Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Background: Obesity and chronic pain are related in both directions, according to earlier observational research.This research aimed to analyze the causal association between obesity and chronic pain at the genetic level, as well as to assess whether common factors mediate this relationship. Methods: This study used bidirectional two sample Mendelian randomization (MR) technique to analyze the association between obesity and chronic pain. Obesity's summary genome-wide association data were obtained from European ancestry groups, as measured by body mass index (BMI), waist-to-hip ratio, waist circumference (WC), and hip circumference (HC), genome-wide association study data for chronic pain also came from the UK population, including chronic pain at three different sites (back, hip, and headache), chronic widespread pain (CWP), and multisite chronic pain (MCP). Secondly, a two-step MR and multivariate MR investigation was performed to evaluate the mediating effects of several proposed confounders. Results: The authors discovered a link between chronic pain and obesity. More specifically, a sensitivity analysis was done to confirm the associations between greater BMI, WC, and HC with an increased risk of CWP and MCP.Importantly, the intermediate MR results suggest that education levels and smoking initiation may mediate the causal relationship between BMI on CWP, with a mediation effect of 23.08% and 15.38%, respectively. Conclusions The authors’ findings demonstrate that the importance of education and smoking in understanding chronic pain’s pathogenesis, which is important for the primary prevention and prognosis of chronic pain.

Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To discuss the effect of long-term use of chlorhexidine on the resistance of Enterococcus faecalis(E.faecalis),and to clarify its mechanism.Methods:The standard strain of E.faecalis was repeatedly exposed to chlorhexidine for 10 generations,and the minimum inhibitory concentration(MIC)was recorded at each passage.The bacteria collected from the 10th generation with increased MIC values were designated as the E.faecalis chlorhexidine-resistant strains(E.faecalis-Cs).The growth curves of two strains were drawn;the morphology of two strains were observed by transmission electron microscope;the number of biofilm formation of two strains was detected by crystal violet staining;the bacterial hydrophobicities of two strains were detected by microbial adhesion to hydrocarbons(MATH)method;the expression levels of S-ribosylhomocysteine lyase(LuxS)mRNA in the bacterial biofilms of two strains were detected by real-time fluorescence quantitative PCR(RT-qPCR)method.Results:From the 0th to the 10th generation,the MIC values of E.faecalis were gradually increased.The growth curves of E.faecalis and E.faecalis-Cs showed no significant differences.The transmission electron microscope observation results showed that both E.faecalis and E.faecalis-Cs appeared oval or diplococcal,with intact cell wall structures,smooth edges,and evenly distributed cytoplasm.There were no significant differences in the morphology,size,cell wall thickness,or integrity between two types of bacteria.The crystal violet staining results showed that compared with E.faecalis,the number of biofilm formation of E.faecalis-Cs was significantly increased(P<0.05).The MATH results showed tha the hydrophobicity of E.faecalis-Cs was significantly higher than that of E.faecalis(P<0.05).The RT-qPCR results showed that the expression level of LuxS mRNA in the biofilms of E.faecalis-Cs was significantly higher than that of E.faecalis(P<0.05).Conclusion:E.faecalis develops the resistance after repeated exposure to the chlorhexidine,and the pathogenicity of the resistant strain is enhanced.The high expressin of quorum sensing(QS)system LuxS gene and stronger biofilm forming ability of bacteria may be the potential mechanism for E.faecalis to tolerate the chlorhexidine.

Objective:To analyze the root canal diameter of the mandibular first premolar by using finite element analysis to simulate the stress distribution of dentin under three different preparation methods,and to provide the basis for clinical root canal preparation strategies of the mandibular first premolars.Methods:Twenty-one patients with complete cone beam computed tomography(CBCT)images were selected.The original DICOM format data from CBCT were imported into Mimics 21.0 software to measure the root canal diameter at 3,6,9,and 12 mm from the apex and the root canal taper was segmentally calculated.Based on this,three-dimensional finite element models of the dental and periodontal tissues were constructed.Control group,maximum diameter preparation group,uniform preparation group,and 0.06 taper instrument preparation group were designed.In ANSYS Workbench 17.0 finite element analysis software,a 200 N load was applied to the buccal,lingual,and occlusal surfaces in various groups,and the stresses on dentin in various groups were analyzed.Results:The analysis of root canal taper at 3-6 mm,6-9 mm,and 9-12 mm from the apex of mandibular first premolar teeth showed that the taper was similar in the mesial-distal direction at 3-6 mm from the apex.The average taper in the buccal-lingual direction at 6-9 mm from the apex was 0.29,which was greater than the taper in the apical 1/3 and coronal 1/3.Under the same load,the peak stress values in dentin of mandibular first premolar teech in various groups were increased sequentially:4.693 6,16.304 0,14.278 0,and 18.682 0 MPa.The stress in maximum diameter preparation group concentrated on the canal wall with the highest stress value.The stress in uniform preparation group concentrated on the root surface,and the stress values on each section were lower than those in maximum diameter preparation group.The stress in 0.06 taper instrument preparation group concentrated on the apical 1/3 of the root surface.Conclusion:The root canal of the mandibular first premolar has a unique elliptical taper shape,and there are significant differences in diameter and taper between the mesial-distal and buccal-lingual directions.Different preparation methods result in different stress distributions on the canal wall,and the uniform preparation is the best method for enlarging the canal.

Objective To establish the sheep model of lumbar spine osteoporosis in vitro,and to search the texture parameters with identification significance and establish its regression formula relation with DXA measured bone mineral density,bone ash density and bone ash degree.Methods The L1-L3 trigeminy verte-bral body in 120 sheep conducted the immersion and decalcification by EDTA-Na2 solution (0.4916 mmol/L) immersion method,the muscles and attachment bone were removed.Then they were randomly divided into 4 groups (group A,B,C and D),30 cases in each group.They were immersed in 10％ formaldehyde solution for anticorrosion.The group A,B,C and D were immersed in the prepared EDTA-Na2 solution for decalcification 0,4,9,15 d to prepare the in vitro osteoporosis models.Thin-slice CT scan and DXA bone density measure-ment on the above-mentioned lumbar vertebrae were performed,and the volume and dry weight of each verte-bral body were measured,and then calcined at a constant temperature of 1100 ℃ in a muffle furnace for 6 h to measure the weight of ashes.The bone ash weight,bone ash density and bone ash degree were measured.The MaZda texture analysis software was used to conduct the texture analysis on the cancellous substance of the vertebral body in the above CT images,and the texture features were screened by the Fisher coefficient,classi-fication error probability combined with average correlation coefficient,interactive information and the three combined method.The 4 groups of bone mineral density conducted the classification analysis by the original data analysis (ODA),principal component analysis (PCA),linear discriminant analysis (LDA) and nonlinear discriminant analysis (NDA).The correlation analysis between the texture parameters screened by the above method with the bone density,bone grey degree and bone ash density for searching the texture parameters with strongest correlation.The texture parameters with strongest correlation served as the independent varia-bles,the bone density,bone grey degree and bone ash density as the dependent variables,and the unitary and binary linear regression analyses were performed for obtaining the regression equation.Results With the pro-longation of decalcification time,the CT images showed that the bone cortex gradually thinned,the cancellous bone density was decreased,and the trabecular bone became sparse.The identification ability of FPM com-bined with NDA was strongest,and the false judgment rate was only 2.5％.Among them,the contrast in the gray symbiosis matrix had strongly negative correlation with the bone gray degree (r=-0.938).The entropy in the gray co-occurrence matrix had strongly negative correlation with the bone ash density and bone mineral density (r=-0.927,-0.896).The unitary linear regression equation was expressed as bone grey degree=0.692-0.002×Contrast,bone ash density=0.802-0.121×Entropy,bone density=1.301-0.200×Entro-py.Conclusion The significant correlation exists between some texture parameters and bone mineral density related parameters in thin slice CT images of sheep lumbar spine,which could establish a regression formula relationship.

Pharmacological perturbation studies based on protein-level signatures are fundamental for drug dis-covery.In the present study,we used a mass spectrometry(MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds.The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells.Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol,as well as the noncanonical targets of clinically approved tamoxifen,lovastatin,and their derivatives.Furthermore,the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints.This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.