Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

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 explore the relevant factors affecting the accuracy of scanning glucose monitoring (FGM) technology in critically ill patients.Methods:A total of 53 patients who were admitted to the Intensive Care Unit (ICU) of the Second Affiliated Hospital of Soochow University and used FGM glucose monitoring from September 2022 to December 2023 were selected by means of a convenience sampling method. The paired data of arterial blood glucose and FGM glucose were analysed. The accuracy of FGM blood glucose measurement in critically ill patients was evaluated using Bland-Altman analysis. The blood glucose data were divided into two groups: the FGM monitoring accuracy group and the FGM monitoring non-accuracy group.. The t-test and χ2 test were used for the comparison of one-way analysis of arterial versus FGM accuracy among critically ill patients with different demographic characteristics. Logistic regression analysis was used to analyze the factors influencing the accuracy of FGM. Results:The results of Bland-Altman analysis of the 53 patients indicated that the mean bias value of FGM blood glucose was elevated at 1.215 mmol/L in comparison with arterial-blood gas analysis blood glucose values. An incidence of exceeding the upper and lower limits of the range was observed, amounting to 6.349%. The discrepancy between the studies was found to be statistically significant (95% CI:1.0394~1.3908, P<0.001). The effects of the changes in height ( OR=0.877, 95% CI:0.780~0.987, P=0.029), changes in leukocyte counts( OR=0.917, 95% CI:0.868~0.969, P=0.002), changes in C-reactive protein( OR=1.009, 95% CI:1.002~1.017, P=0.016), changes in albumin counts( OR=0.986, 95% CI:0.974~0.999, P=0.031), and whether or not sepsis ( OR=3.937, 95% CI:1.192~13.008, P=0.025) on the accuracy of FGM had a statistically significant. Conclusion:The mean bias value of the accuracy of FGM was relatively higher compared with that of arterial blood gas analysis blood glucose values, and the influencing factors involved height, white blood cells, C-reactive protein, albumin, and whether or not sepsis was present. With the development of science and technology, applying the FGM system to critically ill patients has an absolute advantage in determining the overall glycemic trend, and the application value of FGM technology deserves further study.

Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp domain. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.
Nipah Virus/chemistry* ; Cryoelectron Microscopy ; Viral Proteins/genetics* ; RNA-Dependent RNA Polymerase/genetics* ; Phosphoproteins/genetics* ; Humans ; Models, Molecular ; Protein Binding

Objective:To study the correlation between hair fluorine level and hypertension of permanent residents in high altitude areas of Tibet Autonomous Region (Tibet).Methods:A random cluster sampling method was used to select 5 villages in the high altitude areas of Tibet from June to August 2021 and June to August 2022, respectively, and questionnaire survey, physical examination, and biochemical indicator testing were conducted on permanent Tibetan residents in the above mentioned villages. At the same time, hair samples were collected, the hair fluorine level was determined by ion selective electrode method, and the correlation between various indicators and hair fluorine level and hypertension was analyzed.Results:A total of 227 individuals were included, with hair fluorine level of (15.06 ± 0.16) mg/kg. Correlation analysis showed that there was no correlation between the study subjects' systolic blood pressure, diastolic blood pressure, body mass index, pulse, neck circumference, chest circumference, uric acid level and hair fluorine level ( P > 0.05). Abdominal circumference, hip circumference, and hemoglobin level were positively correlated with hair fluorine level ( r = 0.23, 0.14, 0.29, P < 0.05), while blood glucose level and finger pulse oxygen were negatively correlated with hair fluorine level ( r = - 0.23, - 0.24, P < 0.001). Binary logistic regression analysis showed that age ( OR = 1.04, 95% CI: 1.01 - 1.06), chest circumference ( OR = 1.10, 95% CI: 1.01 - 1.20), and hair fluorine level ( OR = 1.22, 95% CI: 1.02 - 1.46) had an impact on hypertension ( P < 0.05). Conclusion:There is a certain correlation between hair fluoride level and hypertension in the population of high altitude areas in Tibet.

Objective To develop an evaluation system for quality palliative care and provide an evaluation tool for quality palliative care service.Methods A preliminary evaluation system was drafted by using literature review and group discussion,aligning with the U.S.National Consensus Project for Quality Palliative Care(NCP).The system was revised and refined by two rounds of Delphi consultation with 15 palliative care experts(including specialists in clinical practice,nursing management,nursing research and education)from Tier-IIIA hospitals in Guangdong Province.Indicator weights were determined via consensus.Results Both rounds of expert consultation achieved 100.00%response rates.Expert authority coefficient(Cr)was 0.855.The importance scores of the level-1,level-2 and level-3 indicators of the second round of expert consultation were 4.90-5.00,4.80-5.00 and 4.37-5.00,respectively.Coefficients of variation were 0-0.06,0-0.1 and 0-0.19,respectively.The full score ratio ranged between 0.93 and 1.00,0.8 and 1.00,and 0.67 and 1.00.Kendall's W coefficients were 0.214,0.287 and 0.245,respectively(all P<0.01).The nine level-1 indicators were identified as care structure and process,physiological care,psychological care,social care,mental care,cultural care,end-of-life care,ethical care and quality improvement,with the weight coefficients of 0.123,0.153,0.110,0.106,0.098,0.082,0.119,0.092 and 0.117,respectively.The final evaluation system for quality palliative care included 9 indicators in level-1,22 in level-2 and 69 in level-3.Conclusion The evaluation system for quality palliative care developed on the basis of NCP is scientifically innovative and valid in content.Further studies are required to evaluate its validity..

Objective To develop an evaluation system for quality palliative care and provide an evaluation tool for quality palliative care service.Methods A preliminary evaluation system was drafted by using literature review and group discussion,aligning with the U.S.National Consensus Project for Quality Palliative Care(NCP).The system was revised and refined by two rounds of Delphi consultation with 15 palliative care experts(including specialists in clinical practice,nursing management,nursing research and education)from Tier-IIIA hospitals in Guangdong Province.Indicator weights were determined via consensus.Results Both rounds of expert consultation achieved 100.00%response rates.Expert authority coefficient(Cr)was 0.855.The importance scores of the level-1,level-2 and level-3 indicators of the second round of expert consultation were 4.90-5.00,4.80-5.00 and 4.37-5.00,respectively.Coefficients of variation were 0-0.06,0-0.1 and 0-0.19,respectively.The full score ratio ranged between 0.93 and 1.00,0.8 and 1.00,and 0.67 and 1.00.Kendall's W coefficients were 0.214,0.287 and 0.245,respectively(all P<0.01).The nine level-1 indicators were identified as care structure and process,physiological care,psychological care,social care,mental care,cultural care,end-of-life care,ethical care and quality improvement,with the weight coefficients of 0.123,0.153,0.110,0.106,0.098,0.082,0.119,0.092 and 0.117,respectively.The final evaluation system for quality palliative care included 9 indicators in level-1,22 in level-2 and 69 in level-3.Conclusion The evaluation system for quality palliative care developed on the basis of NCP is scientifically innovative and valid in content.Further studies are required to evaluate its validity..

Objective:To study the correlation between hair fluorine level and hypertension of permanent residents in high altitude areas of Tibet Autonomous Region (Tibet).Methods:A random cluster sampling method was used to select 5 villages in the high altitude areas of Tibet from June to August 2021 and June to August 2022, respectively, and questionnaire survey, physical examination, and biochemical indicator testing were conducted on permanent Tibetan residents in the above mentioned villages. At the same time, hair samples were collected, the hair fluorine level was determined by ion selective electrode method, and the correlation between various indicators and hair fluorine level and hypertension was analyzed.Results:A total of 227 individuals were included, with hair fluorine level of (15.06 ± 0.16) mg/kg. Correlation analysis showed that there was no correlation between the study subjects' systolic blood pressure, diastolic blood pressure, body mass index, pulse, neck circumference, chest circumference, uric acid level and hair fluorine level ( P > 0.05). Abdominal circumference, hip circumference, and hemoglobin level were positively correlated with hair fluorine level ( r = 0.23, 0.14, 0.29, P < 0.05), while blood glucose level and finger pulse oxygen were negatively correlated with hair fluorine level ( r = - 0.23, - 0.24, P < 0.001). Binary logistic regression analysis showed that age ( OR = 1.04, 95% CI: 1.01 - 1.06), chest circumference ( OR = 1.10, 95% CI: 1.01 - 1.20), and hair fluorine level ( OR = 1.22, 95% CI: 1.02 - 1.46) had an impact on hypertension ( P < 0.05). Conclusion:There is a certain correlation between hair fluoride level and hypertension in the population of high altitude areas in Tibet.

Objective·To analyze the clinical and genetic characteristics of Chinese pediatric patients with Barth syndrome(BTHS)and provide data to support the prevention and treatment of BTHS.Methods·Eighteen pediatric patients diagnosed with BTHS at Shanghai Children's Medical Center,Shanghai Jiao Tong University School of Medicine,from January 2010 to November 2023,were included.Clinical data(age,birth weight,family history,electrocardiogram,echocardiogram,urine tandem mass spectrometry,complete blood count,blood biochemistry,and genetic test results)were collected to analyze the clinical characteristics,genetic findings,and prognoses of the patients.Results·The study included 18 male patients with BTHS(including 2 monozygotic twins),consisting of one Yi ethnic and 17 Han Chinese patients.The median age at diagnosis was 3.0(1.0,5.6)months.Fifteen patients experienced decreased cardiac function at disease onset,with a left ventricular ejection fraction(LVEF)below 50%.Dilated cardiomyopathy(DCM)was observed in 15 patients,left ventricular non-compaction(LVNC)in 12 patients,and myocardial hypertrophy in 9 patients.During the diagnosis and follow-up,QTc interval prolongation occurred in 9 patients,ventricular arrhythmias in 2 patients,neutropenia in 9 patients,and monocytosis in 10 patients.Urine tandem mass spectrometry revealed 3-methylglutaconic aciduria(3-MGCA)in 8 of 13 tested patients.Fifteen types of TAZ gene mutation were identified in the 18 patients,including 5 novel mutations.Genetic testing of the parents of 16 patients indicated maternal inheritance in 15 cases.The median follow-up period was 8.5(2.6,29.3)months,during which 12 patients died.The median age at death was 7.5(6.0,12.8)months.Causes of death included heart failure(7 cases,with 4 concurrent infections),sudden death(3 cases),ventricular fibrillation(1 case),and accidental death(1 case).Conclusion·BTHS is a rare genetic disorder with multisystem involvement.Its primary clinical manifestations include cardiomyopathy and neutropenia.The condition typically presents early in life,with severe progression and poor prognosis.Prompt recognition,accurate diagnosis,and early intervention are essential for managing this disease.

Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.