Effective annotation of in vivo drug metabolites using liquid chromatography-mass spectrometry (LC-MS) remains a formidable challenge. Herein, a metabolic reaction-based molecular networking (MRMN) strategy is introduced, which enables the "one-pot" discovery of prototype drugs and their metabolites. MRMN constructs networks by matching metabolic reactions and evaluating MS² spectral similarity, incorporating innovations and improvements in feature degradation of MS² spectra, exclusion of endogenous interference, and recognition of redundant nodes. A minimum 75% correlation between structural similarity and MS² similarity of neighboring metabolites was ensured, mitigating false negatives due to spectral feature degradation. At least 79% of nodes, 49% of edges, and 97% of subnetworks were reduced by an exclusion strategy of endogenous ions compared to the Global Natural Products Social Molecular Networking (GNPS) platform. Furthermore, an approach of redundant ions identification was refined, achieving a 10%-40% recognition rate across different samples. The effectiveness of MRMN was validated through a single compound, plant extract, and mixtures of multiple plant extracts. Notably, MRMN is freely accessible online at https://yaolab.network, broadening its applications.

Objective To explore the efficacy and safety of remimazolam combined with propofol for gastroscopy in school-age children.Methods A total of 106 children who underwent painless gastroscopy from january to february 2024 were selected,56 males and 50 females,aged 7-12 years,ASA physical status Ⅰ or Ⅱ.Children were randomly divided into two groups:propofol group(group P)and remimazolam combined with propofol group(group RP),53 children in each group.After intravenous injec-tion of alfentanil 8 μg/kg,group P was intravenously injected with propofol 2.5 mg/kg,and group RP was intravenously injected with remimazolam 0.183 mg/kg and propofol 1 mg/kg in turn.Gastroscopy was per-formed when the eyelash reflex disappeared and the modified observer's assessment alertness/sedation scale(MOAA/S)score≤1.The onset time of anesthesia,examination time,and recovery time were recorded.The number of add propofol and successful sedation cases were recorded.Adverse reactions such as respira-tory depression,hypotension,bradycardia,injection pain,hiccups,nausea and vomiting were recorded.Results Compared with group P,the onset time of anesthesia in group RP was significantly prolonged,and the recovery time was significantly shortened(P＜0.05).Compared with group P,the incidence of add propofol,hypotension,respiratory depression and injection pain in group RP were significantly decreased(P＜0.05).Conclusion Remazolam combined with propofol for gastroscopy in children can not only en-sure the sedative effect,but also reduce the incidence of adverse reactions,stabilize hemodynamic changes and shorten the recovery time.

Objective:To determine the median effective dose (ED 50) and 95% effective dose (ED 95) of remimazolam for gastroscopy when combined with propofol in pediatric patients of different ages. Methods:This was a prospective study. American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ pediatric patients, aged 3-12 yr, who underwent painless gastroscopy in Hainan Women and Children′s Medical Center from January to February 2024, were divided into the following groups: preschool group (3-6 yr) and school-age group (7-12 yr). Penehyclidine 0.01 mg/kg, afentanil 8 μg/kg and corresponding doses of remimazolam and propofol 1 mg/kg were intravenously injected, and gastroscopy was performed when the Modified Observer′s Assessment of Alertness/Sedation Scale score)≤1. Up-and-down sequential allocation was used. A positive response was defined as bucking, nausea, vomiting, body movement, and frowning occurred when the gastroscope entered the pharynx. The initial dose of remimazolam was 0.2 mg/kg, and the dose of remimazolam was increased/decreased by 0.02 mg/kg each time in the next patient. Probit regression method was applied to calculate the ED 50, ED 95 and 95% confidence interval ( CI) of remimazolam inhibiting responses to gastroscope placement when combined with propofol. The anesthesia-related adverse events were recorded. Results:A total of 27 pediatric patients completed the trial in preschool group and 26 cases in school-age group. The ED 50 of remimazolam was 0.266 mg/kg (95% CI 0.249-0.285 mg/kg) and the ED 95 was 0.302 mg/kg (95% CI 0.283-0.409 mg/kg) in preschool group. The ED 50 of remimazolam was 0.16 mg/kg (95% CI 0.147-0.170 mg/kg) and ED 95 was 0.183 mg/kg (95% CI 0.172-0.234 mg/kg) in school-age group. The ED 50 and ED 95 were significantly decreased in school-age group as compared with preschool group ( P<0.05). During anesthesia, 3 patients suffered hypotension (11%) in preschool group, and 3 patients suffered hypotension (12%), 2 patients suffered respiratory depression (8%), 2 patients suffered hiccup (8%), 1 patient suffered injection pain (4%) and 1 patient suffered muscle rigidity (4%) in school-age group. There was no significant difference in the incidence of adverse reactions between the two groups ( P>0.05). Conclusions:When combined with propofol, the ED 50 of remimazolam for gastroscopy in preschool and school-age pediatric patients is 0.266 mg/kg and 0.160 mg/kg, respectively, and the ED 95 is 0.302 mg/kg and 0.183 mg/kg, respectively, indicating a stronger anesthetic potency in school-age children. The probability of adverse reactions is low when the two are combined.

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 explore the effects of magnanimous therapy on the magnanimous and enterprising traits of lung cancer patients and the analysis of related factors.Methods:Totally 197 patients with lung cancer were divided into individual group ( n=62), team group ( n=75) and control group ( n=60). Comparison and correlation analysis were applied to the data before and after the electroencephalogram and the magnanimous questionnaire, the cancer response questionnaire, the T-type psychological scale, the cancer heart state questionnaire and the cancer patient's life function index scale. t test, analysis of variance and Pearson correlation analysis were processed by SPSS 23.0. Results:After treatment, the " enterprising" dimension and " magnanimous" dimension of individual group and the " enterprising" dimension of the team group ((3.035±0.309), (3.041±0.265), (3.173±0.371)) were higher than that before treatment((2.934±0.326), (2.908±0.315), (3.130±0.387), all P<0.05). There was negative correlation between " magnanimous" dimension of the magnanimous questionnaire and " subconscious" dimension of the T-type psychological scale in individual group( r=-0.280, P<0.05). In team group, the " enterprising" dimension of the magnanimous questionnaire was negatively correlated with " Psychological" and " Yield" dimension of the cancer heart state questionnaire( r=-0.279, -0.285, P<0.05), and positively correlated with " Facing" of the cancer response questionnaire, " Good physical condition and ability" and " Psychological well-being" dimension of the cancer patient's life function index scale( r=0.367, 0.402, 0.379, P<0.05). There was a negative correlation between the " enterprising" dimension of the magnanimous questionnaire and the beta wave value in individual group. Conclusion:The magnanimous therapy can improve enterprising and magnanimous level of patients with lung cancer, and the effects are related with the above-mentioned psychosomatic factors.