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 organize a nationwide interlaboratory comparison for measurement of gross α and gross β radioactivity in water, and improve the laboratory analysis of gross α and gross β radioactivity in water. Methods A unified comparison protocol was developed by the organizers. The groundwater with high natural radioactivity was used as water sample and distributed randomly to the participating laboratories. The participating laboratories used routine analytical methods to measure the samples and provided information such as analytical results, original records, and test reports. The results were evaluated using z-score. Results A total of 76 laboratories participated in the comparison, all employing the evaporation concentration-α/β counting method. Among them, 69 laboratories achieved |z| ≤ 2 for both gross α and gross β radioactivity measurements, and 32 laboratories achieved |z| ≤ 0.50 for both gross α and gross β radioactivity measurements. There were 69 laboratories with qualified results and 30 laboratories with excellent results, yielding a qualified rate of 90.8% and an excellent rate of 39.5%. Seven laboratories showed unqualified results and the unqualified rate was 9.2%. Conclusion Most laboratories have the ability to analyze gross α and gross β radioactivity in water. The main reasons for the deviation in comparison results are calibration efficiency, errors in the total residue mass caused by improper water sample processing operations. By analyzing the main technical problems existed in unqualified laboratories, their ability for measurement of gross α and gross β radioactivity in water has been improved.

Purpose To evaluate the differential diagnostic value of 5.0T MRI susceptibility-weighted imaging(SWI)in hepatocellular carcinoma(HCC)and mass-forming intrahepatic cholangiocarcinoma(MICC).Materials and Methods A total of 56 patients with HCC and 36 patients with MICC confirmed by pathology from March 2023 to November 2024 in Anhui Provincial Hospital were retrospectively enrolled.Two radiologists independently analyzed three features of the lesions,including the low-signal rims around the lesion,hemorrhage within the lesion,and the relationship between lesions and adjacent vessels,on the SWI sequence between the two groups,respectively,via inter-rater consistency analysis.These above features between the two groups were compared and contrasted them with those obtained from conventional MR plain and enhanced scans,respectively.For intralesional hemorrhages,the diagnostic value was quantified by calculating the internal tissue susceptibility signal.Results The radiologists showed good consistency in the low-signal rims,intratumoral hemorrhage as well as the relationship between the lesion and the blood vessel on the SWI in the HCC group and the MICC group(Kappa=0.802-0.929,all P<0.001).Compared with conventional MR plain,SWI significantly enhanced the detection rates of perilesional low-signal rims and intratumoral hemorrhage(χ2=89.409,46.210,both P<0.001).These findings were more prevalent in HCC patients.The internal tissue susceptibility signal grading showed that HCC predominantly exhibited grade 3,whereas MICC predominantly exhibited grade 1,with statistically significant differences(Z=-4.059,P<0.05).Additionally,compared with enhanced MRI,SWI demonstrated higher accuracy in diagnosing the relationship between lesions and blood vessels in both groups;however,these differences were not statistically significant(χ2=0.275,0.247,P=0.871,0.619).In the HCC group,the relationship between tumors and blood vessels was primarily characterized by compression and tumor thrombus formation,while in the MICC group,it was predominantly marked by invasive changes,including vessel encasement,stenosis or occlusion,with a statistically significant difference between the two groups(Z=-6.809,P<0.001).Conclusion SWI sequence of 5.0T MRI provides clear visualization of the internal and peripheral structures of HCC and MICC.It can accurately delineate the relationship between lesions and blood vessels without the need for contrast agents,offering significant clinical utility in differentiating these two conditions.

Purpose To evaluate the differential diagnostic value of 5.0T MRI susceptibility-weighted imaging(SWI)in hepatocellular carcinoma(HCC)and mass-forming intrahepatic cholangiocarcinoma(MICC).Materials and Methods A total of 56 patients with HCC and 36 patients with MICC confirmed by pathology from March 2023 to November 2024 in Anhui Provincial Hospital were retrospectively enrolled.Two radiologists independently analyzed three features of the lesions,including the low-signal rims around the lesion,hemorrhage within the lesion,and the relationship between lesions and adjacent vessels,on the SWI sequence between the two groups,respectively,via inter-rater consistency analysis.These above features between the two groups were compared and contrasted them with those obtained from conventional MR plain and enhanced scans,respectively.For intralesional hemorrhages,the diagnostic value was quantified by calculating the internal tissue susceptibility signal.Results The radiologists showed good consistency in the low-signal rims,intratumoral hemorrhage as well as the relationship between the lesion and the blood vessel on the SWI in the HCC group and the MICC group(Kappa=0.802-0.929,all P<0.001).Compared with conventional MR plain,SWI significantly enhanced the detection rates of perilesional low-signal rims and intratumoral hemorrhage(χ2=89.409,46.210,both P<0.001).These findings were more prevalent in HCC patients.The internal tissue susceptibility signal grading showed that HCC predominantly exhibited grade 3,whereas MICC predominantly exhibited grade 1,with statistically significant differences(Z=-4.059,P<0.05).Additionally,compared with enhanced MRI,SWI demonstrated higher accuracy in diagnosing the relationship between lesions and blood vessels in both groups;however,these differences were not statistically significant(χ2=0.275,0.247,P=0.871,0.619).In the HCC group,the relationship between tumors and blood vessels was primarily characterized by compression and tumor thrombus formation,while in the MICC group,it was predominantly marked by invasive changes,including vessel encasement,stenosis or occlusion,with a statistically significant difference between the two groups(Z=-6.809,P<0.001).Conclusion SWI sequence of 5.0T MRI provides clear visualization of the internal and peripheral structures of HCC and MICC.It can accurately delineate the relationship between lesions and blood vessels without the need for contrast agents,offering significant clinical utility in differentiating these two conditions.

Objective:To develop a novel magnetic composite nanoparticle with excellent targeting and biocompatibility and verify synergistic magnetic hyperthermia/radiotherapy efficacy in HeLa cells.Methods:Bovine serum albumin(BSA)was used to modify ferroferric oxide(Fe 3O 4)nanoparticles, and then L-selenocystine and folic acid(FA)were coupled on the surface of BSA by carbodiimide method to synthesize magnetic composite nanoparticles Fe 3O 4@BSA@SeCyc2@FA.The as-prepared nanoparticles were characterized to determine the structure, composition, and properties of the nanoparticles to support their biological applications.By evaluating the magnetothermal properties of the as-prepared nanoparticles, analyzing the internalization effect of HeLa cells on the particles and using CellTiter and reactive oxygen species(ROS)kits to detect the cell viability and ROS production of different experimental groups, respectively, the killing and inhibiting effects on HeLa cells were evaluated when hyperthermia was combined with radiotherapy. Results:The average particle size of the Fe 3O 4@BSA@SeCyc2@FA nanoparticles was(19.31 ± 4.84)nm, and the zeta potential was -25.4 mV(pH=7), which indicated that the as-prepared nanoparticles maintained acceptable dispersion and stability for biological experiments.By BSA and FA characteristic absorption peaks combined with the measured content of Se(10.89 μM), L-selenocystine and FA were successfully modified on the surface of the composite nanoparticles.The saturation magnetization value of the Fe 3O 4@BSA@SeCyc2@FA nanoparticles was 47.2 emu/g.The as-prepared nanoparticles maintained the specific absorption rate(SAR)value of 125.4 W/g at the alternating magnetic field of 518 kHz/16 kAm -1, indicating excellent heat generation efficiency(the temperature level ΔT=7 ℃ within 15 min).No significant toxicity was found for HUVEC cells even within the concentration range from 0 to 200 μg/ml and inhibition of cell viability of the HeLa was shown.When magnetic hyperthermia combined with high-energy X-ray, the cell viability of the HeLa decreased significantly to 54.7%, and the intracellular ROS production increased by 108.2% compared with the control group, which showed that the as-prepared nanoparticles significantly enhanced the radiosensitivity of HeLa cells, and the synergistic effect of magnetic hyperthermia combined with radiotherapy was more effective in inhibiting and killing them. Conclusions:The as-prepared nanoparticles show great promise for use as a multifunctional nanoplatform for the synergistic magnetic hyperthermia/radiotherapy to overcome the limitations of monotherapy for cancer treatment.

Pyran- and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans, respectively, exhibiting diverse physiological and medical bioactivities. However, the biosynthetic mechanisms for their core structures remain poorly understood. Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants. These included three distinct P. praeruptorum prenyltransferases (PpPT1-3) responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors, and two novel CYP450 cyclases (PpDC and PpOC) crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds. Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring. The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific mutagenesis. We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process. This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

ObjectiveTo reveal the molecular mechanism of Angong Niuhuangwan（AGNH） in improving traumatic brain injury（TBI） based on single cell sequencing. MethodSeventy-five male SD rats were randomly divided into the sham group， model group， piracetam group（3.6 g·kg^-1）， AGNH low- and high-dose groups（0.09， 0.27 g·kg^-1）， with 15 rats in each group. In addition to the sham group， the other 4 groups used the modified Feeney free-fall impact method to prepare TBI model， and the drugs were administered by gavage immediately after modeling， 24 hours later， the modified neurological deficit score（mNSS） was performed， and brain tissue was isolated to determine the degree of cerebral edema. Hematoxylin-eosin（HE） staining was used to observe the injury degree in the cortex， CA1 region and CA3 region of brain tissue. The expression levels of cyclooxygenase-2（COX-2）， interferon regulatory factor 1（IRF1）， Janus kinase 2（JAK2） and suppressor of cytokine signaling 3（SOCS3） were observed by immunofluorescence（IF） staining. The levels of interleukin（IL）-6， IL-18， IL-1β， IL-17A， tumor necrosis factor-α（TNF-α）， Caspase-1 and nucleotide binding oligomerization domain（NOD）-like receptor heat protein domain associated protein 3（NLRP3） inflammasome were determined by enzyme-linked immunosorbent assay（ELISA）. The regulation of AGNH on each cell population was analyzed by single cell sequencing， and differentially expressed genes were analyzed by Gene Ontology（GO） and Kyoto Encyclopedia of Genes and Genomes（KEGG）， which led to construct microglia differentially expressed gene network to search for the key targets， and validated by ELISA and IF. ResultCompared with the sham group， the mNSS and brain water content were significantly increased in the model group（P<0.01）. Compared with the model group， mNSS and brain water content in the low and high dose AGNH groups were decreased（P<0.05，P<0.01）. HE staining results showed that compared with the sham group， the cells in the cerebral cortex and hippocampus of rats in the model group were seriously lost， and the cells were arranged loosely（P<0.01）. Compared with the model group， AGNH could significantly increase the density of neurons in the CA1 and CA3 regions of the cerebral cortex and hippocampus， making the arrangement more compact， as well as improved cell morphology（P<0.05，P<0.01）. ELISA and IF staining showed that AGNH could reduce the levels of Caspase-1， IL-17A， TNF-α， NLRP3 and COX-2 in brain tissue of TBI rats（P<0.05， P<0.01）. A total of 13 cell subsets were identified by single cell sequencing， among which microglia played an important role in neuroimmunity. The results of GO enrichment analysis of differentially expressed genes in microglia showed that AGNH improved TBI in response to inflammation and TNF-α. KEGG enriched IL-17 signaling pathway， TNF signaling pathway， Toll-like receptor signaling pathway， etc. The results of network analysis showed that the key targets of AGNH in regulating TBI might be IL-6， IL-1β， JAK2， SOCS3， IRF1. IF and ELISA verification results showed that compared with the sham group， SOCS3 expression in microglia was decreased in the model group， and the expressions of IL-6， IL-1β， JAK2 and IRF1 were increased（P<0.01）. Compared with the model group， AGNH could increase the expression of SOCS3， decrease the expression of IL-6， IL-1β， JAK2， IRF1 （P<0.05， P<0.01）. ConclusionAGNH can reduce the degree of brain edema and brain injury， decrease the expression of inflammatory factors， and inhibit the expression of NLRP3 and its downstream Caspase-1 in TBI rats， which may act on the targets of IL-6， IL-1β， JAK2， IRF1 and SOCS3 in microglia.

Objective To investigate the main dietary patterns of children in urban areas of Maanshan City, and to explore the association between dietary patterns and subthreshold autism trait (SAT), attention-deficit/hyperactivity disorder (ADHD) symptoms and comorbid behaviors in 3-year-old children. Methods Based on the birth cohort of Maanshan Maternal and Infant Health from June 2015 to June 2016，regular physical examinations were conducted from 4 to 2 to 1, and follow-up was conducted until the age of 3. A semi-quantitative food frequency questionnaire was employed to assess dietary intakes. SAT and ADHD symptoms were assessed by Clancy autism behavior scale (CABS) and the 10-item Chinese version of the Conners Abbreviated Symptom Questionnaire (C-ASQ). Social-demographic information was also collected. Results The detection rates of SAT, ADHD symptoms, and comorbidity were 11.03%, 5.28%, and 2.71%, respectively. The older the father, the higher the mother's education level, and the higher the per capita monthly income of the family, the lower the SAT detection rate (P<0.05). The higher the father's educational level, the lower the detection rate of ADHD symptoms (P<0.05). The older the mother and the higher the education level, the lower the detection rate of comorbid behavior in their children (P <0.05). After adjusting for demographic influencing factors, the low intake level was used as a reference. The vegetarian type with moderate intake level was negatively correlated with SAT, while the processed food type with high intake level was positively correlated with SAT. The vegetarian type with high intake level was negatively correlated with ADHD symptoms, while the snack type with high intake level was positively correlated with ADHD symptoms. The vegetarian type with high intake level was negatively correlated with comorbidity. Conclusion Unhealthy dietary patterns are related to children's SAT and ADHD symptoms. Correcting children's unhealthy eating patterns may help reduce children's behavior problems.

Objective:To investigate the clinical characteristics of congenital esophageal atresia with gastric perforation, and to improve pediatricians′ understanding of this disease.Methods:The clinical data of five neonates with congenital esophageal atresia and gastric perforation treated in the neonatal intensive care unit of the Affiliated Hospital of Qingdao University from 2012 to 2022 were analyzed retrospectively.Results:Among the five neonates, four were boys and one was girl.The gestational age was 28 + 5 to 37 + 6 weeks, the birth weight was 1 100~2 350 g. All of them had dyspnea and feeding difficulties after birth.Gastric perforation occurred in three cases during invasive mechanical ventilation, one case during non-invasive ventilation, and one case during nasal catheter oxygen inhalation.Emergency primary gastric repair was performed, followed by secondary esophageal anastomosis.All the patients were cured and discharged from hospital. Conclusion:Gastric perforation is a rare complication of congenital esophageal atresia, which is more common in premature infants and low birth weight infants.Mechanical ventilation may promote the occurrence of gastric perforation.If gastric perforation is complicated, repair should be performed as soon as possible, and esophageal anastomosis surgery should be performed early after stability to improve the final outcome.

Objective:To study the risk factors and clinical outcomes of early pulmonary hypertension in preterm infants with gestational age(GA)≤32 w.Methods:From October 2017 to May 2021,preterm infants with GA≤ 32 w admitted to NICU of our hospital were retrospectively studied. According to their echocardiography 2 w after birth, the infants were assigned into early-onset pulmonary hypertension (ePH) group and non-PH group. SPSS 21.0 statistical software was used to analyze the general status, complications and clinical outcomes of the two groups. Multiple logistic regression was used to analyze the risk factors of early-onset PH.Results:A total of 183 cases were enrolled, including 24 in the ePH group and 159 in the non-PH group. The incidences of birth asphyxia, hemodynamically significant patent ductus arteriosus (hsPDA), FiO 2≥30% within 6 h after birth, late-onset PH, severe bronchopulmonary dysplasia(BPD) and intracranial hemorrhage(ICH) in the ePH group were significantly higher than the non-PH group( P<0.05). hsPDA was the independent risk factor for early-onset PH ( OR=11.781, 95% CI 4.192-33.108). Conclusions:Preterm infants with GA≤32 w and early-onset PH are at increased risks of ICH, late-onset PH and severe BPD, hsPDA is the independent risk factor for early-onset PH.