Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional "one bug, one drug" paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection in vivo. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.

Identification of disease-specific cell subtypes (DSCSs) has profound implications for understanding disease mechanisms, preoperative diagnosis, and precision therapy. However, achieving unified annotation of DSCSs in heterogeneous single-cell datasets remains a challenge. In this study, we developed the gPRINT algorithm (generalized approach for cell subtype identification with single cell's voicePRINT). Inspired by the principles of speech recognition in noisy environments, gPRINT transforms gene position and gene expression information into voiceprints based on ordered and clustered gene expression phenomena, obtaining unique "gene print" patterns for each cell. Then, we integrated neural networks to mitigate the impact of background noise on cell identity label mapping. We demonstrated the reproducibility of gPRINT across different donors, single-cell sequencing platforms, and disease subtypes, and its utility for automatic cell subtype annotation across datasets. Moreover, gPRINT achieved higher annotation accuracy of 98.37% when externally validated based on the same tissue, surpassing other algorithms. Furthermore, this approach has been applied to fibrosis-associated diseases in multiple tissues throughout the body, as well as to the annotation of fibroblast subtypes in a single tissue, tendon, where fibrosis is prevalent. We successfully achieved automatic prediction of tendinopathy-specific cell subtypes, key targets, and related drugs. In summary, gPRINT provides an automated and unified approach for identifying DSCSs across datasets, facilitating the elucidation of specific cell subtypes under different disease states and providing a powerful tool for exploring therapeutic targets in diseases.
Humans ; Algorithms ; Single-Cell Analysis ; Databases, Genetic ; Molecular Sequence Annotation

(±)-Talapyrones A-F (1-6), six pairs of dimeric polyketide enantiomers featuring unusual 6/6/6 and 6/6/6/5 ring systems, were isolated from the fungus Talaromyces adpressus. Their structures were determined by spectroscopic analysis and HR-ESI-MS data, and their absolute configurations were elucidated using a modified Mosher's method and electronic circular dichroism (ECD) calculations. (±)-Talapyrones A-F (1-6) possess a 6/6/6 tricyclic skeleton, presumably formed through a Michael addition reaction between one molecule of α-pyrone derivative and one molecule of C₈ poly-β-keto chain. In addition, compounds 2/3 and 4/5 are two pairs of C-18 epimers, respectively. Putative biosynthetic pathways of 1-6 were discussed.
Polyketides/isolation & purification* ; Talaromyces/chemistry* ; Stereoisomerism ; Molecular Structure ; Circular Dichroism ; Pyrones/chemistry*

Apoptosis ; Autophagy ; Ferroptosis ; Iron/metabolism* ; Sequestosome-1 Protein/metabolism* ; Ubiquitin-Specific Proteases/metabolism*

Objective To investigate the value of Baveno Ⅶ criteria versus Expanded Baveno Ⅶ criteria in screening for high-risk varices (HRV) in patients with compensated advanced chronic liver disease (cACLD). Methods A total of 146 patients with cACLD who were admitted to Beijing Shijitan Hospital, Capital Medical University, from January 2016 to December 2018 were enrolled, and according to the absence or presence of HRV based on gastroscopy, they were divided into HRV group with 68 patients and control group with 78 patients. Clinical data, liver stiffness measurement (LSM), and gastroscopy findings were analyzed, and different Baveno Ⅶ criteria were analyzed in terms of their sensitivity and specificity in the diagnosis of HRV. The Mann-Whitney U test and the McNemar test were used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data between groups. A univariate logistic regression analysis was performed for the variables used to predict HRV, and a multivariate analysis was performed for the variables with P < 0.1. The two sets of Baveno Ⅶ criteria were compared in terms of their sensitivity and specificity in the diagnosis of HRV. Results A total of 146 patients were enrolled in the study, among whom 68 (46.6%) were found to have HRV. The median age was 54 years (range 29-84 years), male patients accounted for 65.8%, and hepatitis B virus was the main etiology observed in 115 patients (78.8%). The univariate logistic regression analysis showed that LSM and platelet count (PLT) were associated with HRV (both P < 0.05). The multivariate analysis showed that based on Baveno Ⅶ criteria, LSM > 20 kPa or PLT < 150×10 9 /L was associated with HRV (both P < 0.05), and based on Expanded Baveno Ⅶ criteria, LSM > 25 kPa or PLT < 110×10 9 /L was associated with HRV (both P < 0.05). LSM and PLT had an area under the ROC curve of 0.797 (95% confidence interval [ CI ]: 0.723-0.859) and 0.789 (95% CI : 0.714-0.852), respectively, in the diagnosis of HRV. There were significant differences in the prevalence rates of esophageal and gastric varices and HRV between the patients who met Baveno Ⅶ criteria and those who did not meet such criteria ( χ 2 =23.14 and 23.14, both P < 0.001), as well as between the patients who met Expanded Baveno Ⅶ criteria and those who did not meet such criteria ( χ 2 =43.51 and 25.71, both P < 0.001). Although a higher proportion of patients were exempted from gastroscopy based on Expanded Baveno Ⅶ criteria (32.9% vs 13.7%), Baveno Ⅶ criteria had higher sensitivity (0.98 vs 0.88) and negative predictive value (0.95 vs 0.83) and could better avoid the missed diagnosis of HRV (1.0% vs 9.3%). Conclusion Baveno Ⅶ criteria are more suitable for the screening for HRV in cACLD patients in China.

Objective:To investigate the incidences of metachronous advanced adenoma (MAA) in patients with simultaneous multiple primary colorectal cancer (CRC) and patients with sporadic CRC.Methods:From January 1, 2008 to September 30, 2022, at Beijing Shijitan Hospital, Capital Medical University, CRC patients who underwent surgery and 3 years follow-up with endoscopy were enrolled. The patients completed colonoscopy at least 2 times during follow-up in 6 to 36 months after surgery, and the interval between the 2 times colonoscopies was over 6 months. Clinical data including age, gender, and tumor location, stage, pathological features, combined underlying diseases, preoperative carcinoembryonic antigen, hemoglobin and other laboratory results, baseline colonoscopy results, and detection of MAA were collected. According to age (±2 years old), gender, location of primary lesion and stage of tumor, patients with simultaneous CRC or sporadic CRC were matched at 1∶1 ratio by propensity score matching. The cumulative risks of MAA in patients with simultaneous multiple primary CRC and patients with sporadic CRC were calculated. Cox proportional hazard regression was used to analyze the influencing factors in the occurrence of MAA.Results:A total of 814 CRC patients were enrolled and matched. After paired matching, there were 36 cases of simultaneous multiple primary CRC (78 lesions) and 78 cases of sporadic CRC (78 lesions). The cumulative incidences of MAA at 1, 2 and 3 years of simultaneous CRC group were 11.1%(4/36), 22.2%(8/36) and 33.3%(12/36), respectively. The cumulative incidences of MAA at 1-, 2- and 3-year of sporadic CRC group were 3.8%(3/78), 12.8%(10/78) and 20.5%(16/78), respectively.Simultaneous CRC was correlated with an increase in the 3-year cumulative incidence of MAA ( HR=4.163, 95% confidence interval(95% CI) 1.032 to 4.721, P=0.047). Especially in left-sided CRC, the risk of MAA in simultaneous CRC increased ( HR=7.186, 95% CI 1.602 to 20.787, P=0.010). The results of multivariate cox-regression analysis indicated that detection of simultaneous advanced adenoma at baseline endoscopy was an independent risk factor of MAA ( HR=3.175, 95% CI 1.411 to 7.142, P=0.005). Conclusion:Colouoscopy follow-up should be strengthened in patients with simultaneous multiple primary CRC and simultaneous advanced adenomas.

Objective To investigate the effect of ultrasound-guided bilateral superior laryngeal nerve internal branch block combined with endotracheal surface anesthesia in patients with hypertensive cerebral hemorrhage for the duration of postoperative tube insertion.Methods A total of 100 emergency hypertensive intracerebral hemor-rhage surgical patients who visited our hospital from October 2021 to April 2023 were included as the research subjects.They were randomly divided into four groups,25 patients in each group.After surgery,group U received bilateral superior laryngeal nerve internal branch block under guidance of ultrasound combined with endotracheal surface anesthesia,group C1 received bilateral superior laryngeal nerve internal branch block under guidance of ultrasound,group C2 received endotracheal surface anesthesia,and group C3 did not undergo any procedure after surgery.Hemodynamic changes(HR,MAP,and SpO2)at different time points during the postoperative tube insertion in four groups of patients were recorded.The frequency of restlessness within 10 hours after surgery,the dosage of dexmedetomidine and urapidil,the volume of wound drainage,and the satisfaction of bed nurses were also recorded.Results There was no statistically significant difference in general conditions among the four groups(P>0.05).There was no statistically significant difference in HR and MAP at different time points in Group U(P>0.05),while the differences among the other three groups were statistically significant(P<0.05).At the same time point,the MAP and HR of group U and C1 were significantly lower than those of group C3(P<0.05),and the MAP of group U was significantly lower than that of group C2(P<0.05).There was no statistical difference in SPO2 among the four groups of patients at the same time point(P>0.05);The frequency of restlessness,dosage of dexmedetomidine and urapidil,and volume of wound drainage in the U and C1 groups were significantly lower than those in the C2 and C3 groups(P<0.05).Except for the difference in restlessness frequency(P<0.05),there was no statistical difference in other indicators between group U and C1;There was a statistical difference in satisfaction among the four groups of nurses(P<0.05,C3>C2>C1>U group).No nerve block related complications were observed in the U and C1 group.Conclusion Ultrasound-guided bilateral superior laryngeal nerve branch block combined with endotracheal surface anesthesia can maintain hemodynamics steadily of the postoperative patients in the NICU to varying degrees and reduce the frequency of postoperative restlessness,the dosage of sedative and anti-hypertensive drugs,while reducing the flow of wound drainage,and improve the satisfaction of bed nurses.

Objective:To explore the application value of automated machine learning (autoML) model in predicting the risk of preeclampsia in the first trimester.Methods:From January 2017 to October 2020, 2 180 singleton pregnant women who were registered in Jinan Second Maternal and Child Health Hospital and underwent pregnancy examination at 12 weeks of gestation were selected. The pregnant women were divided into preeclampsia group (103 cases) and control group (2 077 cases) according to the occurrence of preeclampsia. The differences in clinical data and hematological indexes in the two groups were compared, and the correlation between each index and the risk of preeclampsia was analyzed too. All the pregnant women were randomly divided into training set and test set according to the ratio of 7∶3, and the autogluon autoML algorithm was used to build a variety of machine learning models, and training and cross-validation were performed in the training set to compare the accuracy of the different models. The importance of each index in the autoML model was analyzed, and the autoML model and the logistic regression model were used to predict the risk of preeclampsia in pregnant women in the test set respectively, and the receiver operating characteristic (ROC) curve was used to evaluate the prediction performance of the autoML and the logistic regression model.Results:The age, pre-pregnancy body mass index, body mass index at 12 weeks of gestation, waist circumference at 12 weeks of gestation, proportion of drinking history, high-sensitivity C-reactive protein (hs-CRP), triglyceride, low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), platelet distribution width (PDW), mean platelet volume, thyroid stimulating hormone (TSH) and β-human chorionic gonadotropin were all significantly higher than those in the control group (all P<0.05), and the free tri-iodothyronine (free T3), free thyroxine (free T4), placental growth factor (PIGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and pregnancy-associated plasma protein-A (PAPP-A) were all significantly lower than those in the control group (all P<0.05). Correlation analysis showed that the correlation between pre-pregnancy body mass index, body mass index at 12 weeks gestation, waist circumference at 12 weeks gestation, hs-CRP, triacylglycerol, AST, TSH, free T3, free T4, β-HCG, PIGF, sFlt-1, PAPP-A and preeclampsia risk were obviously higher; but the correlation between each index were lower. A total of 18 models in 8 categories were constructed with the autoML model algorithm, and the neural network _L2 based on FastAI had the highest accuracy in the training set (0.963) and the validation set (0.971). The TSH, LDL-C, PDW, waist circumference at 12 weeks of gestation, sFlt-1, AST were more important in the model, while the free T4, total cholesterol, pregnancy times, drinking history, parity and family history of hypertension were less important indicators. The area under the ROC curve of the autoML model for predicting the risk of preeclampsia in the first trimester was significantly higher than that of the logistic regression model (0.984 vs 0.765, P=0.002), while there was no statistical difference in the prediction accuracy of the two prediction models in the training set ( P>0.05). The prediction accuracy and sensitivity of the autoML model in the test set were both significantly higher than those of the logistic regression model (99.54% vs 98.32%, 93.75% vs 75.00%, both P<0.05). Conclusions:Factors such as TSH, LDL-C, PDW, waist circumference, sFlt-1 and AST in the first trimester of pregnancy have a certain correlation with the risk of preeclampsia. The autoML model based on the indicators of the first trimester has a high predictive value for the risk of preeclampsia.

To study the molecular mechanism of salt stress response of peanut small GTP binding protein gene AhRabG3f, a 1 914 bp promoter fragment upstream of the start codon of AhRabG3f gene (3f-P) from peanut was cloned. Subsequently, five truncated fragments (3f-P1-3f-P5) with lengths of 1 729, 1 379, 666, 510 and 179 bp were obtained through deletion at the 5' end, respectively. Plant expression vectors where these six promoter fragments were fused with the gus gene were constructed and transformed into tobacco by Agrobacterium-mediated method, respectively. GUS expression in transgenic tobacco and activity analysis were conducted. The gus gene expression can be detected in the transgenic tobacco harboring each promoter segment, among which the driving activity of the full-length promoter 3f-P was the weakest, while the driving activity of the promoter segment 3f-P3 was the strongest. Upon exposure of the transgenic tobacco to salt stress, the GUS activity driven by 3f-P, 3f-P1, 3f-P2 and 3f-P3 was 3.3, 1.2, 1.9 and 1.2 times compared to that of the transgenic plants without salt treatment. This suggests that the AhRabG3f promoter was salt-inducible and there might be positive regulatory elements between 3f-P and 3f-P3 in response to salt stress. The results of GUS activity driven by promoter fragments after salt treatment showed that elements included MYB and GT1 between 1 930 bp and 1 745 bp. Moreover, a TC-rich repeat between 682 bp and 526 bp might be positive cis-elements responsible for salt stress, and an MYC element between 1 395 bp and 682 bp might be a negative cis-element responsible for salt stress. This study may facilitate using the induced promoter to regulate the salt resistance of peanut.
Arachis/genetics* ; Fabaceae/genetics* ; GTP-Binding Proteins/metabolism* ; Gene Expression Regulation, Plant ; Glucuronidase/metabolism* ; Plant Proteins/metabolism* ; Plants, Genetically Modified/genetics* ; Salt Stress ; Stress, Physiological/genetics* ; Tobacco/genetics*