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 differences in eosinophil(EOS)infiltration in cervical tissue and its relationship with cervical-related diseases,and to clarify the effect of EOS on the occurrence and development of cervical intraepithelial neoplasia(CIN)and cervical cancer.Methods:The clinical data of 256 patients with cervical diseases were collected and divided into cervical cancer group(n=46,including 26 cases of squamous cell carcinoma,15 cases of adenocarcinoma,and 5 cases of adenosquamous carcinoma),chronic cervicitis group(n=50),CIN stage Ⅰ group(n=50),CIN stage Ⅱ group(n=50),CIN stage Ⅲ group(n=30),and normal group(adjacent normal cervical tissue,n=30)based on their conditions.Colposcopy was used to observe the morphology of cervical tissue of the patients in various groups;thin-layer liquid-based cytology test(TCT)was used to observe the morphology of the cervical exfoliated cells in various groups;hybrid capture-chemiluminescence method was used to detect the human papillomavirus(HPV)infection in cervical tissue of the patients in various groups;HE staining was used to observe the pathomorphology of cervical tissue of the patients in various groups;Congo red staining was used to detect the numbers of EOS infiltration in cervical tissue of the patients in various groups;Pearson correlation analysis was used to analyze the correlation between the number of EOS infiltration and the malignancy degree of cervical cancer.Results:The cervical surface of the patients in normal group was smooth and pink,with uniformly distributed capillaries;the cervical surface of the patients in chronic cervicitis group showed red inflammatory changes,with some accompanied by Nabothian cysts and varying degrees of erosion and ulcers;the patients in CIN stage Ⅰ,CIN stage Ⅱ,and CIN stage Ⅲ groups showed epithelial ulcers,thickening,and irregular morphology,with mosaic and punctate vessels;the cervical surface of the patients in cervical cancer group showed raised areas with neoplasms and necrotic ulcers,and they were fragile and prone to bleeding.After acetic acid staining,no obvious changes of the patients in normal group were observed.The cervix of the patients in chronic cervicitis group showed slight white changes that lasted for a short time;in CIN stage Ⅰ,CIN stage Ⅱ,and CIN stage Ⅲ groups,irregular thin acetowhite epithelium with map-like borders was observed,with increasingly acetowhite reactions and larger areas as the stages advanced.The cervix of the patients in cervical cancer group showed thick acetowhite epithelium that lasted longer,with rigid and clear contours.After iodine staining,the cervix of the patients in normal group was brown,with uniform coloration;the cervix of the patients in chronic cervicitis group showed poor coloration in inflammatory lesion areas;the cervix of the patients in CIN stage Ⅰ group showed iodine coloration in metaplastic areas,while the cervix of the patients in CIN stage Ⅲ group showed poor coloration in larger lesion areas;the cervix of the patients in cervical cancer group showed irregular surfaces with cauliflower-like growth and no coloration after iodine staining,appearing orange-yellow or mustard yellow.The TCT observation results showed there were no heteromorphic cells and few inflammatory cells in cervical exfoliated cells of the patients in infiltration in normal group;there were numerous neutrophils and EOS in exfoliated cervical cells without heteromorphic cells in chronic cervicitis group.The heteromorphic binucleated cells with high nuclear-cytoplasmic ratios and deeply stained nuclei were observed in cervical exfoliated cells of the patients in CIN stage Ⅰ and CIN stage Ⅱ groups.More heteromorphic cells with high nuclear-cytoplasmic ratios and irregular nuclear membranes were showed in cervical exfoliated cells of the patients in CIN stage Ⅲ group.The cervical exfoliated cells of the patients in cervical cancer group showed large and prominent nucleoli,clustering into syncytial changes.Compared with normal group,the atypial of cervical exfoliated cells in CIN stage Ⅰ,CIN stage Ⅱ,CIN stage Ⅲ,and cervical cancer groups was increased.The hybrid capture-chemiluminescence results showed that compared with normal and chronic cervicitis groups,the numbers of HPV infection and TCT heteromorphic cells of the patients in CIN stage Ⅰ,CIN stage Ⅱ,and CIN stage Ⅲ groups were increased(P<0.05);compared with CIN stage Ⅰ,CIN stage Ⅱ,and CIN stage Ⅲ groups,the numbers of HPV infection and TCT heteromorphic cells of the patients in cervical cancer group were increased(P<0.05).The HE staining results showed normal cell morphology and structure in normal group,with infiltration of inflammation cells such as neutrophils,monocytes,macrophages,EOS,and lymphocytes;in chronic cervicitis group,the infiltration of inflammatory cells was increased;in CIN group,the cervical cells showed slightly larger nucleoli and heteromorphic cells,with inflammatory cells mainly distributing around the hetermomorphic cells;in cervical cancer group,the cervical cells showed large and deeply stained nucleoli with significant atypia,and the infiltration of inflammatory cells around the cancer cells was increased.Compared with normal group,the numbers of inflammatory cells and EOS infiltration in cervical tissue of the patients in chronic cervicitis group were increased(P<0.05),and the numbers of inflammatory cells and EOS infiltration of the patients in CIN group were increased(P<0.05);compared with chronic cervicitis group,the number of inflammatory cells and EOS infiltration of the patients in CIN group were decreased(P<0.05);compared with chronic cervicitis group and CIN group,the numbers of inflammatory cells and EOS infiltration of the patients in cervical cancer group were increased(P<0.05).The EOS in cervical cancer tissue was mainly distributed around the cancer nests;compared with CIN stage Ⅰ group,the numbers of EOS infiltration in CIN stage Ⅱ and CIN stage Ⅲ groups were increased(P<0.05);compared with CIN stage Ⅱ group,the number of EOS infiltration in CIN stage Ⅲ group was increased(P<0.05).The higher the malignancy degree of the tumor,the more EOS infiltration was observed,and the number of EOS infiltration was positively correlated with the invasion depth of cervical cancer(r=0.533 0,P<0.01).Conclusion:HPV infection and EOS infiltration play a role in promoting the and occurrence development of cervical precancerous lesions and cervical cancer.

Objective To observe the changes of plasma gastrointestinal hormones in motion sickness sensitive and insensitive individuals before and after vertical oscillation stimulation,and to construct a susceptibility prediction model for motion sickness.Methods A total of 60 healthy male volunteers were enrolled to receive sinusoidal vertical oscillation stimulation for 45 min.The motion sickness susceptibility questionnaire(MSSQ)was filled out before the experiment.Immediately after motion,the severity of motion sickness was evaluated by Graybiel scale.The motion sickness sensitive(Graybiel score≥8 and MSSQ susceptibility index＞21,n=15)and insensitive(Graybiel score≤2 and MSSQ susceptibility index＜5,n=15)participants were screened.Plasma levels of glucagon-like peptide-1(GLP-1),cholecystokinin(CCK),leptin,ghrelin,neuropeptide Y(NPY)and orexin A(OXA)were detected by enzyme-linked immunosorbent assay before and after vertical oscillation stimulation.Logistic regression model was used to analyze the predictive effect of plasma gastrointestinal hormone levels on susceptibility to motion sickness,and a combined predictive model was established.Receiver operating characteristic(ROC)curve was used to analyze predictive value of the model.Results Ghrelin and CCK levels were significantly increased in the sensitive group after stimulation compared with those before stimulation(both P＜0.01),while NPY and leptin levels were significantly decreased(both P＜0.01).Similar results were also observed when compared with the insensitive group after stimulation.Multivariate logistic regression analysis showed that plasma ghrelin,CCK and NPY were independent predictors of susceptibility to motion sickness.The established susceptibility prediction model for motion sickness was logit(P)=-0.051 ×ghrelin+0.060× NPY-0.169 ×CCK+33.397.ROC curve analysis showed that area under curve(AUC)value of the prediction model was 0.988,the sensitivity and specificity were 100.0％and 93.3％,respectively,and the prediction effect was better than ghrelin,CCK and NPY alone(AUC=0.792,0.880,0.838).Conclusion The changes of peripheral gastrointestinal appetite regulating hormone levels may be related to the susceptibility to motion sickness.The combined use of these indicators can predict the susceptibility to motion sickness.

Objective To analyze the detection efficiency of p16INK4a protein combined with human papillomavirus and liquid-based cytology(LCT)in the screening of cervical precancerous lesions,and to provide a basis for cervical cancer preven-tion and treatment.Methods The results of p16INK4a staining of cervical epithelial cells,human papillomavirus testing and cer-vical cytology were analyzed in 139 inpatients at Guangzhou Women's and Children's Medical Center between January 2019 and December 2020.Of them,there were 111 patients with cervical intraepithelial neoplasia(CIN)and 28 cases of cervical inflam-matory disease.The efficacy of the three methods alone and in combination to screen for CIN lesions was compared.Results In the detection of CIN patients,the sensitivity of p16INK4a,microfluidic microarray and cervical cytology for detecting CIN and a-bove lesions was 91.89% ,94.59% and82.88% ,with specificity of 57.14% ,17.86% and46.43% ,and AUC of 0.75,0.56 and 0.65,respectively;while the sensitivity of"p16INK4a+LCT","p16INK4a+hrHPV","LCT+hrHPV"and their sen-sitivity were 96.40% ,97.30% ,94.59% and 99.10% ,their specificity was 85.71% ,92.86% ,89.29% and 92.86% ,and the AUC was 0.91,0.95,0.92 and 0.96,respectively.Conclusion The combined p16INK4a and hrHPV test helps to improve diagnostic accuracy and early detection,thus allowing for earlier intervention or treatment.This combined application allows for more accurate identification of low-grade and high-grade cervical intraepithelial neoplasia,providing more information for indi-vidualized patient management.

Objective To study the effects of radiation on the morphology,function,and NLRP3 expression of mouse salivary gland tissue,and provide new ideas to repair radiation-induced damage to salivary gland tissue.Methods We established a mouse model of radiation-induced submandibular gland injury and Recorded the weight of drinking water.The salivary flow rate was assessed,and HE staining was used to observe submandibular gland injury.Immunohistochemistry and Real-time PCR were used to assess expression of NLRP3 and Caspase-1 in the radiation-injured submandibular gland of mice at 1,3,7 and 14 days after radiation exposure.Results Over time,the amount of water consumed by radiation group mice was gradually increased,the salivary flow rate was decreased,and inflammatory cells in the submandibular gland continued to increase.Acinar cells gradually showed lesions,such as nuclear pyknosis and vacuolization.At 7 and 14 days after radiation exposure,expression levels of NLRP3 and Caspase-1 proteins and genes in the radiation group were significantly higher than those in the normal group(P＜0.05).Conclusions Radiation damages mouse submandibular gland tissue and activates the NLRP3 inflammasome to increase its expression level.

Objective:To understand the characteristics of sexualized drug use (SDU) among men who have sex with men (MSM) in Chengdu and classify their behavioral patterns by applying the two-step cluster (TSC) algorithm and by exploring the association between SDU patterns and high risk sexual behaviors, in order to provide a reference basis for the development of HIV prevention interventions.Methods:Supported by an MSM-friendly organization in Chengdu from December 2021 to February 2022, MSM were recruited by on-site survey and peer referral to collect information on sociodemographics, SDU characteristics, sexual behaviors, STD diagnosis, and HIV status. TSC was performed to classify the characteristics of SDU, and the differences between groups were compared. Chi-square test and multiple binary logistic regressions were used to identify the relationship between SDU clusters and HIV-related risk sexual behaviors.Results:A total of 727 MSM were surveyed, and 39.8% (289/727) of the respondents reported SDU experience with a same-sex partner in the last six months. TSC clustered SDU-MSM into three behavioral pattern groups. There were significant differences in monthly income, types of drugs used for SDU, mode, frequency, polydrug use, multiple sexual partners, non-adherence to condom use, and group sex among the three groups of SDU-MSM ( P<0.05). Multivariate binary logistic regression analysis showed that the third category of SDU-MSM was 2.22 (95% CI: 1.06-4.66) times more likely than the first category not to use condoms consistently; the third and second categories were 2.82 (95% CI: 1.18-6.77) times and 8.78 (95% CI: 3.42-22.42) times. Conclusions:The prevalence of SDU among MSM in Chengdu was more than 1/3, and different SDU clustering pattern was associated with high-risk sexual behaviors. MSM with higher SDU frequency, drug use, and polydrug abuse are more difficult to adhere to condom use and more likely to have group sex and high risk sexual behaviors, increasing the risk of STD and HIV infection, and need to strengthen SDU surveillance and intervention.

【Objective】 To investigate the situation of carbapenem-resistant Enterobacteriaceae(CRE) colonization in patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT). 【Methods】 A total of 241 consecutive patients who underwent haplo-HSCT in the First Affiliated Hospital of Soochow University from June 1, 2021 to June 1, 2022 were enrolled. Anal swab screening was performed within 48 hours of admission and blood cultures were taken when the patient developed fever. Univariate and multivariate analysis were used to analyze the colonization rate, distribution, risk factors and the correlation between CRE colonization and post-transplant bloodstream infection(BSI). 【Results】 Among 241 patients with haplo-HSCT, there were 90 cases in CRE colonization positive group, with a colonization rate of 37.3% (90/241). Multivariate logistic regression analysis showed that sex (OR 2.42, 95% CI 1.38-4.22, P<0.05) and history of infection within 30 days before transplantation (OR 3.37, 95% CI 1.59-7.17, P<0.05) may be independent risk factors for CRE intestinal colonization. Of the 95 CRE strains, the top five species were carbapenem-resistant Klebsiella pneumoniae (38/95, 40.0%), carbapenem-resistant Escherichia coli (29/95, 30.5%), carbapenem-resistant Enterobacter cloacae (13/95, 13.6%), carbapenem-resistant Klebsiella acidophilus (6/95, 6.3%) and carbapenem-resistant Proteus mirabilis (3/95, 3.1%). The incidence of post-transplant BSI was 12.0% (29/241) in the CRE-colonized group and 3.3% (8/241) in the non-colonized group. In the colonization group, 100% of the pathogens of BSI were identical with those of CRE colonization. 【Conclusion】 Bacterial culture of anal swab during haplo-HSCT is helpful for detection of CRE colonization in intestinal tract, which provides some clinical basis for active monitoring of key flora, prevention and control of infection.

The high-content image-based assay is commonly leveraged for identifying the pheno-typic impact of genetic perturbations in biology field.However,a persistent issue remains unsolved during experiments:the interferential technical noises caused by systematic errors(e.g.,tempera-ture,reagent concentration,and well location)are always mixed up with the real biological signals,leading to misinterpretation of any conclusion drawn.Here,we reported a mean teacher-based deep learning model(DeepNoise)that can disentangle biological signals from the experimental noises.Specifically,we aimed to classify the phenotypic impact of 1108 different genetic perturbations screened from 125,510 fluorescent microscopy images,which were totally unrecognizable by the human eye.We validated our model by participating in the Recursion Cellular Image Classification Challenge,and DeepNoise achieved an extremely high classification score(accuracy:99.596％),ranking the 2nd place among 866 participating groups.This promising result indicates the success-ful separation of biological and technical factors,which might help decrease the cost of treatment development and expedite the drug discovery process.The source code of DeepNoise is available at https://github.com/Scu-sen/Recursion-Cellular-Image-Classification-Challenge.

Pyroptosis is a newly discovered way of proinflammatory programmed cell death. Pyroptosis is mediated by caspase-1 (Caspase-1). Through the cleavage and activation of GSDM family proteins, small pores are formed on the cell membrane, thus rapid lysis of the cell membrane process, and then leads to intracellular inflammatory content release thereby causing inflammatory response. The three pyroptosis pathways are the classical pathway of Caspase-1, the non-classical pathway of Caspase-4, 5, and 11, and the special pathway of Caspase-3 or Hela cells. Pyroptosis plays an important role in the occurrence, invasion, and metastasis of breast cancer, and is closely related to the prevention and treatment of breast cancer. This article reviews the biological mechanism of pyroptosis and its research progress in breast cancer, to provide a new idea for clinicians in the treatment of breast cancer.

Objective    To explore the mechanism of dihydrouridine synthase 4-like (DUS4L) on the development of lung adenocarcinoma (LUAD). Methods    The RNA-seq expression data of LUAD was downloaded from The Cancer Genome Atlas (TCGA), and the relationship between its clinical pathological characteristics and DUS4L mRNA expression was evaluated. The effect of DUS4L knockdown on the proliferation of A549 cells was detected by EDU proliferation assay. The gene expression profile of lung adenocarcinoma A549 cells in the DUS4L knockdown group (KD group) and control group (NC group) was detected by transcriptome sequencing technique. The differential genes were screened by DESeq2. ClusterProfiler was used to perform GO functional enrichment analysis of differential genes. Results    The expression of DUS4L mRNA in LUAD tissues was higher than that in normal tissues, and the up-regulation of DUS4L was related to the clinical pathological characteristics of LUAD patients. EDU proliferation assay suggested that knocking down DUS4L could inhibit the proliferation of A549 cells. A total of 456 differential genes were screened, including 289 up-regulated genes and 167 down-regulated genes [|log2(fold change)|>1 and Padj<0.05]. STC2 and TRIB3 were significantly down-regulated (P<0.05). Differential genes were mainly involved in the production of interleukin-8, angiogenesis, vascular endothelial cell proliferation and other biological pathways. Conclusion    DUS4L can widely regulate the gene expression of LUAD cells, which provides a new idea for further studying the function and role of DUS4L in the occurrence and development of LUAD and finding new therapeutic targets for LUAD.