Objective To observe the influence of tumor necrosis factor-alpha(TNFα) on skeletal muscle protein catabolism in rats with chronic obstructive pulmonary disease (COPD) and the effects of indomethacin (IND) on it. Methods Duplicated COPD model rats were divided into two groups: the malnutrition group and the normal nutrition group. The malnutrition group were further divided by randomized block design into four groups. Isotonic physiologic saline was administered to group A, the control and the normal nutrition group, and different doses of oral IND were administered to groups B, C, and D weight, concentrations of TNFα, contents of 3-methyl-histidine ( 3- M H ) and tyrosine (Tyr) in the diaphragm and extensor digitorum longus muscle homogenates were measured before and after the intervention. Results Before the intervention, the concentrations of TNFα in the serum of malnutrition groups were all significantly higher than those of normal nutrition group and the control group. After the intervention: (1) The concentrations of TNFα in the serum of the rats of group B, C and D were significantly lower than the group A, especially in group C. The levels of TNFα in serum and body weight of model group rats were negatively correlated ( r = -0. 846, P ＜0. 01 ), as well as the diaphragm and extensor digitorum longus muscle weights ( r = - 0. 778, P ＜ 0. 01; r = - 0. 772, P ＜ 0. 01 ). (2) The levels of 3-methyl-histidine in the diaphragm and extensor digitorum longus muscles of the intervention group C was lower than the COPD normal nutrition group, as well as the intervention groups B and D. The contents of tyrosine in the diaphragm and extensor digitorum longus muscles of the intervention group C was lower than that of the COPD normal nutrition group,as well as the groups B and D. The body weight growth value of the intervention group B were slightly higher than the group A, without significant difference( P ＞ 0. 05 ), while the group C was significantly higher than the group A ( P ＜ 0. 01 ). Conclusions TNFα is involved in the occurrence of COPD malnutrition and skeletal muscle amyotrophy. IND can reduce the TNFα levels in the serum and the catabolic rates of the skeletal muscle proteins in malnutrition rats with COPD, so as to improve partly the skeletal muscle atrophy.

Objective:To explore the value of changes of plasma amino acids in the diagnosis of neonatal intrahepatic cholestasis caused by Citrin deficiency (NICCD).Methods:A total of 144 infants diagnosed with cholestasis and undergoing blood tandem mass spectrometry in Jiangxi Children′s Hospital From January 2016 to December 2018 were studied.They were divided into 3 groups: NICCD group(11 cases), biliary atresia group (BA group, 40 cases), and Cholestatic Cytomegalovirus hepatitis group (CMV group, 93 cases). The plasma amino acids and biochemical results of the 3 groups were compared, and the data of the 3 groups were statistically analyzed by Kruskal- Wallis test.The items with statistical discrepancy were examined by Mann- Whitney test between groups. Results:Compared with BA group and CMV group, the levels of arginine(Arg), methionine(Met), tyrosine(Tyr), citrulline (Cit), glutamic oxaloacetic transaminase and glutamic-pyruvic transaminase ratio(AST/ALT) in NICCD group increased significantly, while the level of alanine(Ala) decreased.The above discrepancy were statistically significant(all P<0.05). The Arg, Met, Tyr, Cit, AST/ALT, and Ala levels of NICCD group were 68.518(19.714, 108.470) μmol/L, 111.724(42.156, 214.585) μmol/L, 104.394(75.642, 146.086) μmol/L, 165.664(119.874, 291.327) μmol/L, 3.17(1.97, 3.98), and 140.297(112.052, 184.015) μmol/L, respectively.The Arg, Met, Tyr, Cit, AST/ALT, and Ala levels of BA group were 29.470(10.739, 48.124) μmol/L, 32.938(24.918, 44.013) μmol/L, 78.244(66.814, 94.479) μmol/L, 23.698(19.450, 27.714) μmol/L, 1.54(1.23, 1.95), and 244.246(214.554, 295.729) μmol/L, respectively.The Arg, Met, Tyr, Cit, AST/ALT, and Ala levels of CMV group were 16.507(8.220, 28.566) μmol/L, 30.997(23.739, 37.183) μmol/L, 76.120(64.004, 86.290) μmol/L, 21.272(17.040, 24.111) μmol/L, 1.19(0.96, 1.48), and 228.468(191.131, 260.056) μmol/L, respectively.In the receiver operating characteristic (ROC) curve, the area under the ROC curve of Ala, Arg, Met, Tyr, Cit and AST/ALT in diagnosing NICCD were 0.886, 0.770, 0.906, 0.745, 0.999, and 0.887, respectively. Conclusions:The changes of plasma amino acids provides a basis for early diagnosis of NICCD.Elevated Arg, Met, Tyr, Cit and decreased Ala have high diagnostic value of NICCD.Combined with the degree of biochemical changes, plasma amino acids can help with clinical diagnosis of the disease and reduce the misdiagnosis rate.

Objective:To explore the clinicopathological characteristics, immunophenotype, diagnosis and differential diagnosis of renal mucinous tubular and spindle cell carcinoma (MTSCC), and to explore the all-exon mutations, microsatellite stability and tumor mutational burden (TMB) in MTSCC cases.Methods:The data of 5 patients with MTSCC that were submitted to the Department of Pathology, First Affiliated Hospital of Soochow University, China from January 2008 to May 2020, were reviewed and analyzed. The whole exome sequencing (WES) was conducted in all patients, while 3 of them were subject to the analyses of microsatellite stability and TMB.Results:Among the 5 patients, 3 were males and 2 were females. They were 37-76 years old. The maximum diameter of the tumor was 3.5-6.0 cm. The borders of the tumors were well defined. Microscopically, MTSCC was characterized by tubular structure, spindle cell and mucinous stroma, and the nuclear grade of tumor cells was overall low. The average follow-up was 15 months, and no recurrence or metastasis was found. Immunohistochemistry showed that all 5 cases were positive for broad-spectrum cytokeratin (CKpan), cytokeratin (CK)7, CK19, vimentin, PAX8, and P504s (varying expression levels), and the Ki-67 positive index was low. The WES of 5 cases showed that NF2 and PTPN14 exhibited higher mutation rates, which were 3/5 and 2/5, respectively. The microsatellite stability analysis indicated that the 3 cases were all microsatellite stable, and the TMB analysis showed that the TMB of the 3 cases were all <9 mut/Mb.Conclusions:MTSCC is a unique, low-grade pleomorphic kidney tumor. The WES analyses suggest that NF2 and PTPN14 have a higher mutation rate, indicating that the occurrence and development of MTSCC may be closely related to the Hippo pathway. The analysis of microsatellite stability indicates that there is no significant relationship between microsatellite stability and MTSCC, and the TMB analysis suggests that MTSCC patients may not benefit from immunotherapy.

OBJECTIVES: To understand medical students' mental health, professional pride, and intention to work in the front-line during coronavirus disease 2019 (COVID-19) pandemic, and provide a reference for psychological intervention. METHODS: We used the depression-anxiety-stress scale and self-designed questionnaire on professional pride, intention to work in the front-line and the extent of family support. Medical students from 4 medical schools in Fujian and Hunan were investigated. Their mental health status, professional pride and first-line work willingness with different characteristics were compared, and the influential factors for professional pride and first-line work willingness were analyzed. RESULTS: A total of 266 valid questionnaires were collected. During the pandemic, there were significant differences in the proportion of depressed students among different college and universities, majors and stages (<0.05), and the professional pride was significantly different (<0.001). Medical students with different mental health status showed significant differences in professional pride (<0.01). Marriage, pressure and extent of family support were the influential factors for their professional pride (<0.05). The latter two were also influential factors for their intention to work in the front-line (<0.05). CONCLUSIONS During the pandemic, students from college and nursing have relatively better mental health and higher professional pride. The professional pride is low in medical students who married, with abnormal stress or low family support. The intention to work in front-line is decreased in students with abnormal stress or low family support.
Betacoronavirus ; China ; Coronavirus Infections ; psychology ; Family ; Humans ; Intention ; Mental Health ; Pandemics ; Pneumonia, Viral ; psychology ; Professionalism ; Social Support ; Stress, Psychological ; Students, Medical ; psychology ; Surveys and Questionnaires

ObjectiveTo compare the diagnostic accuracy of five different weighting methods of Chinese medicine syndrome and then analyze their diagnostic efficacy and characteristics， by taking Diagnostic Standard for Type 2 Diabetes Mellitus （T2DM） with Dampeness-heat Syndrome （abbreviated as diagnostic standard） as an example. MethodsData from expert questionnaire on the diagnostic standard and a cross-sectional survey of 1021 patients were collected. The comparative diagnostic test accuracy （CDTA） method was used to calculate the area under the ROC curve （AUC）， area under the PR curve （AUPR）， accuracy （ACC）， sensitivity， and specificity of five commonly used weighting methods in two categories， including knowledge-driven weighting methods （expert scoring synthesis method， analytic hierarchy process， and precedence chart method） and data-driven weighting methods （logistic regression contribution method and entropy weighting method）. ResultsAmong 1021 patients with T2DM， 389 cases were diagnosed as dampness-heat syndrome. The expert scoring synthesis method， analytic hierarchy process method， and precedence chart method were basically consistent in the weight scores of each item. The expert scoring comprehensive method， analytic hierarchy process method， and entropy weighting method have a smaller difference in the weight scores of each item， while there was larger difference in the weight scores of each item of the precedence chart method and the logistic regression contribution method. The AUC （95% CI）， AUPR， ACC， sensitivity， and specifi-city of the expert scoring synthesis method were 0.913 （0.893， 0.932）， 0.851， 0.870， 0.868 and 0.875， respectively； while those of the analytic hierarchy process method were 0.910 （0.890， 0.930）， 0.838， 0.879， 0.848 and 0.896； of the precedence chart method were 0.919 （0.900， 0.937）， 0.858， 0.875， 0.871 and 0.875； of the logistic regression contribution method were 0.867 （0.842， 0.891）， 0.792， 0.853， 0.769 and 0.898； and of the entropy weighting method were 0.895 （0.873， 0.916）， 0.820， 0.869， 0.802 and 0.908. ConclusionThe knowledge-driven weighting methods are better than the data-driven weighting methods in terms of diagnostic efficacy and reflecting expert experience.

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R₁₀L₄ was endowed with significant inhibitory activity towards wild-type HIV-1 (EC_50(WT) = 0.007 μmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC₅₀ = 0.017 μmol/L, SI = 13,055), E138K (EC₅₀ = 0.017 μmol/L, SI = 13,123) and Y181C (EC₅₀ = 0.045 μmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R₁₀L₄ was characterized with significantly reduced cytotoxicity (CC₅₀ = 216.51 μmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R₁₀L₄ and HIV-1 RT. Additionally, R₁₀L₄ presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection. Herein, we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.

The main protease (M^pro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent M^pro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent M^pro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent M^pro inhibitors with desirable properties have been developed based on available crystal structures of M^pro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^pro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent M^pro inhibitors are also discussed.