Structural optimization of lead compounds is a crucial step in drug discovery. One optimization strategy is to modify the molecular structure of a scaffold to improve both its biological activities and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. One of the deep molecular generative model approaches preserves the scaffold while generating drug-like molecules, thereby accelerating the molecular optimization process. Deep molecular diffusion generative models simulate a gradual process that creates novel, chemically feasible molecules from noise. However, the existing models lack direct interatomic constraint features and struggle with capturing long-range dependencies in macromolecules, leading to challenges in modifying the scaffold-based molecular structures, and creates limitations in the stability and diversity of the generated molecules. To address these challenges, we propose a deep molecular diffusion generative model, the three-dimensional (3D) equivariant diffusion-driven molecular generation (3D-EDiffMG) model. The dual strong and weak atomic interaction force-based long-range dependency capturing equivariant encoder (dual-SWLEE) is introduced to encode both the bonding and non-bonding information based on strong and weak atomic interactions. Additionally, a gate multilayer perceptron (gMLP) block with tiny attention is incorporated to explicitly model complex long-sequence feature interactions and long-range dependencies. The experimental results show that 3D-EDiffMG effectively generates unique, novel, stable, and diverse drug-like molecules, highlighting its potential for lead optimization and accelerating drug discovery.

Structural optimization of lead compounds is a crucial step in drug discovery.One optimization strategy is to modify the molecular structure of a scaffold to improve both its biological activities and absorption,distribution,metabolism,excretion,and toxicity(ADMET)properties.One of the deep molecular generative model approaches preserves the scaffold while generating drug-like molecules,thereby accelerating the molecular optimization process.Deep molecular diffusion generative models simulate a gradual process that creates novel,chemically feasible molecules from noise.However,the existing models lack direct interatomic constraint features and struggle with capturing long-range dependencies in macromolecules,leading to challenges in modifying the scaffold-based molecular structures,and creates limitations in the stability and diversity of the generated molecules.To address these challenges,we propose a deep molecular diffusion generative model,the three-dimensional(3D)equivariant diffusion-driven molecular generation(3D-EDiffMG)model.The dual strong and weak atomic interaction force-based long-range dependency capturing equivariant encoder(dual-SWLEE)is introduced to encode both the bonding and non-bonding information based on strong and weak atomic interactions.Addi-tionally,a gate multilayer perceptron(gMLP)block with tiny attention is incorporated to explicitly model complex long-sequence feature interactions and long-range dependencies.The experimental results show that 3D-EDiffMG effectively generates unique,novel,stable,and diverse drug-like molecules,highlighting its potential for lead optimization and accelerating drug discovery.

【Objective】 To study the effects of gestational diabetes (GDM) on morphological structure of brain tissue and microribonucleotide (miRNA) expression profile in neonatal mice, and to provide a new research target for the prevention and treatment of abnormal neurodevelopment in GDM progeny. 【Methods】 The pregnant mice were divided into model group and control group,each group consisted of 10 mice. The model group mice established a GDM model by injecting streptozotocin to measure fasting blood glucose (FPG) and random blood glucose (GLU) at different times. Successful molded mice were randomly divided into model group A and model group C, and control mice were divided into control group B and control group D, with 5 mice in each group. The newborn mice in groups A and B were used for hippocampal tissue GeneChip detection and brain morphology structure observation, and group C and D newborn mice were used for qRT-PCR detection of hippocampus tissue expression differences to verify the differentially expressed genes of miRANs obtained by GeneChip screening. After giving birth, the neonatal mice were sacrificed by decapitation, and the brain tissue was dissected to observe the overall morphological structure. The structural changes of hippocampus were observed under HE chromogenic microscope. The Agilent mouse miRNA oligonucleotide gene chip was used to detect the miRNA expression profile of mouse hippocampus, screen differential miRNAs and predict their target genes, and conduct GO analysis and signal transduction pathway analysis of target genes. The relative expression levels of the screened miRNAs were verified by qRT-PCR. 【Results】 Compared with the control group, the GLU increased significantly from the 3rd day after drug administration in the model group (P<0.01). Macroscopic observation of control group B mice had normal brain morphology and structure, smooth appearance, clear gyrus, close arrangement of hippocampus cell structure, uniform staining and complete structure; in model group A, the number of hippocampus cells decreased, loose arrangement and deep staining. In the initial screen of miRNA microarray, there were 11 differentially expressed miRNAs between control and model groups, all of which were downregulated miRNAs, including let-7b-5p、miR-130b-3p、miR-181c-5p、miR-181d-5p、miR-3099-3p、miR-3470a、miR-3473a、miR-3473b、miR-500-3p、miR-532-5p、miR-7047-5p(P<0.05). Two miRNAs (miR-3473b, miR-7047-75p) and 5 target genes (MAPK3, MAPK11, MAPK14, CALM3, AKT3). The relative expression of miR-3473b and miR-7047-5p in model group C were lower than that in control group D (t=19.13 and 6.24, P<0.05), and the validation results were consistent with the microarray test results. 【Conclusion】 Compared with the offspring of normal pregnant mice, GDM offspring mice have abnormal development of brain structure and damage of hippocampal nerve cells, and there are a large number of abnormal expression of miRNAs in hippocampal tissue. Differentially expressed miRNAs can be used as research targets for prevention and treatment of GDM offspring neurodevelopmental abnormalities.

Objective:To compare the differences in lung function between sanitation workers and the general population undergoing routine physical examinations, and to analyze the risk factors for restricted airflow and severity of the condition in sanitation workers.Methods:This study is a large cross-sectional study called "Shanxin Respiratory Health Screening for Ten Thousand People". A total of 1 036 sanitation workers (sanitation group) and 6 701 individuals from the general population undergoing routine physical examinations (control group) were selected as the original study subjects from June 2021 to April 2022 (before matching). Both groups underwent pre-bronchodilator lung function tests, and the differences in lung function characteristics between the two groups were compared. The sanitation group also completed a questionnaire survey. Multivariate and ordinal multinomial logistic regression analysis were used to analyze the risk factors for airflow limitation and its severity.Results:A total of 1 027 individuals from the sanitation group and 999 individuals from the control group were included in the study. There were no significant differences in age, gender, height, weight, and body mass index (BMI) between the two groups (all P>0.05). The rate of airflow restriction was significantly higher in the sanitation group compared to the control group (22.88% vs 8.81%, P<0.001). In the sanitation group, there was no statistically significant difference in a self-assessment test for chronic obstructive pulmonary disease (CAT) scores between individuals with airflow restriction (235 cases) and those without airflow restriction (792 cases) [(1.50±2.50) vs (1.15±2.03) points, P=0.084]. There were no statistically significant differences in forced vital capacity (FVC) as a percentage of predicted value (FVC%pred) between the two groups. However, the sanitation group had significantly lower %pred for forced expiratory volume in one second (FEV 1%pred), FVC/FEV 1 ratio (FEV 1/FVC%pred), forced expiratory flow at 50% of FVC (FEF 50%%pred), forced expiratory flow at 75% of FVC (FEF 75%%pred), and maximal mid-expiratory flow (MMEF%pred) compared to the control group (all P<0.05). The rates of abnormal FEF 50%%pred, FEF 75%%pred, and MMEF%pred were significantly higher in the sanitation group compared to the control group (17.62% vs 10.31%, 17.04% vs 10.01%, 27.26% vs 18.41%, all P<0.001). Small airway parameters and the rate of airflow restriction were significantly higher in past and current smokers of the sanitation group compared to never smokers (all P<0.05). Multifactorial analysis showed that high BMI ( OR=0.929, 95% CI: 0.885-0.974) was a protective factor for airflow restriction, while high smoking index was a risk factor ( OR=1.020, 95% CI: 1.011-1.030). Ordered multinomial logistic regression analysis showed that high BMI ( OR=0.925, 95% CI: 0.882-0.971) was a protective factor for the severity of airflow restriction, while high smoking index ( OR=1.020, 95% CI: 1.011-1.029) was a risk factor for the severity of airflow restriction. Conclusions:The incidences of airflow limitation and small airway abnormalities in sanitation workers are higher than that in general physical examination population. High smoking index and low BMI are independent risk factors for airflow limitation and its severity.

OBJECTIVE： To systematically evaluate the efficacy and safety of TCM compound preparation for tonifying kidney and activating blood circulation， and to provide evidence-based reference for rational drug use in the clinic. METHODS： By retrieving Cochrane library， PubMed， Embase， CBM， CNKI， VIP and Wanfang database， randomized controlled trials （RCTs） about TCM compound preparation for tonifying kidney and activating blood circulation （trial group） versus calcium or non-calcium agents （control group） in the treatment of postmenopausal osteoporosis were included. After literature screening， data extraction and quality evaluation with bias risk evaluation tool and Jadad scale of Cochrane system evaluator manual 5.1.0， Meta-analysis was conducted by using Stata 12.0 software， and trial sequential analysis （TSA） was conducted by using TSA 0.9 software. RESULTS： Totally 18 RCTs were included， involving 1 408 patients. The results of Meta-analysis showed that total response rate [RR＝1.35，95％CI（1.17，1.54），P＜0.000 1] and bone density[SMD＝0.24，95％CI（0.16，0.32），P＜0.000 1] of trial group were significantly higher than those of control group； blood calcium [SMD＝－0.05，95％CI（－0.09，0.00）， P＝0.033] of trial group was significantly lower than that of control group. There was no statistical significance in the levels of urine creatinine [SMD＝－1.60，95％CI（－5.94，2.74），P＝0.470]， urinary calcium/urine creatinine ratio [SMD＝－0.05，95％CI（－0.14，0.04），P＝0.295]， urinary hydroxyproline/urine creatinine ratio [SMD＝－0.16，95％CI（－1.04，0.72），P＝0.726]， ALT [SMD＝0.51，95％CI（－3.26，4.28），P＝0.790]， AST [SMD＝0.23，95％CI（－5.22，4.77），P＝0.929]， serum alkaline phosphatase [SMD＝－0.22，95％CI（－0.68，0.25），P＝0.361]， serum phosphate [SMD＝－0.02，95％CI（－0.11，0.07），P＝0.639]， urea nitrogen [SMD＝－0.19，95％CI（－0.70，0.31），P＝0.453]， estradiol [SMD＝0.62，95％CI（－0.28，1.52），P＝0.177]， IL-6 [SMD＝－1.78，95％CI（－4.86，1.30），P＝0.258] or VAS [SMD＝0.55，95％CI（－1.03，2.13），P＝0.496] between 2 groups. No server ADR was found in 2 groups. TSA showed that there were extract evidences for total response rate of TCM compound preparation in the treatment postmenopausal osteoporosis. CONCLUSIONS： TCM compound preparation for tonifying kidney and activating blood circulation shows significant therapeutic efficacy for postmenopausal osteoporosis， and can improve serum calcium and bone density with good safety.

OBJECTIVE:To observe the efficacy and safety of Guizhi fuling capsule combined with mifepristone in treatment of uterine fibroids. METHODS:116 patients with uterine fibroids were randomly divided into control group and observation group. Control group was orally given Mifepristone tablet 25 mg,2 h before meal in the first day of menstrual period,once a day,for con-tinuous 10 d;observation group was additionally given Guizhi fuling capsule 3 pills in non-menstrual period,3 times a day. 3 months was regarded as a treatment course,it lasted 2 courses. Clinical efficacy,and E2,FSH,SHBG,uterine volume,menstrual blood volume,uterine fibroid volume and incidence of adverse reactions in 2 groups before and after treatment were observed. RE-SULTS:Total effective rate in observation group was significantly higher than control group,the difference was statistically signifi-cant(P<0.05). After treatment,the FSH,E2,uterine volume,menstrual blood volume and uterine fibroid volume in 2 groups were significantly lower than before,and observation group was lower than control group,the differences were statistically signifi-cant(P<0.05);but there were no significant difference in the SHBG and adverse reactions between 2 groups(P>0.05). CONCLU-SIONS:The clinical efficacy of Guizhi fuling capsule combined with mifepristone in treatment of uterine fibroids is more signifi-cant than mifepristone alone,with good safety.

This article was aimed to study the correlation among traditional Chinese medicine (TCM) syndrome elements in the first year after ischemic stroke. Data of TCM four examinations were collected among subjects all over China by cross-sectional study, using the same observing rating scale. The results showed that internal-heat, internal-wind and phlegm-damp syndrome were risk factors with obvious positive correlation. On the contrary, blood-stasis, internal-heat and qi-deficiency syndrome were in obvious negative correlation. But syndrome of yin-deficiency had no significant correlation with other syndrome elements. It was concluded that there were remarkable positive correlations on excess syndromes, such as wind, fire and phlegm. The syndromes of excess in the branch are easily to be combined.

This article was aimed to study the correlation of traditional Chinese medicine (TCM) syndromes with re-gion factor in the first year after first ischemic stroke. Cross-sectional study was applied in the data collection of TCM four examinations among subjects in China using the same observing rating scale. The results showed that sub-jects of North China were mainly presented with the syndromes of qi-deficiency, internal-heat and phlegm-damp;subjects of Middle China were mainly presented with the syndrome of q i-deficiency; and subjects of East and South China were mainly presented with the syndrome of qi-deficiency and blood-stasis. The proportion of internal-heat was obviously higher in North China than in South China; that of phlegm-damp was remarkably higher in North Chi-na than in Middle and East China; and that of blood-stasis was significantly lower in Middle China than in East and South China. It was concluded that the distribution of internal-heat and blood-stasis was significantly affected by factor of region. Patients in North and South China differed greatly in TCM syndrome. Internal-heat is the main syn-drome in North China, while blood-stasis in South China.

AIM:To study the effect of Hand2 (one of basic helix-loop-helix proteins’ transcription factors) expression on the development of the cardiac tissues in the fetal rats from gestational diabetes mellitus ( GDM) parents, and to investigate the potential pathogenesis of GDM-induced congenital cardiac defects in rats.METHODS: The adult Spra-gue-Dawley female rats were randomly divided into blank control group (n=24), GDM group (n=30), negative control group ( n=30) and insulin intervened group ( n=30) .The GDM model was established by intraperitoneal injection of 2%streptozotocin (STZ, 40 mg/kg body weight) to the pregnant rats on the successive day.The rats in insulin intervened group were injected with intermediate-acting insulin in order to keep the fasting blood glucose in the normal range.The rats in negative control group were injected with citric acid-sodium citrate buffer solution in the same position.Blood glucose and body weight were examined every day 72 h after STZ injection.On E12, E15 and E19, the rats were anesthetized and the embryonic cardiac tissues were collected after caesarean section.The histopathological changes of the cardiac tissues were observed under microscope with HE staining.The expression of Hand2 was analyzed by the method of immunohisto-chemistry.The expression of Hand2 in the cardiac tissues at mRNA and protein levels was determined by real-time fluores-cence quantitative PCR and Western blotting.RESULTS:During the development of embryonic heart, the protein expres-sion of Hand2 in the cardiac tissues was showed dynamic changes.Observed on E12, obviously increased on E15, and at the highest level on E19.Compared with the other 3 groups, the protein and mRNA expression of Hand2 in GDM group was decreased at the time points of E12 and E15.CONCLUSION:The morbidity of fetal cardiac malformation is significantly increased in GDM group, suggesting that Hand2 may be involved in the development of cardiac malformation in GDM.

OBJECTIVEA novel bHLH-like gene, designated SmbHLH1, was isolated from Salvia miltiorrhiza, in order to identify a bHLH gene in related to danshinone biosysnthesis.

METHODSmbHLH1 was isolated by RT-PCR,and Semi-quantitative RT-PCR was used to detect the gene expression level.

RESULTThe full length of SmbHLH1 cDNA has an open reading frame of 999 bp. The deduced amino acid sequence of SmbHLH1 has 332 amino acid residues which forms a 36 kDa polypeptide with a calculated pI of 5.4. SmbHLH1 gene was expressed at high level in root, but low level in stem, leaf and flower of S. miltiorrhiza. The transcripts of SmbHLH1 was suppressed when the plants were treated with exogenous MeJA, Yeast + Ag+. The transcripts of SmbHLH1 constitutively accumulated in response to exogenous ABA and low concentration of salicylic acid.

CONCLUSIONSmbHLH is a new member of the S. miltiorrhiza bHLH family, and its possible roles in brassinosteriods signaling responses.