06, 1.12). This study showed that older adults, men, people with a lower education level, a lower ratio of family income to poverty (PIR), a lower body mass index (BMI), or a history of blood transfusion, people who lived with a companion or with a total number of people in the family >3, people living in the United States for a longer time, U.S. citizens by birth or naturalization, and people not born in the United States were associated with higher blood lead exposure, and blood lead had a positive association with HBcAb (+).

For the on-orbit service spacecraft attitude tracking task with external disturbances, considering the limited capacity of its actuators and high control performance required, an improved performance constraint control algorithm based on command filters is proposed in this paper. For the proposed control algorithm, before the theoretical control signal is transmitted to the actuator, it needs to be filtered by the command filter. This filter can constrain the rate, magnitude, and bandwidth of the signals, smooth the command signals and avoid peak interference. In terms of performance constraints, inspired by the performance constraint curve, this paper uses the determined points to re-design a new performance constraint function, which shows the maximum settling time parameters, allowing designers to pre-defined this limited time of the closed-loop system according to needs. Therefore, the maximum settling time of the actual closed-loop system will be less than the pre-defined maximum settling time. The controller based on the command filter is designed, and on this basis, the corresponding performance-constrained control algorithm with pre-defined maximum settling time guaranteed is proposed. Through the proof and simulation, the rationality and effectiveness of the proposed controller are further demonstrated.

In this paper, for the precise relative motion control of the 6-DOF on-orbit service spacecraft, motivated by discovering a proper method to flexibly adjust the settling time before the control system design, a constraint function is proposed. Considering the ability of pre-defined performance techniques to pre-design response behaviors, a relevant control named by Pre-defined Maximum Settling Time Control (PMSTC) is investigated. Under the proposed framework, a PMSTC for spacecraft systems is designed with the aid of the power integrator-adding technique. The proposed controller allows us to design the response performance of a closed-loop system in advance, e.g., maximum settling time, maximum steady-state error, and maximum overshoot. More importantly, the PMSTC is able to separate the coupling of the settling time and the choosing of control parameters, which thus alleviate the complexity of the control design. The closed-loop system of the 6-DOF spacecraft showcases the full power of this approach, based on which, the rationality and effectiveness of the algorithm have been verified. To illustrate the characteristics of this algorithm, this paper compares the proposed algorithm with some state-of-the-art algorithms and analyzes the effect of parameters in detail.

Objective To inspect the pesticide residues in longan samples from 10 cities of Guangdong Province and evaluate the health risk of dietary exposure. These collected data were expected to be useful in regulating the concentration of the pesticide residues, and also in supporting safe consumption of longan fruit. Methods 200 longan samples were collected randomly and 50 kinds of pesticde residues were analyzed. The dietary exposure risk was assessed by risk entropy which based on the statistics of pesticide residues. Results 20 kinds of pesticide residues were found in 84.00%(168/200) of the samples, and carbendazim with detection ratio of 33. 00%(66/200) was found to be in the highest frequencies of detected pesticides. Further results showed that 27. 50%(55/200) samples contained two or more pesticides. For 20 kinds of pesticides with detectable residues, acceptable daily intake(% ADI) was in the range of 0.00% to 8. 56%, which was less than 9.00%. The acute reference dose(%ARfD) was ranged from 0. 02% to 70.00%, which was less than 100.00%. These 20 kinds of pesticides were divided into three groups namely high risk group(5), medium risk group(7), and low risk group(8) by considering the residue risk score. Conclusion Chronic dietary intake risk and acute dietary intake risk of pesticide residues were relatively low in longan from 10 cities of Guangdong Province, and normal consumption of longan would not cause adverse health effects.

Based on the abundant core data of oil sands in the Mackay river in Canada, the termination frequency of muddy interlayers was counted to predict the extension range of interlayers using a queuing theory model, and then the quantitative relationship between the thickness and extension length of muddy interlayer was established. An equivalent upscaling method of geologic model based on tortuous paths under the effects of muddy interlayer has been proposed. Single muddy interlayers in each coarse grid are tracked and identified, and the average length, width and proportion of muddy interlayer in each coarse grid are determined by using the geological connectivity tracing algorithm. The average fluid flow length of tortuous path under the influence of muddy interlayer is calculated. Based on the Darcy formula, the formula calculating average permeability in the coarsened grid is deduced to work out the permeability of equivalent coarsened grid. The comparison of coarsening results of the oil sand reservoir of Mackay River with actual development indexes shows that the equivalent upscaling method of muddy interlayer by tortuous path calculation can reflect the blocking effect of muddy interlayer very well, and better reflect the effects of geological condition on production.

Background: Drug-induced liver injury (DILI) caused by Chinese patent medicines is increasing in China. The incidence of invasive fungal infections (IFIs) is increasing due to the suppression of the immune function in greater numbers of patients. Invasive procedures such as deep vein catheterization and the use of glucocorticoids are also predisposing factors to IFIs. The clinical presentation of IFI in teenagers is often atypical, challenging to diagnose, difficult to treat, and associated with a high fatality rate.Case presentation: Herein, we report 2 teenagers with liver failure after receiving oral Chinese patent medicines. Case 1 was a 14-year-old boy who presented with subacute liver failure who had been administered a Chinese patent medicine that included acetaminophen. Administration of glucocorticoids and non-bioartificial liver treatment improved his condition. Subsequently, invasive pulmonary Aspergillus (IPA) was diagnosed and was successfully treated with voriconazole for 85 days. Case 2 was a 17-year-old girl who presented with acute liver failure after taking the Chinese patent medicine QubaiBabuqi tablets for vitiligo. Chest computed tomography (CT) revealed multiple pulmonary nodules with an intermittent low-grade fever, and she was diagnosed with IPA. She was initially treated with caspofungin (23 days) and then voriconazole (406 days) for 429 days. Her liver function returned to normal, and lung lesions were absorbed in 2 patients. At the same time, two to three histopathological examinations of the liver biopsy showed that the drug-induced autoimmune-like phenomena could be improved by glucocorticoid therapy.Conclusion: To the best of our knowledge, this is the first report of the successful treatment of 2 cases of liver failure (Child–Pugh class C) caused by Chinese patent medicines complicated with IPA in teenagers. Drug-induced autoimmune-like phenomena could be improved by glucocorticoid therapy.

Nanpu 1-29 Area of Jidong Oilfield in China is currently in the stage of high water cut and low recovery degree. The remaining oil development and adjustment are difficult because of the complex reservoir heterogeneity and the lack of analysis of the reservoir architecture due to the unclear river type. This study first used sedimentary background, granularity, core, and sand body distribution to determine the river type and believed it belongs to the wandering braided river. Combined with core and logging data, four types of sedimentary architectural elements were found in the study area, namely, channel bar, braided channel, floodplain, and basalt. Based on the scale measurement of many similar modern wandering braided rivers, core data, and empirical formulas, the scales of the braided rivers were determined. The quantitative relationships among the scale of the braided river, the channel bar, and the braided channel were established. With this constraint, the reservoir architecture was anatomized. The results showed two filling types of the braided channels, including sandy filling and muddy filling. The combination patterns of the channel bars and the braided channels could be divided into three types, namely, superimposed, standalone, and contact, and the contact type was the primary type. On the whole, it showed the geometric morphological characteristics of the flat top convex at the bottom of the channel bar and the flat bottom convex at the top of the braided river channel. A careful measure of the architectural element was executed. The length of the single braided flow belts was 365.16-1349.72 m, and the width was 270.57-1160.54 m. The channel bar’s length was distributed 158.89-318.32 m, and the width was distributed 75.97-116.41 m. The braided river’s width was distributed 16.81-180.05 m. The length and width ratio of the channel bar was concentrated between 2 and 4, which manifested wide bar and narrow river channel mode. Finally, the static distribution model and dynamic response curve were compared to verify the correctness of the reservoir architecture characteristics to guide the subsequent development of the oilfield.

Introduction Hepatitis B virus (HBV) related acute-on-chronic liver failure (ACLF) is still a common type of liver failure in China. Therefore, we conduct this multicentre, non-blinded, randomised controlled clinical trial to investigate the efficacy and safety of combination treatment of double plasma molecular adsorption system (DPMAS) and low volume plasma exchange (PE) for patients with HBV related ACLF.Methods and analysis A total of 200 patients with HBV related ACLF in the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou Eighth People’s Hospital, Nanfang Hospital of Southern Medical University, The Third People’s Hospital of Shenzhen, Xiangya Hospital of Central South University and The First Affiliated Hospital of Anhui Medical University, will be recruited into this trial. Eligible patients will undergo randomisation at a 1:1 ratio to two arms: the control group and the trial group. Patients in control group will receive comprehensive internal medical treatment. Patients in trial group will receive treatment of DPMAS and sequential low volume PE for three times, and comprehensive internal medical treatment. Clinical safety will be assessed by the analysis of adverse events (AEs) and laboratory tests. The primary efficacy outcome will be the incidence of unfavored events including death, liver transplantation and treatment abandonment. The secondary efficacy outcome will be the model for end-stage liver disease score variation. All evaluations will be performed at baseline, and 4, 8, 12, 24, 36, 48 weeks after enrolment. All AEs will be reported as soon as they are noted during the entire study procedure.Ethics and dissemination This study was approved by Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University (approval no. (2020)02-173-01). The results and conclusions of this clinical trial will be published at academic conferences or in journals.Trial registration number NCT04597164.

Chronic hepatitis B (CHB) patients with severe liver fibrosis would be more likely to progress to a poorer prognosis. Treatment is considered once the liver fibrosis reaches significant liver fibrosis (≥S2). Leukocyte cell-derived chemotaxin-2 (LECT2) has been shown to contribute to liver fibrosis progression. No research has focused on the role of LECT2 in liver fibrosis in CHB patients. This study enrolled 227 CHB patients and divided them into the training group (n = 147) and validation group (n = 80), respectively. The expression of LECT2 in serum, protein and mRNA of the human liver tissues was detected to analyze the possible associations between LECT2 and liver fibrosis. A receiver operating characteristic curve (ROC) was used to estimate the efficacy of LECT2 for predicting liver fibrosis. The data showed that there was a positive relationship between LECT2 and the progression of liver fibrosis. In the training group, LECT2 was demonstrated to have better effectiveness than APRI and FIB-4. The AUC was 0.861, 0.698, and 0.734 for significant liver fibrosis, and 0.855, 0.769, and 0.752 for advanced liver fibrosis. Besides, the efficacy of LECT2 in different statuses of patients with CHB was examined and the effectiveness of LECT2 had also been confirmed in the validation group. All the results confirmed that LECT2 could act as a perfect predictor and thus offers a novel and direct biomarker to estimate liver fibrosis more accurately.

Although knowledge of the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas system has been applied in many research areas, comprehensive studies of this system in Salmonella, particularly in analysis of antibiotic resistance, have not been reported. In this work, 75 Salmonella isolates obtained from broilers or broilers products were characterized to determine their antimicrobial susceptibilities, antibiotic resistance gene profiles, and CRISPR array diversities, and genotyping was explored. In total, 80.00% (60/75) of the strains were multidrug resistant, and the main pattern observed in the isolates was CN-AZM-AMP-AMC-CAZ-CIP-ATM-TE-SXT-FOS-C. The resistance genes of streptomycin (aadA), phenicol (floR-like and catB3-like), β-lactams (blaTEM, blaOXA, and blaCTX), tetracycline [tet(A)-like], and sulfonamides (sul1 and sul2) appeared at higher frequencies among the corresponding resistant isolates. Subsequently, we analyzed the CRISPR arrays and found 517 unique spacer sequences and 31 unique direct repeat sequences. Based on the CRISPR spacer sequences, we developed a novel typing method, CRISPR locus three spacer sequences typing (CLTSST), to help identify sources of Salmonella outbreaks especially correlated with epidemiological data. Compared with multi-locus sequence typing (MLST), conventional CRISPR typing (CCT), and CRISPR locus spacer pair typing (CLSPT), discrimination using CLTSST was weaker than that using CCT but stronger than that using MLST and CLSPT. In addition, we also found that there were no close correlations between CRISPR loci and antibiotics but had close correlations between CRISPR loci and antibiotic resistance genes in Salmonella isolates.

Compressive sensing (CS) is a signal sampling theory that originated about 16 years ago. It replaces expensive and complex receiving devices with well-designed signal recovery algorithms, thus simplifying the imaging system. Based on the application of CS theory, a single-pixel camera with an array-detection imaging system is established for high-pixel detection. Each detector of the detector array is coupled with a bundle of fibers formed by fusion of four bundles of fibers of different lengths, so that the target area corresponding to one detector is split into four groups of target information arriving at different times. By comparing the total amount of information received by the detector with the threshold set in advance, it can be determined whether the four groups of information are calculated separately. The simulation results show that this new system can not only reduce the number of measurements required to reconstruct high quality images but can also handle situations wherever the target may appear in the field of view without necessitating an increase in the number of detectors.

Aspergillus-related disease was confirmed to be associated with immune disorders in patients, severe patients with severe fever with thrombocytopenia syndrome (SFTS) infected by novel phlebovirus were confirmed to have severe immune damage including cellular immunosuppression and cytokine storms. Secondary invasive pulmonary aspergillosis (IPA) in severe SFTS patients can increase fatality rate. This study investigated early-warning predictive factors of secondary IPA in severe SFTS patients. Receiver operating characteristic analysis was used to assess the value of immune parameters to predict IPA in SFTS patients. The cut-off values of CD4+ and CD8+ T-cell counts to predict IPA were 68 and 111 cells/mm3, with sensitivities of 82.6% and 72%, and specificities of 56.7% and 83.3%, respectively. Cut-off values of IL-6, TNF-α, IL-8, and IL-10 to predict IPA incidence in critically ill SFTS patients were 99 pg/mL, 63 pg/mL, 120 pg/mL, and 111 pg/mL, with sensitivities of 90.0%, 86.7%, 83.3% and 90.0% and specificities of 80.4%, 71.7%, 82.6% and 65.2%, respectively. Lower CD4+ and CD8+ T-cells counts, higher levels of IL-6, TNF-α, IL-8 and IL-10, higher incidence of pancreatic and renal damage, early antibacterial therapy of carbapenems, and intensive care unit admission were risk factors of IPA in SFTS patients. Multivariate logistic regression analysis indicated counts of CD4+ T-cells 99 pg/ml combined with IL-10 >111 pg/ml (OR 17.614, 95% CI 2.319–133.769, p=0.006), and brain natriuretic peptide level >500 pg/ml (OR 13.681, 95% CI 1.994–93.871, p=0.008) were independent risk factors for IPA in SFTS patients. The mortality in the IPA group was significantly higher than in the non-IPA group (p=0.001). Early antifungal treatment of IPA patients was significantly associated with improved survival (log-rank, p=0.022). Early diagnosis of IPA and antifungal treatment can improve the prognosis of SFTS patients. Besides, we speculate SFTS may be as a host factor for IPA.

Background: Ubiquitination is one of the most common post-translational modifications in cells and dysregulation is closely associated with the development of cancer. However, a comprehensive analysis of the role of ubiquitination in hepatocellular carcinoma (HCC) is still lacking. In this study we analyzed expression and prognostic value of Ubiquitin-Specific Proteases (USPs) in HCC, and the immunological role of USP36 in HCC. Methods: Expression data, prognostic data, and DNA methylation data in cases of HCC were obtained from the cancer genome atlas (TCGA). Overexpression of USP36 in HCC was confirmed in the gene expression omnibus (GEO) database and verified by quantitative PCR in 10 pairs of HCC samples. ULCAN was used to analyze the correlation between USP36 and clinicopathological features. TIMER2.0 and DriverDBv3 were used to analyze the USP36 mutational profile. GSEA analysis explored the potential signaling pathways of USP36 affecting HCC. The immune and stromal scores of HCC samples were calculated using the ESTIMATE algorithm. TIMER1.0 was used to explore the correlation between USP36 and immune cell infiltration. Finally, we analyzed the correlation of USP36 expression with immune checkpoint molecules and determined the IC50 values of 6 chemotherapeutic drugs using the pRRophetic software package. Results: Most USPs are abnormally expressed in HCC, among which USP36 and USP39 are most closely associated with HCC prognosis. We also found that USP36 is associated with TP53 mutational status. GSEA analysis indicated that USP36 may affect HCC progression through the dysregulation of various pathways such as ubiquitin-mediated proteolysis. USP36 expression positively correlated with both macrophage infiltration levels and multiple immune checkpoint molecules. Finally, chemosensitivity analysis indicated that chemosensitivity was lower in cells within the USP36 high expression group. Conclusions: Most USPs are abnormally expressed in HCC. Overexpression of USP36 in HCC is closely related to poor prognosis. In particular, the unique immunological role of USP36 may have potential clinical application value.

A set of thermo-hydro-mechanical coupling control equations was established, and the healing process of the joints between Gaomiaozi bentonite (GMZ01) buffer material blocks and the influence of the joint parameters were numerically simulated. The calculations consider the effect of joints on solute migration, the permeability and thermal conductivity of the buffer material, and the evolution of the healing effect. The effects of the joint design parameters, including the type, number, width, splicing form, and average dry density of the joint, are investigated. Studies show that, under an external water head, the joints will become hydraulic priority channels due to their higher permeability, which will shorten the saturation time of the blocks. As the bentonite gradually saturates, the swelling force compresses the joint material. This action improves the overall uniformity of the buffer material and reduces the priority channel effect. Meanwhile, the final average permeability and diffusion coefficient of the buffer material are found to mainly depend on the average dry density of the buffer material. The higher the average dry density of the buffer material is, the lower the final average permeability and diffusion coefficient are, whereas the distribution of joints and the block splicing are less affected by the average dry density of the buffer material. The findings of this study can provide a reference for the design of bentonite buffer material blocks in the repository.

Defining the trajectory of hydraulic fractures crossing bedding planes and other fractures is a significant issue in determining the effectiveness of the stimulation. In this work, a damage evolution law is used to describe the initiation and propagation of the fracture. The model couples rock deformation and gas seepage using the finite element method and is validated against classical theoretical analysis. The simulation results define four basic intersection scenarios between the fluid-driven and preexisting fractures: (a) inserting—the hydraulic fracture inserts into a bedding plane and continues to propagate along it; (b) L-shaped crossing—the hydraulic fracture approaches the fracture/bedding plane then branches into the plane without crossing it; (c) T-shaped crossing—the hydraulic fracture approaches the fracture/bedding plane, branches into it, and crosses through it; (d) direct crossing—the hydraulic fracture crosses one or more bedding planes without branching into them. The intersection scenario changes from (a) → (b) → (c) → (d) in specimens with horizontal bedding planes when the stress ratio β (β=σy/σx) increases from 0.2 to 5. Similarly, the intersection type changes from (d) → (c) → (a) with an increase in the bedding plane angle α (0° → 90°). Stiffness of the bedding planes also exerts a significant influence on the propagation of hydraulic fractures. As the stiffness ratio E1¯/E2¯ increases from 0.1 to 0.4 and 0.8, the seepage area decreases from 22.2% to 41.8%, and the intersection type changes from a T-shaped crossing to a direct crossing.

ABSRTACT Klebsiella pneumoniae is a common cause of human-pneumonia-derived sepsis with high morbidity and mortality. The microbiota promotes and maintains host immune homeostasis. The mechanisms by which the gut microbiota affects the host defenses in the respiratory system systematically, however, remain poorly understood. Here, we show that gut microbiota depletion increases susceptibility to extracellular K. pneumoniae infections in terms of increased bacterial burdens in lung and decreased survival rates. Oral supplementation with gut microbiota-derived short-chain fatty acids (SCFAs), subsequently activating G protein-coupled receptor 43 (GPCR43), enhances a macrophage’s capacity to phagocytose invading K. pneumoniae. Furthermore, SCFAs and GPR43 increase macrophage bacterial clearance by upregulating LAMTOR2, which is further identified as an antibacterial effector and elucidated to facilitate phagosome-lysosome fusion and extracellular signal-regulated kinase (ERK) phosphorylation. Lastly, conditional ablation of Lamtor2 in macrophages decreases their antimicrobial activity, even though mice were pretreated with exogenous SCFA supplementation. IMPORTANCE These observations highlight that SCFAs promote macrophage elimination of K. pneumoniae via a LAMTOR2-dependent signal pathway and suggest that it is possible to intervene in K. pneumoniae pneumonia by targeting the gut microbiota.

ABSTRACT Enrofloxacin is an important antibiotic used for prevention and treatment of Salmonella infection in poultry in many countries. However, oral administration of enrofloxacin may lead to the alterations in the microbiota and metabolome in the chicken intestine, thereby reducing colonization resistance to the Salmonella infection. To study the effect of enrofloxacin on Salmonella in the chicken cecum, we used different concentrations of enrofloxacin to feed 1-day-old chickens, followed by oral challenge with Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium). We then explored the distribution pattern of S. Typhimurium in cecum contents in vivo and analyzed the microbial community structure of cecum contents using microbial 16S amplicon sequencing. Untargeted metabolomics was used to explore the gut metabolome on day 14. Faecalibacterium and Anaerostipes, which are closely related to the chicken intestinal metabolome, were screened using a multi-omics technique. The abundance of S. Typhimurium was significantly higher in the enrofloxacin-treated group than in the untreated group, and S. Typhimurium persisted longer. Moreover, the cecal colony structures of the three groups exhibited different characteristics, with Lactobacillus reaching its highest abundance on day 21. Notably, S. Typhimurium infection is known to affect the fecal metabolome of chickens differently. Thus, our results suggested that enrofloxacin and Salmonella infections completely altered the intestinal microbiota and metabolism of chickens. IMPORTANCE In this study, we examined the effects of S. Typhimurium infection and enrofloxacin treatment on the microbiota and metabolite synthesis in chicken cecum, in order to identify target metabolites that may promote S. Typhimurium colonization and aggravate inflammation and to evaluate the important microbiota that may be associated with these metabolites. Our findings may facilitate the use of antibiotics to prevent S. Typhimurium infection.

Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis in human and is associated with high morbidity and mortality. The microbiota promotes and maintains host immune homeostasis during bacterial infections. However, the mechanisms by which the gut microbiota affects immune responses in the lung still remain poorly understood. Here, we performed cecal metabolomics sequencing and fecal 16s rRNA sequencing in K. pneumoniae-infected mice and uninfected controls and showed that K. pneumoniae infection led to profound alterations in the gut microbiome and thus the cecal metabolome. We observed that the levels of Lactobacillus reuteri and Bifidobacterium pseudolongum were significantly decreased in K. pneumoniae-infected mice. Spearman correlation analysis showed that alterations in the richness and composition of the gut microbiota were associated with profound changes in host metabolite concentrations. Further, short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, were detected in cecal contents and serum by gas chromatography-mass spectrometry (GC-MS). We observed that the concentrations of these three SCFAs were all lower in the infected groups than in the untreated controls. Lastly, oral supplementation with these three SCFAs reduced susceptibility to K. pneumoniae infections, as indicated by lower bacterial burdens in the lung and higher survival rates. Our data highlight the protective roles of gut microbiota and certain metabolites in K. pneumoniae-pneumonia and suggests that it is possible to intervene in this bacterial pneumonia by targeting the gut microbiota.

ObjectiveThe aims of this study were to describe azithromycin (AZM) susceptibility patterns among Shigella isolates in Anhui, China and identify predictors of resistance with mobile element-mediated genes.MethodsA total of 517 non-duplicate Shigella isolates (449 S. flexneri and 68 S. sonnei) were collected in the Anhui Province of China from September 2011–September 2015, and screened for the plasmid-mediated genes of decreased susceptibility to AZM (DSA), using polymerase chain reaction amplification and sequencing. Conjugation experiments and pulsed-field gel electrophoresis were conducted for all mphA-positive DSA isolates.ResultsThe DSA rate for 449 S. flexneri isolates was 33.6%, compared with 39.7% for 68 S. sonnei isolates. Among 161 DSA S. flexneri isolates, 93 (57.8%) carried the mphA gene. Among 27 DSA S. sonnei isolates, 11 (40.7%) carried the mphA gene. However, other plasmid-mediated DSA genes were not found in these isolates. A total of 89 transconjugants (95.7%) were obtained from 93 mphA-positive S. flexneri isolates through conjugation, and 10 transconjugants (90.9%) were obtained from 11 mphA-positive S. sonnei isolates. Furthermore, the minimum inhibitory concentrations (MICs) of AZM among 89 S. flexneri transconjugants ranged from 4 to 128 μg/mL, with an MIC50 of 8 μg/mL and MIC90 of 32 μg/mL. The MICs of AZM among 10 S. sonnei transconjugants ranged from 4 to 256 μg/mL, with an MIC50 of 8 μg/mL and MIC90 of 64 μg/mL. Thirteen clusters were found for mphA-positive S. flexneri, and five clusters were found for mphA-positive S. sonnei. Furthermore, 10 homologous isolates among 13 mphA-positive S. flexneri isolates with high-level DSA were from Sixian county and were multidrug-resistant strains. Of the 10 homologous S. flexneri isolates, eight were from children (≤5 years old), and two from the elderly (>60 years old).ConclusionOur study demonstrates that the DSA for Shigella isolates was severe, and the plasmid-mediated mphA gene was the most common macrolide resistance gene detected in Shigella isolates collected in Anhui, China. The mphA-positive S. flexneri isolates with high-level DSA facilitated clonal spread in children and the elderly. This finding is noteworthy and warrants further study.

Although persistent hepatitis B virus (HBV) infection is associated with natural killer (NK) cell dysfunction, it remains obscure whether HBV viral antigens are responsible for NK cell dysfunction in patients with chronic hepatitis B (CHB) infection. In this study, we found that the percentage of NK cells expressing the inhibitory receptor, NKG2A, was increased in CHB patients, and NKG2A blockade restored NK cell function. Furthermore, in CHB patients, the frequency of NK cells expressing NKG2A positively correlated with the number of regulatory T cells (Tregs) and production of interleukin-10 (IL-10) in these Tregs. Moreover, exposure of peripheral blood mononuclear cells (PBMCs) isolated from healthy controls to sera from CHB patients resulted in increased proportion of NKG2A+ NK cells; IL-10 blockade reduced the frequency of NKG2A+ NK cells while increasing the percentage of IFN-γ+ NK cells. In addition, stimulation of NK cells and Tregs from healthy controls with CHB sera together with anti-IL-10 antibody increased IFN-γ production in the culture supernatant. The frequencies of NKG2A+ NK cells and IL-10+ Tregs, along with serum levels of alanine transferase and HBV DNA, were significantly increased in CHB patients positive for the Hepatitis B e antigen (HBeAg, a marker of viral replication) when compared to HBeAg-negative CHB patients. Importantly, exposure of PBMCs from healthy controls to HBeAg resulted in increased IL-10 production but reduced levels of TNF and IFN-γ, and IL-10 blockade rescued the generation of TNF and IFN-γ in this assay. The reduced production of TNF and IFN-γ was also observed in NK cells and Tregs from healthy controls that were stimulated with HBeAg, while IL-10 blockade increased the secretion of these two cytokines. We conclude that HBeAg induces IL-10 production in Tregs, thereby leading to increased expression of NKG2A on NK cells, which contributes to NK cell dysfunction during CHB infection. These data suggest that HBeAg is associated with NK cell dysfunction in CHB.

The bearing response of pile foundations for cross-sea bridge subjected to lateral loading is investigated through threedimensional finite element numerical analyses. In the analyses, non-linear behavior of concrete is simulated using smeared cracking model, and the strain-stress relationship of rebar is modeled through perfectly elasto-plastic model obeying Mises yield criterion. The finite element model is validated against published lateral static loading test in situ. The effect of reinforcement ratio of reinforced concrete and vertical load level is explored on the displacement of pile head and lateral capacity of pile. The results show that for the pile with low reinforcement ratio, the allowable lateral capacity is controlled by concrete cracking, however the allowable lateral capacity is controlled by the displacement of pile head with high reinforcement ratio. The vertical load applied on the pile head may reduce its displacement but increase simultaneously the maximum moment in the pile body. Therefore, the optimum vertical load level is 0.4~0.6 times of the vertical ultimate load of a single pile.