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.

A microchannel-based electrochemiluminescence(ECL)sensor was developed for detection of tetracycline(TC)utilizing luminol/H2O2 as ECL reporting system.The low excitation potential of luminol/H2O2 effectively mitigated the impact of clamping voltage,thereby enhancing the detection performance of the microchannel-based ECL sensor.The microchannel modified with TC aptamer selectively recognized and captured target TC.The positively charged TC reduced the surface charge density within the microchannel,thereby increasing the ionic current in the microchannel,leading to change of ECL signal of system.The experimental conditions such as electrolyte concentration,TC-aptamer concentration,and reaction time between TC and TC-aptamer were optimized.Under optimal conditions,the difference of ECL signal in the absence and presence of TC(?ECL)exhibited a good linear relationship with TC concentration in the range from 1.00 ng/mL to 200 ng/mL,with a detection limit as low as 0.69 ng/mL.The sensor had good selectivity and was successfully used in detection of TC in milk samples.

Objective To analyze the activity concentrations of gross α, gross β, and radionuclides in atmospheric fallout around Daya Bay Nuclear Power Plant from 2019 to 2022, and provide foundational scientific data for the healthy development of nuclear energy. Methods Five monitoring sites were set up at different distances (1.2, 6.9, 12.4, 42.3, and 69.2 km) from Daya Bay Nuclear Island 1. Stainless steel sampling barrels were used to collect atmospheric fallout, with a monitoring cycle of three months. The collected samples were ashed using radiochemical method. Subsequently, the gross α and gross β radioactivity were quantified using a low-background α/β measurement instrument. The remaining ash samples were mixed with water and left to equilibrate for over three weeks before γ-nuclide analysis using a low-background, high-purity germanium γ-spectrometer. Results The gross α activity concentration in atmospheric fallout around Daya Bay Nuclear Power Plant from 2019 to 2022 averaged (25.3 ± 10.6) Bq/m²/season and ranged from 5.8 to 73.4 Bq/m²/season. The gross α activity concentrations in sampling sites #1 to #5 were 5.8-34.4, 11.9-35.2, 14.4-46.4, 7.2-73.4, and 13.1-43.1 Bq/m²/season, respectively. The gross β activity concentration averaged (50.5 ± 23.4) Bq/m²/season and ranged from 13.9 to 139.3 Bq/m²/season. The gross β activity concentrations of sampling sites #1 to #5 were 17.1-107.4, 17.6-87.5, 25.8-102.0, 13.9-139.3, and 23.4-99.2 Bq/m²/season, resprctively. The activity concentrations of ²³⁸U, ²²⁶Ra, ²³²Th, ⁴⁰K, ²¹⁰Pb, and ⁷Be in atmospheric fallout were < lower limit of detection (LLD)-4.2, < LLD-5.8, < LLD-6.3, < LLD-42.1, < LLD-514.0, and 35.7-1761.0 Bq/m²/season, respectively. Gross α and gross β activity concentrations were significantly positively correlated with ²¹⁰Pb activity concentration (r=0.770, α < 0.001; r=0.882, α < 0.001, respectively). Gross β activity concentration showed a significant positive correlation with ⁷Be (r=0.833, α < 0.001). The activity concentrations of ⁵⁴Mn, ⁵⁷Co, ⁵⁸Co, ⁶⁰Co, ⁵⁹Fe, ⁹⁵Zr, ¹⁰³Ru, ¹⁰⁶Ru, ^110mAg, ¹³¹I, ¹³⁴Cs, ¹³⁷ Cs, ¹⁴⁰Ba and ¹⁹²Ir were lower than the LLD of the instrument, and no artificial radionuclides were detected. Conclusion The gross α and gross β radioactive activity concentrations in the atmospheric fallout in the surrounding area of Daya Bay Nuclear Power Plant during 2019-2022 were affected by natural radionuclides ²¹⁰Pb and ⁷Be, and were in the normal fluctuation ranges. No artificial radionuclides were found in the atmospheric fallout, and the Daya Bay Nuclear Power Plant was in a safe and stable state of operation.

Objective:To investigate the effect of dulagopeptide on physical examination indexes,plasma glucose metabolism and islet function in type 2 diabetes mellitus(T2DM)patients with poorly controlled plasma glucose.Methods:135 T2DM patients with poorly controlled plasma glucose who were admitted in our hospital from January 2023 to July 2024 were selected.A prospective randomized controlled design was adopted,they were divided into control group 1(received treatment with sitagliptin,n=45),control group 2(received treatment with insulin glargine,n=45),and observation group(received treatment with dulaglutide,n=45)according to the random number table method.Physical examination indexes,plasma glucose indicators,islet function,and incidence of adverse reactions were compared among the three groups.Results:12 weeks after treatment,body mass index(BMI),waist circumference,fasting plasma glucose(FPG),glycated hemoglobin(HbA1c),and postprandial 2-hour plasma glucose(2hPG)in the observation group were lower than those in control group 1 and control group 2(P＜0.05).12 weeks after treatment,the observation group had the highest HbA1c compliance rate,reaching 71.1％(P＜0.05).12 weeks after treatment,the fasting C-peptide(FC-P)and HOMA-islet(CP-DM)levels in the observation group were higher than those in control group 1 and control group 2(P＜0.05).Conclusion:Dulagopeptide can effectively improve physical examination indexes,plasma glucose indicators,and islet function in T2DM patients with poorly controlled plasma glucose.

Objective:To investigate the effect of dulagopeptide on physical examination indexes,plasma glucose metabolism and islet function in type 2 diabetes mellitus(T2DM)patients with poorly controlled plasma glucose.Methods:135 T2DM patients with poorly controlled plasma glucose who were admitted in our hospital from January 2023 to July 2024 were selected.A prospective randomized controlled design was adopted,they were divided into control group 1(received treatment with sitagliptin,n=45),control group 2(received treatment with insulin glargine,n=45),and observation group(received treatment with dulaglutide,n=45)according to the random number table method.Physical examination indexes,plasma glucose indicators,islet function,and incidence of adverse reactions were compared among the three groups.Results:12 weeks after treatment,body mass index(BMI),waist circumference,fasting plasma glucose(FPG),glycated hemoglobin(HbA1c),and postprandial 2-hour plasma glucose(2hPG)in the observation group were lower than those in control group 1 and control group 2(P＜0.05).12 weeks after treatment,the observation group had the highest HbA1c compliance rate,reaching 71.1％(P＜0.05).12 weeks after treatment,the fasting C-peptide(FC-P)and HOMA-islet(CP-DM)levels in the observation group were higher than those in control group 1 and control group 2(P＜0.05).Conclusion:Dulagopeptide can effectively improve physical examination indexes,plasma glucose indicators,and islet function in T2DM patients with poorly controlled plasma glucose.

Further evidence is needed to explore the impact of high-altitude environments on the neurologic function of neonates.Non-invasive techniques such as cerebral near-infrared spectroscopy and amplitude-integrated electroencephalography can provide data on cerebral oxygenation and brain electrical activity.This study will conduct multiple cerebral near-infrared spectroscopy and amplitude-integrated electroencephalography monitoring sessions at various time points within the first 3 days postpartum for healthy full-term neonates at different altitudes.The obtained data on cerebral oxygenation and brain electrical activity will be compared between different altitudes,and corresponding reference ranges will be established.The study involves 6 participating centers in the Chinese High Altitude Neonatal Medicine Alliance,with altitude gradients divided into 4 categories:800 m,1 900 m,2 400 m,and 3 500 m,with an anticipated sample size of 170 neonates per altitude gradient.This multicenter prospective cohort study aims to provide evidence supporting the impact of high-altitude environments on early brain function and metabolism in neonates.[Chinese Journal of Contemporary Pediatrics,2024,26(4):403-409]

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Background::Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods::The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. Results::Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions::The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.

This study aimed to assess the role of prostate-specific antigen density (PSAD) and negative multiparametric magnetic resonance imaging (mpMRI) in predicting prostate cancer for biopsy-naïve men based on a large cohort of the Chinese population. From a prostate biopsy database between March 2017 and July 2021, we retrospectively identified 240 biopsy-naïve patients with negative prebiopsy mpMRI (Prostate Imaging Reporting and Data System version 2 [PI-RADS v2] score <3). Logistic regression analysis was performed to select the potential predictors for clinically significant prostate cancer (csPCa). Receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) were performed to assess the diagnostic accuracy. The negative predictive values of mpMRI in excluding any cancer and csPCa were 83.8% (201/240) and 90.8% (218/240), respectively. ROC curve analysis indicated that PSAD was the most promising predictor, with an AUC value of 0.786 (95% confidence interval [CI]: 0.699-0.874), and multiparametric logistic regression analysis confirmed that higher PSAD remained a significant marker for predicting csPCa (odds ratio [OR]: 10.99, 95% CI: 2.75-44.02, P < 0.001). Combining negative mpMRI and PSAD below 0.20 ng ml^-2 obviously increased the predictive value in excluding PCa (91.0%, 101/111) or csPCa (100.0%, 111/111). If a PSAD below 0.20 ng ml^-2 was set as the criterion to omit biopsy, nearly 46.3% of patients (463 per 1000) with negative mpMRI could safely avoid unnecessary biopsy, with approximately 4.2% of patients (42 per 1000) at risk of missed diagnosis of PCa and no patients with csPCa missed. A PI-RADS v2 score <3 and a PSAD <0.20 ng ml^-2 could be potential criteria for the Chinese population to omit prompt biopsy safely.
Male ; Humans ; Prostatic Neoplasms/pathology* ; Prostate-Specific Antigen ; Multiparametric Magnetic Resonance Imaging ; Magnetic Resonance Imaging/methods* ; Retrospective Studies ; Biopsy ; Image-Guided Biopsy/methods*

OBJECTIVE: To investigate the changes in myocardial calcium currents in rats subjected to forced running exercise during acute hypoxia and their association with myocardial injury. METHODS: Forty SD rats were randomized into quiescent group and running group either in normal oxygen (NQ and NR groups, respectively) or in acute hypoxia (HQ and HR groups, respectively). Hypoxia was induced by keeping the rats in a hypobaric oxygen chamber (PaO₂=61.6kpa) for 4 h a day; the rats in the two running groups were forced to run on running wheels for 4 h each day. Rat ventricular myocytes was isolated by enzymatic digestion for recording action potentials and currents using patch clamp technique, and confocal Ca²⁺ imaging was used to monitor intracellular Ca²⁺ levels. The expressions of Cav1.2 channel and the cardiac ryanodine receptor (RyR2) were determined using Western blotting. RESULTS: Compared with those in NQ group, the rats in HR group showed significantly decreased SOD activity (P < 0.01), increased h-FABP, hs-CRP and IMA levels (P < 0.05 or 0.01), obvious myocardial pathology, and prolonged APD50 and APD90 (P < 0.05). Of the different stress conditions, forced running in acute hypoxia resulted in the most prominent increase of the densities of ICa, L currents, causing also a significant left shift of the steady state activation curve and a significant right shift of the steady state inactivation curve. Compared with those in NQ group, the rats in NR, HQ and HR groups all exhibited higher rates of spontaneous calcium wave events in the cardiac myocytes, increased frequency of calcium sparks with lowered amplitude, enhanced calcium release amplitude in the ventricular myocytes, and delayed calcium ion reabsorption; in particular, these changes were the most conspicuous in HR group (P < 0.05 or 0.01). There was also a significant increase in the protein levels of Cav1.2 channel and RyR2 receptor in HR group (P < 0.05 or 0.01). CONCLUSIONS The mechanism of myocardial injury in rats subjected to forced running in acute hypoxia may involve the increase of oxidative stress and calcium current and intracellular calcium overload.
Animals ; C-Reactive Protein/metabolism* ; Calcium/metabolism* ; Calcium Signaling ; Fatty Acid Binding Protein 3/metabolism* ; Heart Injuries/metabolism* ; Hypoxia/metabolism* ; Myocytes, Cardiac/metabolism* ; Oxygen/metabolism* ; Rats ; Rats, Sprague-Dawley ; Ryanodine Receptor Calcium Release Channel/metabolism* ; Superoxide Dismutase/metabolism*