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.

SARS-CoV-2 has posed a significant threat to a subset of the patient population.The occurrence of hematological malignancies and tumor treatment can lead to immunosuppression in patients,which significantly increases the risk of serious complications,severe incidence and mortality after SARS-CoV-2 infection.The treatment of a patient with follicular lymphoma infected with SARS-CoV-2 was described in detail.The patient remained positive for RT-PCR tests during the hospitalization for nearly 90 days.After undergoing 5 rounds of antiviral treatment,along with glucocorticoid anti-inflammatory therapy,low-molecular-weight heparin for anticoagulation,antibiotics for infection control,and respiratory support through the use of a ventilator,the patient eventually obtained negative result of the RT-PCR test.Subsequently,the patient was successfully weaned from mechanical ventilation and discharged.By summarizing the treatment process of this case,we hoped to provide reference and experience for future clinical diagnosis and treatment.

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 amplitude-integrated electroencephalography(aEEG)monitoring results of hospitalized neonates in plateau areas.Methods A retrospective analysis was conducted on 5 945 neonates who were admitted to the Department of Neonatology,Kunming Children's Hospital,and received aEEG monitoring from January 2020 to December 2022.According to the aEEG monitoring results,they were divided into a normal aEEG group and an abnormal aEEG group.The incidence rate of aEEG abnormalities was analyzed in neonates with various systemic diseases,as well as the manifestations of aEEG abnormalities and the consistency between aEEG abnormalities and clinical abnormalities.Results Among the 5 945 neonates,the aEEG abnormality rate was 19.28%(1 146/5 945),with an abnormality rate of 29.58%(906/3 063)in critically ill neonates and 8.33%(240/2 882)in non-critically ill neonates(P<0.05).The children with inherited metabolic diseases showed the highest aEEG abnormality rate of 60.77%(79/130),followed by those with central nervous system disorders[42.22%(76/180)]and preterm infants[35.53%(108/304)].Compared with the normal aEEG group,the abnormal aEEG group had significantly lower age and gestational age,as well as a significantly lower birth weight of preterm infants(P<0.05).Among the 1 146 neonates with aEEG abnormalities,the main types of aEEG abnormalities were sleep cycle disorders in 597 neonates(52.09%),background activity abnormalities in 294 neonates(25.65%),and epileptiform activity in 255 neonates(22.25%),and there were 902 neonates(78.71%)with abnormal clinical manifestations.The sensitivity and specificity of aEEG monitoring for brain function abnormalities were 33.51%and 92.50%,respectively.Conclusions In plateau areas,there is a relatively high rate of aEEG abnormalities among hospitalized neonates,particularly in critically ill neonates and those with smaller gestational ages and younger ages,suggesting a high risk of brain injury.Therefore,routine aEEG monitoring for the hospitalized neonates can help with the early detection of brain function abnormalities,the decision-making in treatment,and the formulation of brain protection strategies.

A 5-year-old girl was admitted due to one episode of melena and one episode of hematemesis.Upon admission,gastroscopy revealed esophageal and gastric varices.Abdominal CT scan,MRI,and color Doppler ultrasound suggested cirrhosis,intrahepatic bile duct dilation,and bilateral kidney enlargement.Genetic testing identified compound heterozygous mutations in the PKHD1 gene:c.2264C>T(p.Pro755Leu)and c.1886T>C(p.Val629Ala).The c.2264C>T(p.Pro755Leu)mutation is a known pathogenic variant with previous reports,while c.1886T>C(p.Val629Ala)is a novel mutation predicted to have pathogenic potential according to Mutation Taster and PolyPhen2.The child was diagnosed with autosomal recessive polycystic kidney disease.In children presenting with gastrointestinal bleeding without obvious causes,particularly those with liver or kidney disease,consideration should be given to the possibility of autosomal recessive polycystic kidney disease,and genetic testing should be conducted for definitive diagnosis when necessary.

Periodontitis is a critical risk factor for the occurrence and development of diabetes.Porphyromonas gingivalis may participate in insulin resistance(IR)caused by periodontal inflammation,but the functional role and specific mechanisms of P.gingivalis in IR remain unclear.In the present study,clinical samples were analysed to determine the statistical correlation between P.gingivalis and IR occurrence.Through culturing of hepatocytes,myocytes,and adipocytes,and feeding mice P.gingivalis orally,the functional correlation between P.gingivalis and IR occurrence was further studied both in vitro and in vivo.Clinical data suggested that the amount of P.gingivalis isolated was correlated with the Homeostatic Model Assessment for IR score.In vitro studies suggested that coculture with P.gingivalis decreased glucose uptake and insulin receptor(INSR)protein expression in hepatocytes,myocytes,and adipocytes.Mice fed P.gingivalis tended to undergo IR.P.gingivalis was detectable in the liver,skeletal muscle,and adipose tissue of experimental mice.The distribution sites of gingipain coincided with the downregulation of INSR.Gingipain proteolysed the functional insulin-binding region of INSR.Coculture with P.gingivalis significantly decreased the INSR-insulin binding ability.Knocking out gingipain from P.gingivalis alleviated the negative effects of P.gingivalis on IR in vivo.Taken together,these findings indicate that distantly migrated P.gingivalis may directly proteolytically degrade INSR through gingipain,thereby leading to IR.The results provide a new strategy for preventing diabetes by targeting periodontal pathogens and provide new ideas for exploring novel mechanisms by which periodontal inflammation affects the systemic metabolic state.

A 72-year-old female patient was admitted to the emergency department of Qintang District People′s Hospital of Guigang City in August 2023 due to chills and fever, abdominal distension and pain, diarrhea, cough and shortness of breath for 1 day. She had a history of chronic obstructive and pulmonary heart disease, stage Ⅲ hypertension, and ceftazidime allergy. Clinical diagnosis of acute bacterial infection of chronic obstructive pneumonia was made and levofloxacin combined with piperacillin/tazobactam were given as symptomatic treatment. The blood culture reported Campylobacter fetus after four days, and the patient was cured and discharged after seven days with negative blood culture. The morphology and mass spectrometry identification of the strain were consistent with the definition of Campylobacter fetus. Whole genome sequencing predicted the multi-site sequence type as Campylobacter fetus subsp. fetus( Cff) ST20, carrying the tetracycline resistance gene tet (O/M/O), 18 flagella genes (including rpoN gene from Campylobacter jejuni. these genes were not found in the other two Campylobacter fetus subspecies), and six virulence genes (including like-typhoidal toxin and typhoid toxin genes). The pathogen has the ecological characteristics of parasitic farmed animal colonization and the biological characteristics of high mobility and virulence. These attributes facilitated its entry into the bloodstream via the fecal-oral route, leading to invasive infections.

Objective:This study aims to demonstrate the feasibility of using Bio-layer Interferometry (BLI) for label-free detection of peripheral blood biomarkers, using C-reactive protein (CRP) as a model molecule.Methods:A total of 85 clinical remnant serum samples from routine laboratory tests were collected from Fuwai Hospital, Chinese Academy of Medical Sciences, from July 2021 to May 2022. The biotinylated anti-CRP antibody was immobilized onto streptavidin-functionalized BLI probes. The GatorPrime BLI system was used to detect series of diluted CRP standards in real-time, and to generate dynamic binding curves for establishing standard curves based on the relationship between concentration and initial binding rates. The sensitivity of the method, including the limit of blank (LoB), limit of detection (LoD), and limit of quantitation (LoQ), was evaluated according to Clinical & Laboratory Standards Institute (CLSI) guidelines. Serum samples and third-party quality control materials were used to evaluate the precision, while linearity was verified through the dilution of a high-concentration serum series. Method comparison between the label-free BLI assay and conventional clinical laboratory immunoassays was conducted using Passing-Bablok regression and Spearman correlation analysis.Results:The GatorPrime BLI system demonstrated a dynamic detection range of 0.6-300 mg/L for CRP standards, and the linearity within this range was validated using serum samples. The LoB, LoD, and LoQ for this method were determined to be 0.246 mg/L, 0.573 mg/L, and 2.158 mg/L, respectively. Precision analysis showed that the total laboratory imprecision of the four levels of quality control materials (21.15-57.26 mg/L) ranged from 5.8% to 9.0%, and the total imprecision of the two serum samples (2.32 mg/L and 100.06 mg/L) was 22.3% and 7.4%, respectively. Methodological comparison with two commonly used clinical laboratory immunoassays revealed a strong correlation with our method(Passing-Bablok regression: Y=?1.065+1.119 X and Y=?0.452+1.034 X, r=0.993 and r=0.976, P<0.001). Conclusions:The label-free BLI immunoassay method enables the detection of CRP across a broad concentration range in blood samples, with analytical performance meeting the requirements for laboratory testing. This method shows potential as a reliable and efficient alternative for CRP measurement in clinical practice.

Purpose To investigate the changes of interhemispheric functional connectivity and functional connectivity between the selected region of interest(ROI)and other brain areas of the whole brain in resting state in early-blind adolescents(EBAs)via the voxel-mirrored homotopic connectivity(VMHC)and seed-based functional connectivity methods.Materials and Methods A total of 23 EBAs in the Guangdong Province Blind School and 21 age-and gender-matched normal-sighted controls were recruited from June to August 2015.Brain resting-state magnetic resonance imaging scans were performed on all participants.The VMHC were calculated and compared between these two groups.And take the most significant brain area of VMHC as the ROI,the functional connectivity between it and all voxels in the whole brain were calculated and compared,respectively.Results Compared with the control groups,the EBAs groups showed decreased VMHC values in the occipital visual cortex with bilateral calcarine as peak point,bilateral cerebellum and right inferior temporal gyrus(FDR corrected,P<0.05).The EBAs group showed a decreased functional connectivity between bilateral calcarine(brain areas with significantly reduced VMHC),set as ROI and the right cuneus and middle cingulum gyrus,while the enhanced functional connectivity between the bilateral calcarine and the right cerebellum-Crus1 when compared with normal-sighted controls(false discovery rate,FDR corrected,P<0.05).Conclusion The visual cortex interhemispheres mainly in the primary visual cortex of EBAs and its functional connections with multiple brain regions are abnormal,which may indicate abnormal coordination between the primary visual center and other perceptual cortex,and may be related to the brain structure and function remodeling caused by visual loss.