Thymocyte selection-associated high mobility group box (TOX), a member of the high mobility group protein super-family, plays an important role in T cell development, functional maintenance, and exhaustion. It has been recently found that TOX exerts critical immunoregulatory functions during pathogen infections, and TOX expression is strongly associated with the intensity and tolerance of host immune responses. This review systematically summarizes the structural and functional features of TOX and focuses on its expression dynamics, mechanisms of action, and immunomodulatory effects during viral, bacterial, and parasitic infections, which provides a theoretical support to better understanding of the role of TOX in infectious diseases and provides new insights into development of potential immunotherapeutic strategies targeting TOX.

Objective To investigate the effect of spinal cord electrical stimulation on diabetic peripheral neuropathy.Methods A total of 120 patients with diabetic peripheral neuropathy were randomly assigned to three groups,with 40 cases in each group.Group A was treated with pregabalin.Group B received radiofrequency therapy of lumbar sympathetic ganglion.Group C was treated with spinal cord electrical stimulation.The treatment course was six months.Pain,EMG parameters,hemorheology indexes,quality of life,sleep quality,and HbA1c were compared among groups.Results Group C had higher therapeutic effective rate than groups A and B(P<0.05)after 6 months of treatment.After 1 week,3 months,6 months and 12 months of treatment,the visual analogue scale(VAS)scores and HbA1c levels of group C were lower than those of groups A and B(P<0.05).After 6 months of treatment,the motor nerve and sensory nerve conduction velocities of the median nerve and peroneal nerve in group C were higher than those in groups A and B(P<0.05).After 6 months of treatment,the whole blood viscosity and capillary plasma viscosity of group C were lower than those of groups A and B(P<0.05).After 6 months of treatment,the 36-item short form health survey(SF-36)score of group C was higher than that of groups A and B,and the Pittsburgh sleep quality Index(PSQI)score of group C was lower than that of groups A and B(P<0.05).The incidence of adverse reactions in group C was lower than that in groups A and B(P<0.05).Conclusion Compared with drugs and lumbar sympathetic ganglion radiofrequency therapy,spinal cord electrical stimulation has a better efficacy in the treatment of diabetic peripheral neuropathy.It can continuously relieve neuropathic pain,increase the velocity of motor and sensory nerve conduction,improve the hemorheology,HbA1c levels,quality of life and sleep quality,and has high safety and significant clinical value.

Objective To map the genome-wide distribution profile of histone H3K27me3 modification in diffuse gastric cancer tissues,identify target genes regulated by H3K27me3,and primarily explore the potential mechanism of its modification reprogramming in the occurrence and development of the tumor.Methods Normal gastric mucosal tissues and diffuse gastric cancer tissues were harvested from the patients who underwent examinations or treatments in the departments of gastroenterology and gastrointestinal surgery of our medical center between 2021 and 2023.There were 14 patients in the normal group(6 males and 8 females,average age of 46 years)and 14 patients in the gastric cancer group(8 males and 6 females,average age of 63 years).Cleavage under target and tagmentation(CUT&Tag)technology was employed to capture genomic regions modified by H3K27me3,and analyze the reprogramming characteristics of these modifications.RNA sequencing data,data from high-throughput chromosome conformation capture(Hi-C)technology,and publicly available single-cell data were integrated to investigate the target genes regulated by the reprogramming of H3K27me3 modifications in diffuse gastric cancer cells.Results The quality of the CUT&Tag and RNA sequencing data met the standards required for subsequent analysis.Histone H3K27me3 modifications in normal gastric mucosa and diffuse gastric cancer tissues were primarily distributed in distal intergenic regions and intronic regions.In gastric cancer tissues,compared to normal tissues,there was significant reprogramming of H3K27me3 modifications,characterized by a marked reduction in overall H3K27me3 signal intensity.The loss of 2 912 H3K27me3 signal peaks might lead to the up-regulation of 822 tumor-associated genes.Among them,56 genes displayed the most significant up-regulation(fold change in signal intensity≥2,P<0.05),with notable enrichment in the mammalian target of rapamycin complex 1(mTORC1)signaling pathway.Specifically,the methionine transporter SLC7A5 and the cystine transporter SLC7A11 were found to have the highest expression levels in gastric cancer tissues.Single-cell data revealed that the abnormal overexpression of SLC7A11 in diffuse gastric cancer was primarily observed in tumor epithelial cells.Further validation using public data and immunohistochemical experiments confirmed the elevated expression of SLC7A11 in diffuse gastric cancer,which is associated with poor prognosis in gastric cancer patients.Conclusion The reprogramming of histone H3K27me3 modification is an important epigenetic characteristic in diffuse gastric cancer.Loss of H3K27me3 signal peaks may up-regulate the expression of SLC7A11 in diffuse gastric cancer cells,and thereby promote tumor progression.

Objective:To explore the expression of nectin-4 and vanin-1 in esophageal squamous cell carcinoma(ESCC)and its influence on the malignant biological behaviors of ESCC cells,as well as the underlying mechanisms.Methods:Transcriptome sequencing combined with GO and KEGG enrichment analysis was used to identify the downstream target gene(vanin-1)regulated by nectin-4.The mRNA expression of vanin-1 in ESCC tissues was studied using the Timer2.0 database,and the mRNA and protein expression of vanin-1 in normal esophageal epithelial HET-1 and ESCC cells was detected by qPCR and Western blot,identifying ESCC KYSE-410 and KYSE-510 cells with the most significant differential expression.The expression of vanin-1 in KYSE-410 and KYSE-510 cells was knocked down using siRNA.The effects of vanin-1 knockdown on cell proliferation,migration,and invasion were measured using CCK-8 assay,wound healing assay,and Transwell chamber assay.Furthermore,KEGG and GO enrichment analyses were conducted for vanin-1-related signaling pathways.Immunohistochemistry was performed to compare the expression of vanin-1 between ESCC tissues and adjacent non-tumor tissues.Results:Timer2.0 database analysis and qPCR results showed that vanin-1 was highly expressed in both ESCC tissues and cell lines(both P<0.01).WB assay also confirmed high expression of vanin-1 protein in ESCC cells(P<0.01).siRNA successfully knocked down vanin-1 expression in KYSE-410 and KYSE-510 cells.Knockdown of vanin-1 significantly inhibited the proliferation,migration,and invasion capabilities of KYSE-410 and KYSE-510 cells(P<0.05 or P<0.01 or P<0.001 or P<0.000 1).KEGG and GO enrichment analysis suggested that vanin-1 might function through pathways related to pantothenic acid and coenzyme A synthesis metabolism.Immunohistochemistry results indicated that vanin-1 was highly expressed in ESCC tissues(P<0.000 1).Conclusion:Vanin-1 is highly expressed in ESCC tissues and promotes the proliferation,migration,and invasion of KYSE-410 and KYSE-510 cells through the nectin-4/vanin-1 axis.Targeting vanin-1 might offer a new therapeutic strategy for ESCC.

In order to investigate the effects of porin genes ompW,ompS and ompD on the biological properties and virulence of Salmonella typhimurium,the corresponding mutant strains were con-structed using the λ Red homologous recombination system,and the growth curves,motility,bio-chemical properties,in vitro genetic stability,biofilm-forming ability,drug resistance,and lethal dose at half capacity(LD50)between the standard strain and each mutant strain were detected by comparative assays for Salmonella typhimurium.The results showed that,compared with the standard strain,the ompD and ompW mutation had less effect on the growth rate and motility of the bacteria,while the ompS mutation significantly reduced the growth rate and motility;none of the three genetic mutation affected the biochemical characteristics of Salmonella typhimurium,nor the genetic stability,but affected its susceptibility to a variety of commonly used antibiotics to varying degrees and caused a highly significant decrease(P＜0.01)in the ability to form a biofilm,and the results showed that the three mutant strains had a significant reduction in the ability to form a biofilm.The result of LD50 virulence assay showed that all three genetic mutation led to a decrease in the virulence of Salmonella typhimurium,among which the ompS mutant strain showed the most obvious decrease in virulence,LD50 was 25 times that of the standard strain.In conclusion,mutations of the pore protein ompW,ompS,and ompD genes can affect some biological properties of Salmonella typhimurium.The results of this study laid an experimental foundation for further research on the biological functions of the pore protein ompW,ompS and ompD genes and Salmonella pathogenicity.

Objective To summarize the experience of integrative palliative care at Peking Union Medi-cal College Hospital and provide a reference for promoting the integrative palliative care model.Methods Twenty cases receiving integrative palliative care at Peking Union Medical College Hospital were collected.The clinical characteristics,reasons for initiating integrative palliative care,the process of integrative palliative care,and feedback from these cases were summarized.Results Insomnia(11 cases,55％)and pain(9 cases,45％)were the most common symptoms requiring control in the 20 cases.The integrative palliative care team assisted in medical decision-making for 17 cases(85％),prepared end-of-life for 9 cases(45％),assisted in the transfer for 3 cases(15％),and provided comfort care for all the 20 cases(100％).Conclusions The integrative palliative care model can help alleviate suffering in end-of-life patients and provide support to patients'families and the original medical teams.This model is worth further promotion within class A tertiary hospitals.

Objective This paper aims to evaluate the effectiveness of the Plan Do Check Act(PDCA)cycle in the quality improvement of medical device adverse event report forms to provide references for developing improvement strategies.Methods This study randomly selected 271 report forms from hospitals in Guangdong Province from January 1,2022,to March 31,2022 as the pre-implementation group.Another 462 report forms from January 1,2023,to March 31,2023 were randomly selected after implementing the PDCA cycle as the post-implementation group.The effect evaluation was concluded by comparing the average score on quality assessment of report forms between the two groups from 21 cities in Guangdong Province.Results The post-implementation group showed significantly higher overall average score on quality assessment as compared to the pre-im-plementation group(P＜0.05).After the implementation,the form completions on medical devices,adverse events,and usage,were significantly improved(P＜0.05).Conclusion The PDCA cycle can effectively improve the quality of medical device ad-verse event report forms,which is significant for standardizing the monitoring of medical device adverse events and subsequent in-vestigation and resolution of risk.

OBJECTIVE To investigate the regulatory effects of couplet medicinals of Atractylodes macrocephala-Aucklandia lappa on gut microbiota and short-chain fatty acids （SCFAs） in the diarrhea-type irritable bowel syndrome （IBS-D） rats with spleen deficiency. METHODS The IBS-D rat model with spleen deficiency was induced by intragastric administration of Senna alexandrina combined with restraint stimulation. The model rats were divided into model group， positive control group （pinaverium bromide 1.5 mg/kg）， A. macrocephala-A. lappa low-dose， medium-dose and high-dose groups （0.7， 1.4， 2.8 g/kg）， with 6 rats in each group. Another 6 healthy rats were taken as the blank control group. The blank control group and the model group were given normal saline intragastrically， and other groups were given relevant drug liquid intragastrically， once a day， for consecutive 14 days. The general characteristics of rats and fecal water content were observed， and intestinal sensitivity [evaluating by abdominal wall withdrawal reflex （AWR） threshold] and the intestinal propulsion rate were determined. The serum levels of 5- hydroxytryptamine（5-HT）and SP were detected， and the pathological changes of colon tissue were observed； the protein expressions of 5-HT-3 receptor（5-HT3R）， 5-HT4R and 5-HT transporter（SERT） in colon tissue of rats were detected. 16S rRNA sequencing was performed for the feces of rats in blank control group， model group and A. macrocephala-A. lappa high-dose group； the contents of acetic acid， propionic acid and butyric acid in the feces of the rats were determined. RESULTS Compared with the model group， the body weight after 7 and 14 days of medication， fecal water content， AWR threshold， and the protein expressions of 5-HT4R and SERT in colon tissue were increased significantly in the A. macrocephala-A. lappa medium-dose and high-dose groups （P＜0.05 or P＜0.01）； serum contents of 5-HT and SP， intestinal propulsion rate （except for A. macrocephala-A. lappa medium-dose group）， the protein expression of 5-HT3R in colon tissue were decreased significantly （P＜0.01）； diarrhea relief， mental state recovery， and partially recovery of the structure of colon tissue were all found； moreover， the diversity and species number of gut microbiota were reduced in A. macrocephala-A. lappa high-dose group and the content of butyric acid in fecal samples was significantly reduced （P＜0.05）. CONCLUSIONS The compatibility of A. macrocephala and A. lappa can improve intestinal motility and sensitivity of IBS-D model rats with spleen deficiency， and alleviate diarrhea. This may be related to improving changes in intestinal microbiota structure， reducing 5-HT expression and butyric acid content， and increasing 5-HT4R and SERT expression.

Dexmedetomidine displays multiple mechanisms of neuroprotection in ameliorating ischemic brain injury. In this study, we explored the beneficial effects of dexmedetomidine on blood-brain barrier (BBB) integrity and neuroinflammation in cerebral ischemia/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h and reperfusion for 24 h to establish a rat model of cerebral ischemia/reperfusion injury. Dexmedetomidine (9 µg/kg) was administered to rats 30 min after MCAO through intravenous injection, and SB203580 (a p38 MAPK inhibitor, 200 µg/kg) was injected intraperitoneally 30 min before MCAO. Brain damages were evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, Nissl staining, and brain water content assessment. BBB permeability was examined by Evans blue staining. Expression levels of claudin-5, zonula occludens-1, occludin, and matrix metalloproteinase-9 (MMP-9) as well as M1/M2 phenotypes-associated markers were assessed using immunofluorescence, RT-qPCR, Western blotting, and gelatin zymography. Enzyme-linked immunosorbent assay was used to examine inflammatory cytokine levels. We found that dexmedetomidine or SB203580 attenuated infarct volume, brain edema, BBB permeability, and neuroinflammation, and promoted M2 microglial polarization after cerebral ischemia/reperfusion injury. Increased MMP-9 activity by ischemia/reperfusion injury was inhibited by dexmedetomidine or SB203580. Dexmedetomidine inhibited the activation of the ERK, JNK, and p38 MAPK pathways. Moreover, activation of JNK or p38 MAPK reversed the protective effects of dexmedetomidine against ischemic brain injury. Overall, dexmedetomidine ameliorated brain injury by alleviating BBB permeability and promoting M2 polarization in experimental cerebral ischemia/reperfusion injury model by inhibiting the activation of JNK and p38 MAPK pathways.

Background:The core circadian clock gene Bmal1 has been shown to be involved in the formation of visceral sensitization in irritable bowel syndrome(IBS)by affecting the tryptophan hydroxylase 1(TPH1)-5-hydroxytryptamine(5-HT)pathway,but the exact mechanism of its regulation is unknown.Aims:To investigate the molecular mechanism by which Bmal1 regulates the TPH1-5-HT pathway through the clock-controlled gene Piezo1.Methods:Dexamethasone was used to synchronize the expression of the circadian clock genes in RIN-14B cells.Bmal1 expression was up-regulated or down-regulated in RIN-14B cells by plasmid and siRNA transfection of the enterochromaffin cell(EC)model.The expression levels of target genes and proteins were detected by immunofluorescence staining,RT-qPCR,and Western blotting.5-HT content was detected by ELISA method.Results:(1)This study was the first to report the oscillation characteristics of RIN-14B circadian clock genes in EC model,among which the oscillation of Bmal1 was the most significant.Immunofluorescence showed that RIN-14B cells expressed CGA,Bmal1 and Piezo1.(2)After transfected with the Bmal1 overexpression plasmid,the mRNA and protein expression of Bmal1 were significantly up-regulated in RIN-14B cells compared with the negative control group(all P<0.001);while transfected with Bmal1 siRNA significantly decreased the mRNA and protein expression of Bmal1 in RIN-14B cells compared with the negative control group(all P<0.05).(3)After transfected with Bmal1 overexpression plasmid,the mRNA and protein expression of Piezo1,the protein expression of TPH1,and the intracellular content of 5-HT were significantly increased(all P<0.051).(4)After transfected with Bmal siRNA,mRNA expression of Piezo1 and TPH1 in RIN-14B cells was significantly down-regulated(all P<0.05),and the protein expression of Piezo1,TPH1,the intracellular 5-HT content tended to be decreased by 21%,31%,and 10%,respectively.Conclusions:RIN-14B cells have the characteristics of rhythmic oscillation of circadian clock genes,and Bmal1 overexpression and underexpression EC models can be successfully established by using RIN-14B cells.Overexpression and underexpression of Bmal1 can lead to significant changes in the clock-controlled Piezo1-TPH1-5-HT signaling pathway,suggesting that Bmal1 can be expressed by clock-control signals through the Piezo1-TPH1 pathway.This suggests that Bmal1 may be involved in the development of visceral hypersensitivity in IBS through regulation of 5-HT synthesis by the clock-controlled gene Piezo1.