OBJECTIVES: In recent years, the role of remnant cholesterol (RC) in the development and progression of cardiovascular diseases has gained increasing attention. However, evidence on the association between RC and subclinical atherosclerosis is limited. This study aims to examine the relationship between RC and atherosclerotic plaques in single and multiple vascular territories. METHODS: This retrospective cross-sectional study used baseline data from participants enrolled between October 2022 and May 2024 in the National Key Research Program "Study on the Prevention and Control System of Risk Factors for Panvascular Diseases". Color Doppler ultrasonography was performed to detect plaques in 4 vascular territories: Bilateral carotid arteries, bilateral subclavian arteries, abdominal aorta, and iliac-femoral arteries. RC was calculated as total cholesterol minus the sum of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). Participants were categorized into quartiles (Q1-Q4) according to RC levels. The proportions of participants with ≥2 plaques in a single vascular territory and with plaques in ≥2 vascular territories were compared across RC quartiles. Multivariate ordinal Logistic regression was used to assess the association between RC and the number of plaques in a single vascular territory, as well as the risk of multiple vascular territory involvement. Additionally, the effects of LDL-C/RC concordance on plaque distribution were analyzed. RESULTS: A total of 3 539 participants were included, of whom 2 169 (61.29%) were male, with a age of (51.94±9.22) years. From Q1 to Q4, the proportion of participants with ≥2 plaques in a single vascular territory (bilateral carotid, subclavian, abdominal aorta, and iliac-femoral arteries), as well as those with plaques in ≥2 vascular territories, increased progressively. Compared with Q1, both Q3 and Q4 were significantly associated with higher plaque numbers in a single vascular territory (both P<0.05). When treated as a continuous variable, higher RC levels were associated with an increased risk of greater plaque numbers within a single vascular territory (all P<0.05). RC levels were also significantly associated with multiple vascular territory involvement: Compared with Q1, Q4 had a 1.015-fold higher risk [odds ratio (OR)=2.015, 95% confidence interval (CI) 1.669 to 2.433], and each 1 mmol/L increase in RC corresponded to a 0.160-fold increased risk (OR=1.160, 95% CI 1.073 to 1.271). In LDL-C/RC coordination analysis, compared with the low LDL-C/low RC group, the low LDL-C/high RC group was significantly associated with multiple vascular territory involvement (OR=1.576, 95% CI 1.220 to 2.036). CONCLUSIONS Elevated RC levels are closely associated with atherosclerotic plaques in both single and multiple vascular territories, even among individuals with normal LDL-C, suggesting that RC should be considered in clinical risk assessment and management of atherosclerosis.
Humans ; Plaque, Atherosclerotic/diagnostic imaging* ; Male ; Female ; Cross-Sectional Studies ; Middle Aged ; Retrospective Studies ; Cholesterol/blood* ; Cholesterol, LDL/blood* ; Aged ; Cholesterol, HDL/blood* ; Risk Factors ; Atherosclerosis ; Ultrasonography, Doppler, Color ; Femoral Artery/diagnostic imaging*

BACKGROUND AND AIM: Remnant cholesterol (remnant-C) mediates the progression of major adverse cardiovascular events. It is unclear whether remnant-C, and particularly cumulative exposure to remnant-C, is associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether remnant-C, not only baseline but cumulative exposure, can be used to independently evaluate the risk of NAFLD. METHODS: This study included 1 cohort totaling 21,958 subjects without NAFLD at baseline who underwent at least 2 repeated health checkups and 1 sub-cohort totaling 2,649 subjects restricted to those individuals with at least 4 examinations and no history of NAFLD until Exam 3. Cumulative remnant-C was calculated as a timeweighted model for each examination multiplied by the time between the 2 examinations divided the whole duration. Cox regression models were performed to estimate the association between baseline and cumulative exposure to remnant-C and incident NAFLD. RESULTS: After multivariable adjustment, compared with the quintile 1 of baseline remnant-C, individuals with higher quintiles demonstrated significantly higher risks for NAFLD (hazard ratio [HR] 1.48, 95%CI 1.31-1.67 for quintile 2; HR 2.07, 95%CI 1.85-2.33 for quintile 3; HR 2.55, 95%CI 2.27-2.88 for quintile 4). Similarly, high cumulative remnant-C quintiles were significantly associated with higher risks for NAFLD (HR 3.43, 95%CI 1.95-6.05 for quintile 2; HR 4.25, 95%CI 2.44-7.40 for quintile 3; HR 6.29, 95%CI 3.59-10.99 for quintile 4), compared with the quintile 1. CONCLUSION Elevated levels of baseline and cumulative remnant-C were independently associated with incident NAFLD. Monitoring immediate levels and longitudinal trends of remnant-C may need to be emphasized in adults as part of NAFLD prevention strategy.
Adult ; Humans ; Cohort Studies ; Non-alcoholic Fatty Liver Disease/etiology* ; Cholesterol ; Proportional Hazards Models ; Risk Factors

Objective To overcome the limitations of existing human respiratory syncytial virus(hRSV)animal models,such as semi-permissiveness and short duration of infection,this study established an IL2rg gene knockout(IL2rg-/-)rat model using TALEN gene editing technology.Methods The animal model was infected with hRSV intranasally.Clinical characteristics,body weight,and temperature changes were observed over the infection period(0～35 days).The total viral loads in respiratory organs,such as the nasal tissue,trachea,and lungs,were measured at various time points(4,11,20,and 35 days post-infection).Pathological analysis was conducted on target organs at the endpoint of observation(35 days post-infection).Changes in peripheral blood T,B,NK,and NKT cells and various cytokines were assessed at various time points(4,20,and 35 days post-infection).Results(1)IL2rg/-knockout rats sustained high viral loads in the nasal cavity upon intranasal inoculation with hRSV.The average peak titer rapidly reached 1 × 1010 copies/g in nasal tissue and 1 × 107 copies/g up to 5 weeks post-infection.(2)However,no significant pathological changes were noted in nasal,tracheal,or lung tissues.(3)An increase was observed in the content of peripheral blood B cells in hRSV-infected IL2rg--rats.(4)IL-6 and MCP-1 were increased in the early stage of infection and then decreased at the end of the observation period.Conclusions This study established a new IL2rg-/-rat model using TALEN technology and found that this model effectively supported high-level replication and long-term infection of hRSV,providing a good basis for antiviral drug screening and in vivo efficacy evaluation of anti-hRSV antibodies.

ObjectiveThrough improving the potential of vascular endothelial growth factor receptor (VEGFR)-humanized mouse model (hKDR^+/+) with C57BL/6N background to allow the growth of different mouse tumor cell lines, to establish novel tumor-bearing mouse models which can support in vivo tumorigenesis of different mouse tumor cell lines and be used to evaluate drugs targeting VEGFR.MethodsFirstly, a method to evaluate the in vivo activity of antibody targeting VEGFR based on the hKDR^+/+ humanized mouse model was established. Recombinant activating gene 1 (Rag1) knockout mice (Rag1^-/-) were established using CRISPR/Cas9 technology. Then these Rag1^-/- mice were crossed with hKDR^+/+ mice to get a double gene modified homozygous hKDR^+/+/Rag1^-/- mouse model by screening. Finally, tumor cell lines derived from different mouse strains were tested on the double gene-modified mouse model to compare the differences in tumor growth. ResultsAntibodies designed for VEGFR showed significant anti-tumor activity in hKDR^+/+ mice, which significantly reduced tumor volume and weight compared with the PBS group (P<0.01, P<0.05). The number of B cells and T cells in the peripheral blood of Rag1^-/- mice and hKDR^+/+/Rag1^-/- mice decreased (P<0.05, P<0.001). Tumors were observed in hKDR^+/+/Rag1^-/-, Rag1^-/-, wild-type, and hKDR^+/+ mice after 7 d of inoculation of MC38 cells derived from C57BL/6 mice. Tumors were only observed in groups of hKDR^+/+/Rag1^-/- and Rag1^-/- mice, but not in the wild-type and hKDR^+/+ mice after 10 d of inoculation with CT26 cells derived from BALB/c mice. After 3 weeks of inoculation, the tumor volume of hKDR^+/+/Rag1^-/- mice was significantly larger than that of Rag1^-/- mice (P<0.01). ConclusionRag1 knockout mice were obtained and a novel hKDR^+/+/Rag1^-/- double genes modified mouse model was further screened. The tumor cell lines from different mouse strain origins were more prone to growth in mice with Rag1 gene deficiency. The results suggest that the reduced immune response of hKDR^+/+ humanized mice will improve the capacity of supporting the growth of mouse tumor lines in the model. As a result, more tumor-bearing mouse models may be constructed for the evaluation of drugs targeting VEGFR in this way.

Objective: To establish the knowledge graph of “disease-syndrome-symptom-method-formula” in Treatise on Febrile Diseases (Shang Han Lun,《伤寒论》) for reducing the fuzziness and uncertainty of data, and for laying a foundation for later knowledge reasoning and its application. Methods: Under the guidance of experts in the classical formula of traditional Chinese medicine (TCM), the method of “top-down as the main, bottom-up as the auxiliary” was adopted to carry out knowledge extraction, knowledge fusion, and knowledge storage from the five aspects of the disease, syndrome, symptom, method, and formula for the original text of Treatise on Febrile Diseases, and so the knowledge graph of Treatise on Febrile Diseases was constructed. On this basis, the knowledge structure query and the knowledge relevance query were realized in a visual manner. Results: The knowledge graph of “disease-syndrome-symptom-method-formula” in the Treatise on Febrile Diseases was constructed, containing 6 469 entities and 10 911 relational triples, on which the query of entities and their relationships can be carried out and the query result can be visualized. Conclusion The knowledge graph of Treatise on Febrile Diseases systematically realizes its digitization of the knowledge system, and improves the completeness and accuracy of the knowledge representation, and the connection between “disease-syndrome-symptom-treatment-formula”, which is conducive to the sharing and reuse of knowledge can be obtained in a clear and efficient way.

Plant fungal pathogens secrete numerous proteins into the apoplast at the plant-fungus contact sites to facilitate colonization.However,only a few secretory proteins were functionally characterized in Magnaporthe oryzae,the fungal pathogen causing rice blast disease worldwide.Asparagine-linked glycosylation 3(Alg3)is an a-l,3-mannosyltransferase functioning in the N-glycan synthesis of N-glycosylated secretory proteins.Fungal pathogenicity and cell wall integrity are impaired in Aalg3 mutants,but the secreted proteins affected in Aalg3 mutants are largely unknown.In this study,we compared the secretomes of the wild-type strain and the Aalg3 mutant and identified 51 proteins that require Alg3 for proper secretion.These proteins were predicted to be involved in metabolic processes,interspecies interactions,cell wall organization,and response to chemicals.Nine proteins were selected for further validation.We found that these proteins were localized at the apoplastic region surrounding the fungal infection hyphae.Moreover,the N-glycosylation of these proteins was significantly changed in the Aalg3 mutant,leading to the decreased protein secretion and abnormal protein localization.Furthermore,we tested the biological functions of two genes,INV1(encoding invertase 1,a secreted invertase)and AMCase(encoding acid mammalian chinitase,a secreted chitinase).The fungal virulence was significantly reduced,and the cell wall integrity was altered in the Ainv1 and Aamcase mutant strains.Moreover,the N-glycosylation was essential for the function and secretion of AMCase.Taken together,our study provides new insight into the role of N-glycosylated secretory proteins in fungal virulence and cell wall integrity.

Objective    To detect the expression of PITX2 and KCNQ1 in the left atrial appendage of patients with atrial fibrillation after modified mini-maze procedure, and to detect the clinical risk factors of different types of atrial fibrillation. Methods    We collected left atrial appendage tissue of 59 atrial fibrillation patients who received modified mini-maze procedure and left atrial appendectomy from February 2017 to August 2018. The expression levels of PITX2 and KCNQ1 of left atrial appendage tissue were quantitatively analyzed by western blotting assay between paroxysmal attial fibrillation and persistent atrial fibrillation groups. The correlation between protein expression and prognosis after surgery was also analyzed based on clinical data. Results    Binary-logistic regression analysis showed that KCNQ1 expression level was an independent risk factor for the progression from paroxysmal atrial fibrillation to persistent atrial fibrillation. Receiver operating characteristic (ROC) curve confirmed that KCNQ1 expression level (the ratio of KCNQ1 to actin in the analysis) was 0.60, which was the best cut-off point for the progression of paroxysmal atrial fibrillation to persistent atrial fibrillation. Conclusion    High expression of KCNQ1 in left atrial appendage is a risk factor for progression from paroxysmal atrial fibrillation to persistent atrial fibrillation.

Objective To investigate the effects of Qishen Erlian Decoction on serum MMP-1 and TIMP-1 levels in thioacetamide (TAA) induced liver fibrosis rats; To discuss its mechanism of action. Methods Liver fibrosis model was created by the TAA gavage method. 120 SD male rats were randomly assigned to control group, model group, colchicine group, Qishen Erlian Decoction low-, medium- and high-dose group (20 in each group). Each medication group was given relevant medicine for gavage. Control group and model group were given the same amount of normal saline for gavage, once a day for 5 weeks. HE staining and Masson trichrome staining were used to observe the pathological changes in liver tissue and liver tissue damage. Biochemistry, radioimmunoassay, and ELISA were used to detect the serum liver function, hepatic fibrosis index, MMP-1 and TIMP-1 levels. Results Compared with the model group, serum ALT, AST, TBIL, γ-GGT, HA, LN, Ⅳ-C and PCⅢ levels, MMP-1 and the ratio of MMP-1/TIMP-1 increased significantly and level of TIMP-1 decreased significantly in Qishen Erlian Decoction groups, with statistical significance (P<0.05, P<0.01). And there is a certain dose-effect relationship, with Qishen Erlian Decoction high-dose group the best effect. Conclusion Qishen Erlian Decoction can improve the liver function and liver fibrosis indexes, regulate the level of MMP-1 and TIMP-1, and prevent the progression of liver fibrosis.

Objective:To analyze the characteristics of long non-coding RNA (lncRNA) expression in nonalcoholic fatty liver disease (NAFLD).Methods:lncRNA-mRNA microarray was conducted on the liver tissue samples from 10 patients with simple gallbladder stone (5 NAFLD liver samples and 5 normal liver samples),and the differentially expressed lncRNA was analyzed by bioinformatics technology.Results:Compared with the normal liver samples,there were abnormal expression of 1 735 lncRNAs and 1 485 mRNAs in NAFLD liver samples.Among them,535 lncRNAs and 760 mRNAs were up-regulated,1 200 lncRNAs and 725 mRNAs were down-regulated.Conclusion:Compared with normal liver,the expression oflncRNA in NAFLD tissues is obviously abnormal.These lncRNAs may play an important role in the occurrence and development of NAFLD.

Objective: To analyze the associations between molecular subtypes and overall breast cancer survival among premenopausal and postmenopausal breast cancer in Beijing, and to provide basic information for breast cancer clinical researches and control. Methods: All the resident patients diagnosed with breast cancer in four well-established hospitals were retrieved from Beijing cancer registry, related information, such as TNM stages, receptor status, histological grade, height, weight, were collected by case extraction. Cancer registration information and population-based follow-up information were used to acquire survival outcome. All the patients were followed up until 31 December 2015, 4 531 cases with invasive, primary breast were included in the final analysis. All the cases were classified into Luminal and non-Luminal according to receptor status. Five-year survival rates of the two subtypes were estimated by the life-table method. Multivariable Cox proportional hazards models were employed to evaluate the associations between molecular subtypes and breast cancer survival. Results: Of all the 4 531 patients, premenopausal patients accounted for 44.5% (2 017 cases) and postmenopausal patients accounted for 55.5% (2 514 cases). 643 cases died during the study period. Overall five-year survival was 89.5% (95%CI: 88.6%-90.4%), for premenopausal and postmenopausal patients, they were 92.1% (95%CI: 90.9%-93.3%), and 87.5% (95%CI: 86.2%-88.8%), respectively. Among all the patients, 3 730 patients had molecular subtype, 76.7% (2 861 cases) were Luminal breast cancer, and 23.3% (869 cases) were non-Luminal breast cancer. Five-year survival rates for Luminal and non-Luminal were 91.8% (95%CI: 90.8%-92.8%), and 83.2% (95%CI: 80.7%-85.7%), respectively. No matter in premenopausal or postmenopausal patients, non-Luminal breast cancer had significantly higher risk of death compared to Luminal breast cancer (premenopausal: HR=1.85, 95%CI: 1.26-2.73; premenopausal: HR=1.42, 95%CI: 1.07-1.88). Conclusion For both premenopausal and postmenopausal breast cancer patients, non-Luminal breast cancer had lower five-year survival rates than Luminal breast cancer, which was a risk factor on breast cancer survival.