The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective: To investigate the etiology, complications, and prognostic factors of stage 5 chronic kidney disease (CKD5) in children. Methods: A case series study was conducted to retrospectively analyze the general situation, clinical manifestations, laboratory tests, genetic testing, and follow-up data (until October 2022) of 174 children with CKD5 who were diagnosed and hospitalized at the Children's Hospital of Chongqing Medical University from April 2012 to April 2021. The characteristics of complications in the children were compared based on age, gender, and etiology. Based on the presence or absence of left ventricular hypertrophy (LVH), patients were divided into LVH group and non LVH group for analyzing the influencing factors of cardiovascular disease. Patients were also divided into death group and survival group, peritoneal dialysis group and hemodialysis group based on the follow-up data for analyzing the prognostic factors. The chi-square test, independent sample t-test, Fisher exact probability test, Mann-Whitney U test and Kruskal Wallis test were used to analyze data among different groups. Multivariate Logistic regression analysis was used to identify the prognostic factors. Results: A total of 174 children with CKD5 were enrolled in the study (96 boys and 78 girls), aged 11.2 (8.2, 13.0) years. Congenital kidney and urinary tract malformations (CAKUT) were the most common causes of the CKD5 (84 cases, 48.3%), followed by glomerular diseases (83 cases, 47.7%), and among which 28 cases (16.1%) were hereditary glomerular diseases. The common complications of CKD5 included anemia (98.2%, 165/168), mineral and bone disorder in chronic kidney disease (CKD-MBD) (97.7%, 170/174), lipid metabolism disorders (87.5%, 63/72), hypertension (81.4%, 127/156) and LVH (57.6%,57/99). The incidences of hypertension in primary glomerular disease were higher than that in CAKUT(93.8%(30/32) vs.73.7%(56/76),χ²=5.59,P<0.05). The incidences of hypertension in secondary glomerular disease were higher than that in CAKUT and that in hereditary kidney disease (100.0%(20/20) vs. 73.7%(56/76), 68.2%(15/22), both P<0.05). The incidence of hypocalcemia in CAKUT, primary glomerular disease, and hereditary kidney disease was higher than that in secondary glomerular disease (82.1%(69/84), 88.2%(30/34), 89.3%(25/28) vs. 47.6%(10/21), χ²=10.21, 10.75, 10.80, all P=0.001); the incidence of secondary hyperparathyroidism in women was higher than that in men (80.0%(64/80) vs. 95.0%(57/60), χ²=6.58, P=0.010). The incidence of LVH in children aged 6-<12 was higher than that in children aged 12-18 (73.5%(25/34) vs. 43.1%(22/51), χ²=7.62, P=0.006). Among 113 follow-up children, the mortality rate was 39.8% (45/113). Compared to the survival group, the children in the death group had lower hemoglobin, higher blood pressure, lower albumin, lower alkaline phosphatase and higher left ventricular mass index ((67±19) vs. (75±20) g/L, 142 (126, 154) vs. 128(113, 145) mmHg(1 mmHg=0.133 kPa), (91±21) vs. (82±22) mmHg, 32 (26, 41) vs. 40 (31, 43) g/L, 151 (82, 214) vs. 215 (129, 37) U/L, 48 (38, 66) vs. 38(32, 50) g/m^2.7,t=2.03, Z=2.89, t=2.70, Z=2.49, 2.79, 2.29,all P<0.05), but no independent risk factors were identified (all P>0.05). The peritoneal dialysis group had better alleviation for anemia, low calcium, and high phosphorus than the hemodialysis group ((87±22) vs. (72±16) g/L, (1.9±0.5) vs. (1.7±0.4) mmol/L, (2.2±0.7) vs. (2.8±0.9) mmol/L, t=2.92, 2.29, 2.82, all P<0.05), and the survival rate of the peritoneal dialysis group was significantly higher than that of the hemodialysis group (77.8% (28/36) vs. 48.4% (30/62), χ²=8.14, P=0.004). Conclusions: CAKUT is the most common etiology in children with CKD 5, and anemia is the most common complication. The incidence of complications in children with CKD 5 varies with age, gender and etiology. Anemia, hypertension, hypoalbuminemia, reduced alkaline phosphatase and elevated LVMI may be the prognostic factors in children with CKD5. Peritoneal dialysis may be more beneficial for improving the long-term survival rate.
Male ; Humans ; Child ; Female ; Retrospective Studies ; Alkaline Phosphatase ; Kidney Failure, Chronic/therapy* ; Renal Insufficiency, Chronic/therapy* ; Hypertension ; Risk Factors ; Hypertrophy, Left Ventricular/etiology* ; Anemia/etiology*

This study aimed to investigate the effects and the underlying mechanism of CD36 gene on glucose and lipid metabolism disorder induced by high-fat diet in mice. Wild type (WT) mice and systemic CD36 knockout (CD36
Animals ; Diet, High-Fat/adverse effects* ; Fatty Liver/metabolism* ; Glucose/metabolism* ; Insulin/metabolism* ; Insulin Resistance ; Lipid Metabolism ; Liver ; Mice ; Triglycerides

Objective:To provide a scientific basis for the classification of Phyllanthi Fructus product grades. Method:A total of 30 batches of Phyllanthi Fructus currently available in the market were collected for quantification based on such appearance indexes as diameter， thickness， grain weight， and crust colour （L^*， a^*， and b^* values）. The contents of gallic acid， corilagin， chebulagic acid， and ellagic acid were measured by high performance liquid chromatography （HPLC）， followed by descriptive statistical analysis （DSA）， analysis of variance （ANOVA）， and principal component analysis （PCA） to determine the importance of each main index and explore the correlations between the appearance indexes and internal components. The classification standard of Phyllanthi Fructus product grades was formulated， and its scientificity was verified in hepatocelular carcinoma HepG2 cells. Result:The correlation analysis revealed that the crust colour L^*， a^*， and b^* values were significantly negatively correlated with corilagin， chebulagic acid， and ellagic acid （|r|>0.5， P<0.01）， but irrelevant to gallic acid （|r|<0.1）. Considering the variable coefficient of each index， PCA results， and the requirement of gallic acid as quality indicator for Phyllanthi Fructus in Chinese Pharmacopoeia， the crust colour L^*， a^*， and b^* values and gallic acid content were determined to be the classification indexes. The K-means cluster analysis confirmed that products with crust colour L^*<44， a^*<7， and b^*<10 and gallic acid content >1.6% could be classified into the first class， and those failing to meet the above requirements into the second class. The cell experiment demonstrated that the half-maximal inhibitory concentration （IC₅₀） of the first-class product against hepatocelular carcinoma HepG2 cells was lower than that of the second-class product. A colourimetric card was developed based on crust colour L^*， a^*， and b^* values to provide a visual tool for on-site evaluation of Phyllanthi Fructus products. Conclusion:This study has initially established the classification standard of Phyllanthi Fructus product grades， which contributes to guiding price negotiation of Phyllanthi Fructus products based on quality grade and thus ensuring high quality and high price.

BACKGROUND: In recent years, visual quality has been extensively investigated in various conditions. In this community-based population study, we analyzed the effects of aging, refraction, and Lens Opacification Classification System III (LOCSIII) score on retinal imaging quality in healthy Chinese adults. METHODS: This cross-sectional study was conducted on sub-group subjects from The Handan Eye Study between October 2012 and January 2013. Healthy subjects over 30-years-old with logarithm of the minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) less than 0 were included. Retinal image quality was measured by optical quality analysis system (OQAS) and recorded as modulation transfer function cutoff frequency (MTFcutoff), OQAS value (OV) 100%, OV20%, OV9%, Strehl ratio (SR), and objective scatter index (OSI). The correlation between age, spherical equivalent refraction (SE), LOCSIII score, and optical quality parameters were investigated by multivariate analysis. RESULTS: Among 1108 verified subjects, 690 subjects (1380 eyes) met the inclusion criteria. Their age ranged from 30 to 76 years, SE ranged from -4.75 to 2.75 D. They were divided into five age groups (30-39, 40-49, 50-59, 60-69, and ≥70 years) for further analysis. After multivariate analysis by mixed-effect linear model, SR (t =  -3.03, P = 0.002), OV20% (t = -2.39, P = 0.017), and OV9% (t = -3.16, P = 0.001) significantly decreased with the increasing age, whereas logMAR BCVA (t = 4.42, P < 0.001) and OSI (t = 4.46, P < 0.001) significantly increased with age. As SE increased, SR (t = 2.74, P = 0.01), OV20% (t = 2.31, P = 0.02), and OV9% (t = 2.79, P = 0.005) significantly elevated, and OSI (t = -3.38, P < 0.001) significantly decreased. With the increase in cortical opacity score, all optical quality parameters except for SR significantly decreased, including MTFcutoff (t = -2.78, P = 0.01), OV100% (t = -2.78, P = 0.005), OV20% (t = -2.60, P = 0.009), and OV9% (t = -2.05, P = 0.040). As posterior sub capsular opacity score increased, MTFcutoff (t = -2.40, P = 0.02) and OV100% (t = -2.40, P = 0.01) significantly decreased, while OSI (t = 7.56, P < 0.001) significantly increased. CONCLUSIONS In healthy Chinese adult population, optical quality-related parameters significantly decrease with the increasing age, and OSI significantly increases with age. In normal BCVA subjects, optical quality is significantly impacted by cortical and posterior sub capsular opacity rather than by nuclear opacity.

Background::Fever is the most common chief complaint of emergency patients. Early identification of patients at an increasing risk of death may avert adverse outcomes. The aim of this study was to establish an early prediction model of fatal adverse prognosis of fever patients by extracting key indicators using big data technology.Methods::A retrospective study of patients’ data was conducted using the Emergency Rescue Database of Chinese People’s Liberation Army General Hospital. Patients were divided into the fatal adverse prognosis group and the good prognosis group. The commonly used clinical indicators were compared. Recursive feature elimination method was used to determine the optimal number of the included variables. In the training model, logistic regression, random forest, adaboost, and bagging were selected. We also collected the emergency room data from December 2018 to December 2019 with the same inclusion and exclusion criterion. The performance of the model was evaluated by accuracy, F1-score, precision, sensitivity, and the areas under receiver operator characteristic curves (ROC-AUC).Results::The accuracy of logistic regression, decision tree, adaboost and bagging was 0.951, 0.928, 0.924, and 0.924, F1-scores were 0.938, 0.933, 0.930, and 0.930, the precision was 0.943, 0.938, 0.937, and 0.937, ROC-AUC were 0.808, 0.738, 0.736, and 0.885, respectively. ROC-AUC of ten-fold cross-validation in logistic and bagging models were 0.80 and 0.87, respectively. The top six coefficients and odds ratio (OR) values of the variables in the logistic regression were cardiac troponin T (CTnT) (coefficient = 0.346, OR = 1.413), temperature (T) (coefficient = 0.235, OR = 1.265), respiratory rate (RR) (coefficient= –0.206, OR = 0.814), serum kalium (K) (coefficient = 0.137, OR = 1.146), pulse oxygen saturation (SPO 2) (coefficient = –0.101, OR = 0.904), and albumin (ALB) (coefficient = –0.043, OR = 0.958). The weights of the top six variables in the bagging model were: CTnT, RR, lactate dehydrogenase, serum amylase, heart rate, and systolic blood pressure. Conclusions::The main clinical indicators of concern included CTnT, RR, SPO 2, T, ALB, and K. The bagging model and logistic regression model had better diagnostic performance comprehesively. Those may be conducive to the early identification of critical patients with fever by physicians.

Some Chinese herbal medicine needs to be processed before it can be used as medicine, especially toxic Chinese medicine. Highly toxic Aconti Kusnezoffii Radix(Caowu in Chinese) is widely used in traditional Chinese medicine and Mongolian medicine. In traditional Chinese medicine, Caowu is usually processed by boiling with water(CW) until no white part inside and being tasted without tongue-numbing. In Mongolian medicine, it is usually soaked in Chebulae Fructus(Hezi in Chinese) decoction for several days(CH). Both methods could reduce toxicity according to reports. The biggest difference between CW and CH is that CW needs to be heated for 4-6 h, while CH needs Hezi as processing adjuvants. To explore the toxicity reduction mechanism of CW and CH, we studied the contents of various compounds in Caowu processed by two methods by UPLC-Orbitrap-MS. The results indicated that CW had 14 new ingredients, such as 14-O-anisoylneoline and dehydro-mesaconitine, while N-demethyl-mesaconitine and aconitine disappeared. At the same time, it could significantly decrease the content of diester diterpenoid alkaloids and increase the contents of monoester diterpenoid alkaloids and amine-diterpenoid alkaloids. CH had 9 new ingredients from Hezi, like gallic acid, chebulic acid and shikimic acid. Neither the kinds nor the contents of compositions from Caowu in CH changed little. This suggested that the processing mechanism of CW reduced highly toxic components(diester diterpenoid alkaloids) and increased the content of lowly toxic components(monoester diterpenoid alkaloids and amine-diterpenoid alkaloids). Attenuated principle of CH may be related to the components of Hezi. In this experiment, the conclusion shows that the chemical constituents of CW and CH are essentially different, and the two methods have different toxicity reduction principles.
Aconitine ; Aconitum/chemistry* ; Alkaloids/analysis* ; Chemistry, Pharmaceutical/methods* ; Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal/analysis* ; Mass Spectrometry ; Medicine, Chinese Traditional

Objective To understand healthcare-associated infection(HAI)in group burn/trauma patients,and explore its risk factors.Methods HAI occurred among 25 hospitalized patients with group burn/trauma during a bus deflagration event on May 12,2014 were monitored and analyzed.Results Of 25 burn/trauma patients,7 de-veloped 10 times of HAI,incidence and case incidence of HAI were 28.00% and 40.00% respectively;the main in-fection sites were wound and lower respiratory tract,accounting for 60.00% and 30.00% respectively.30 strains of pathogens were isolated from 7 patients with HAI,including 16 strains (53.34%)of gram-negative bacteria,13 strains(43.33%)of gram-positive bacteria,and 1 fungus (3.33% ).Risk factors for HAI were large burned area, high degree of inhalation injury,arteriovenous catheterization,urinary tract catheterization,tracheotomy,use of ventilator,and surgery.Conclusion Incidence of HAI is high in the group burn/trauma patients,corresponding in-tervention measures should be formulated according to the risk factors,so as to reduce the occurrence of HAI.

The thymus is a vital primary lymphoid organ that provides unique microenvironments for the proliferation, differentiation, and maturation of T cells. With advancing age, however, the thymus gradually undergoes age-related involution and reduction in immune function, which are characterized by decreases in tissue size, cellularity, and naïve T cell output. This dynamic process leads to the reduced efficacy of the immune system with age and contributes to the increased susceptibility to infection, autoimmune disease, and cancer. In addition, bone marrow transplantation, radio-chemotherapy and virus infection also impair the thymus and give rise to the decline in immune function. Therefore, understanding the molecular mechanisms involved in age-related thymic involution and development of novel therapeutic strategies for thymic rejuvenation have gained considerable interests in recent years. This review emphasizes thymic microenvironments and thymocyte-stromal cell interactions and summarizes our current knowledge about thymic rejuvenation in terms of sex steroid, cytokines, growth factors, hormones, transcription factors, cell graft, and microRNAs. At the end of each discussion, we also highlight unanswered issues and describe possible future research directions.
Aging ; Cell Differentiation ; Cytokines ; Gonadal Steroid Hormones ; Hormones ; Humans ; Intercellular Signaling Peptides and Proteins ; Rejuvenation ; Stromal Cells ; T-Lymphocytes ; Thymus Gland

BACKGROUNDData on the epidemiology of hypertension in Chinese non-dialysis chronic kidney disease (CKD) patients are limited. The aim of the present study was to investigate the prevalence, awareness, treatment, and control of hypertension in the non-dialysis CKD patients through a nationwide, multicenter study in China.

METHODSThe survey was performed in 61 tertiary hospitals in 31 provinces, municipalities, and autonomous regions in China (except Hong Kong, Macao, and Taiwan). Trained physicians collected demographic and clinical data and measured blood pressure (BP) using a standardized protocol. Hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, and/or use of antihypertensive medications. BP < 140/90 mmHg and < 130/80 mmHg were used as the 2 thresholds of hypertension control. In multivariate logistic regression with adjustment for sex and age, we analyzed the association between CKD stages and uncontrolled hypertension in non-dialysis CKD patients.

RESULTSThe analysis included 8927 non-dialysis CKD patients. The prevalence, awareness, and treatment of hypertension in non-dialysis CKD patients were 67.3%, 85.8%, and 81.0%, respectively. Of hypertensive CKD patients, 33.1% and 14.1% had controlled BP to < 140/90 mmHg and < 130/80 mmHg, respectively. With successive CKD stages, the prevalence of hypertension in non-dialysis CKD patients increased, but the control of hypertension decreased (P < 0.001). When the threshold of BP < 130/80 mmHg was considered, the risk of uncontrolled hypertension in CKD 2, 3a, 3b, 4, and 5 stages increased 1.3, 1.4, 1.4, 2.5, and 4.0 times compared with CKD 1 stage, respectively (P < 0.05). Using the threshold of < 140/90 mmHg, the risk of uncontrolled hypertension increased in advanced stages (P < 0.05).

CONCLUSIONSThe prevalence of hypertension Chinese non-dialysis CKD patients was high, and the hypertension control was suboptimal. With successive CKD stages, the risk of uncontrolled hypertension increased.

Adult ; Aged ; Awareness ; Female ; Humans ; Hypertension ; complications ; epidemiology ; therapy ; Male ; Middle Aged ; Prevalence ; Renal Insufficiency, Chronic ; complications