ObjectiveA qualitative analysis method was established for the composition of Astragali Radix（AR） before and after rice stir-frying. On the basis of systematic characterization of the chemical compositions in AR and stir-fried AR with rice（ARR）， the structures of their major compounds were deduced and identified， and the differential compositions between them were analyzed. MethodsUltra performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS/MS） was used to detect the samples of AR and ARR in positive and negative ion modes， respectively. The compounds were analyzed and identified through self-constructed databases， literature， and reference standards， etc. And the data were analyzed by chemometrics， in order to screen for the differential components between AR and ARR. ResultsA total of 123 compounds were identified in AR and ARR， including 41 flavonoids， 19 terpenoids， 26 organic acids， 8 amino acids， 5 nucleotides， 5 carbohydrates and 19 other compounds. Among them， there were 95 common components in both， 18 unique components in AR， and 10 unique components in ARR. Principal component analysis（PCA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） results both showed that there were significant differences in the chemical constituents of AR before and after rice stir-frying， and a total of 26 constituents with differences in the content were screened out， including L-canavanine， L-pyroglutamic acid， L-phenylalanine， cis-caffeic acid， and malonylastragaloside Ⅰ. Among them， 19 constituents of ARR were down-regulated and 7 constituents were up-regulated by comparing with AR. ConclusionThis study clarifies that the chemical composition of AR and ARR is mainly composed of flavonoids， terpenoids， and organic acids， and analyzes the components with significant differences in content between the two in combination with chemometrics， and the differential components are dominated by amino acids， organic acids and terpenoids， which can provide reference for the subsequent quality control and material basis research.

Objective:To establish a mice model that is more in line with the human immunocompromised state,and to inves-tigate the regulatory effect of Rosa laevigata Michx.,probiotics and their combination on their immune function.Methods:Immunosup-pressive model of mice was established by using cyclophosphamide with different dosage,time and end point,and compared with im-munosuppressive model induced by hydrocortisone and cyclosporine A,immunosuppressive model of mice was established by injecting 25 mg/kg cyclophosphamide 7 times every other day,without recovery period;changes in the proportion of lymphocytes in spleen(CD4+T cells,CD8+T cells,CD19+B cells)were analyzed by flow cytometry;qRT-PCR was used to detect expression levels of inflam-matory factors(IL-1β and IL-6)mRNA in spleen.Results:After continuous injection of 80 mg/kg cyclophosphamide for 3 days,the thymus was atrophied,the spleen was significantly swelling,proportion of immune cells CD4+T cells,CD8+T cells and CD19+B cells in spleen were significantly decreased,while mRNA expressions of IL-1β and IL-6 were up-regulated.After 7 injections of 25 mg/kg cyclophosphamide every other day,the thymus and the spleen were significantly atrophied,proportion of CD4+T cells and CD8+T cells in spleen showed an increasing trend,and mRNA expressions of IL-1β and IL-6 were up-regulated;after 1 week or 2 weeks recovery period from cyclophosphamide injection,weight and index of immune organs,proportion of spleen lymphocytes and mRNA expres-sions of inflammatory cytokines in spleen were significantly reversed;Rosa laevigata Michx.combined with probiotics could signifi-cantly reverse the up-regulation of CD4+T cells and inflammatory factor IL-1β caused by cyclophosphamide.Conclusion:In this study,an immunocompromised mice model has been established with 7 injections of 25 mg/kg cyclophosphamide every other day and without recovery period.And a certain positive immunomodulatory effect of the combination of Rosa laevigata Michx.and probiotics has been found.

Objective:To explore the association between childhood growing environment and depressive symptoms in young old persons aged 60 to 74 years.Methods:The data of the fourth wave of China Health and Re-tirement Longitudinal Study in 2018 and the life course survey in 2014 were used to secondary analysis.A total of 7 642 young old persons aged 60 to 74 years were included,and the 10-item of the Center for Epidemiological Stud-ies Depression(CES-D-10)scale was used to evaluate the depressive symptoms.The generalized linear mixed effects model was used to explore the relationship between childhood growing environment and depressive symp-toms in the young old persons.Results:The detection rate of depressive symptoms occurrence in the young old per-sons was 37.2％.The risk factors of depressive symptoms included female(OR=1.89),rural(OR=1.35),hav-ing hunger experience(OR=1.22),poor relationship with male dependents(OR=1.72),female caregiver's expe-riences of being bedridden due to illness(OR=1.38),community insecurity(OR=1.59),more harmonious neigh-borhood relationship(OR=1.20)and less harmonious neighborhood relationship(OR=1.81).The protective fac-tors of depressive symptoms occurrence included moderate(OR=0.79)and high(OR=0.50)per capita house-hold income,and educated father(OR=0.84)(P＜0.05).Conclusion:Childhood growing environment is an influ-ential factor of depressive symptoms in the young old persons.The long-term health effects of childhood environ-ment should be paid attention to.

Objective:This article analyzed the current situation, similarities and differences and main problems of the registration and management systems of innovative medical devices in China and the United States.Methods:This article summarized the requirements and policies for the registration management of innovative medical devices in China and the United States, as well as the development and differences of the registration of innovative medical devices in China and the United States, and the main problems in the registration management of innovative medical devices in China.Results:At present, the development level of medical device industry in China and the United States was different, facing different development problems, and there were differences in the access standards and management methods of innovative medical devices. The registration management system established for innovative medical devices in China was gradually improving, and to a certain extent, it had promoted the enthusiasm of innovative product research and development and registration applications, but there were also problems such as unclear innovation evaluation scales, insufficient early intervention of review resources, and insufficient utilization of post-marketing data.Conclusions:Drawing on the beneficial experience of breakthrough device registration management in the United States, we will improve the registration management system for innovative products and shorten the review and approval cycle by clarifying the identification criteria for innovative medical devices, promoting the placement of review resources in the R&D stage, and further strengthening the use of post-marketing data and regulatory scientific research.

Objective Based on the framework of"quantitative analysis of supporting policies",this study focuses on the formulation and implementation of supporting policies for pharmaceutical science and technology innovative enterprises in China,so as to provide a certain reference for the implementation and improvement of policies for pharmaceutical science and technology innovative enterprises in China.Methods This study used Roy Rothwell and Walter Zegveld's innovative policy tools as the basis for analysis,and combined with the dimension of policy type,the policy was quantitatively analyzed.Results A total of 47 effective policy documents were selected,including 22 issued by the state and 25 issued by Beijing municipal government.A total of 104 policy instruments were included through the dismantling of policy provisions.Specifically,environment-based policy tools accounted for the highest proportion(60.58%),while demand-based and supply-based policy tools were relatively few.From the perspective of policy types,there were more planning policy documents(25 articles),while there were relatively few specific implementation policies(22 articles).Conclusion It is necessary to focus on optimizing the formulation stage of support policies and improving the use of supply-oriented and demand-oriented policy tools to better meet the needs of pharmaceutical science and technology innovative enterprises.

Objective To observe the clinical effect of traditional Chinese medicine bone-setting technique using spinal,pelvi-lower extremity line to treat patients with knee osteoarthritis(KOA).Methods 426 patients with KOA were all from the First Affiliated Hospital of Hebei University of Traditional Chinese Medicine.They were randomly divided into experimental group(384 cases,57 cases of elimination,shedding and termination)by computer generated sequence.Traditional Chinese bone setting techniques were applied with spinal-pelvic-lower limb force line(divided into three parts:lumbar fixed point reduction method,hip joint push-pull and extension method and knee peripheral tendon recovery method every 3 days.2 weeks)treatment;The control group was the waiting treatment group(48 cases,6 cases were eliminated,abscission,termination),which was only used for clinical observation for 2 weeks.The main outcome index was WOMAC pain score.Secondary outcome measures were WOMAC stiffness score,functional score,standardized score and quality of life score(SF-12).The test time points were baseline,2 weeks after enrollment,and follow-up(14 weeks after enrollment).The control group was at baseline and 2 weeks after enrollment.Results Compared with baseline,WOMAC pain score,stiffness score,functional score and standardized score were all decreased in 2 groups 2 weeks after enrollment(P<0.05),but the experimental group was significantly decreased compared with the control group(P<0.001).SF-12 quality of life scores were all higher than before(P<0.001),but the experimental group was significantly higher than the control group(P<0.001).At follow-up,compared with 2 weeks after enrollment,WOMAC pain scores were increased(P<0.001),WOMAC stiffness,joint function and standardized scores were decreased(P<0.001),and SF-12 scores were increased(P<0.001).Conclusion The use of spinal-pelvi-lower extremity line of traditional Chinese medicine bone-setting technique in the treatment of KOA is effective in improving the knee joint function and improving the quality of life of patients,but the short-term effect of pain relief is good,and the long-term effect is not good.Its safety is good,and it can be considered in clinical application for KOA patients with joint dysfunction as the main manifestation.

Aim To study the causal relationship between coffee consumption and atherosclerosis risk.Methods Based on the public genome database IEU Open GW AS project website,relevant data were obtained,and in-strumental variables closely related to exposure and outcome were screened.Mendelian randomization analysis was per-formed using the inverse variance weighted method,weighted median method,and MR Egger method to assess the causal relationship between coffee consumption and arteriosclerosis(including coronary atherosclerosis,peripheral atherosclerosis,cerebral atherosclerosis,and other atherosclerosis).In addition,the Egger intercept method was used to detect the level of pleiotropy,the Cochran Q test was used to assess the heterogeneity,and the leave one out method was used to perform sensitivity analysis,so as to ensure the robustness of the results.Results The study showed that the F-values of the instrumental variables included in the study were all greater than 10,and there was no weak instrumental variables bias.Coffee consumption was positively correlated with the risk of coronary atherosclerosis(OR=1.535 5,95％CI=1.108 4～2.127 2,P=0.009 9),peripheral atherosclerosis(OR=2.098 6,95％CI=1.182 2～3.725 7,P=0.011 4),and other atherosclerosis(OR=1.864 7,95％CI=1.052 9～3.302 4,P=0.032 6),but not with the risk of cerebral atherosclerosis.Heterogeneity test Q_pval＞0.05,level pleiotropy test interval P＞0.05.Conclusions The single nucleotide polymor-phisms selected in the study are all strong instrumental variables,and there is no heterogeneity or horizontal pleiotropy,in-dicating reliable results.The research shows that coffee consumption increases the risk of coronary atherosclerosis,pe-ripheral atherosclerosis and other atherosclerosis,and has no significant correlation with the risk of cerebral atherosclerosis.The health management of atherosclerosis patients should reduce coffee consumption.

Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1,423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

OBJECTIVE To explore the mechanism of Kuaisong yin in the prevention and treatment of constipation. METHODS Slow transit constipation （STC） model was established with Compound difenoxylate tablet in mice and rats. Two batches of mice were divided into blank group， model group， positive control group （Maren soft capsule， 0.64 g/kg）， Kuaisong yin low-dose， medium-dose and high-dose groups （3.2， 6.4， 12.8 g/kg）， with 10 mice in each group. The effect of Kuaisong yin on constipation in mice was evaluated by intestinal propulsion experiment and defecation experiment. Rats were divided into blank group， model group， positive control group （Maren soft capsule，0.36 g/kg）， Kuaisong yin low-dose and high-dose groups （2.4， 4.8 g/kg）， with 7 or 8 rats in each group. They were given relevant medicine once a day for 1 week. The metabonomics of serum and urine of rats were analyzed by UPLC-Q-TOF-MS/MS technology. RESULTS Compared with model group， the ink propulsion rate and 5 h defecation volume of mice in Kuaisong yin high-dose group were significantly increased （P＜0.05）； the first defecation time of mice in Kuaisong yin medium-dose and high-dose groups was significantly shortened， and the quality of defecation was significantly reduced within 5 h （P＜0.05 or P＜0.01）. Serum metabonomics screened 16 compounds （such as proline， propionylcarnitine， hemolytic phosphatidylcholine， etc.） and 6 metabolic pathways （such as sphingomyelin metabolism， arginine and proline metabolism， sphingolipid biosynthesis-lactose and neolactone series）. Urine metabonomics screened 20 different metabolites （such as prostaglandin A2， L-valine， phosphatidylcholine， sphingomyelin， etc.） and 8 metabolic pathways （such as valine， leucine and isoleucine biosynthesis， sphingomyelin metabolism， pyruvate metabolism， etc.）. CONCLUSIONS Kuaisong yin can play a role in improving constipation by regulating different metabolites such as hemolytic phosphatidylcholine， phosphatidylcholine， prostaglandin A2， L-valine， proline， and regulating metabolic pathways such as multiple amino acid metabolism， sphingomyelin metabolism， etc.

OBJECTIVE To study the mechanism of Compound zaoren granule in improving insomnia. METHODS Forty-nine mice were divided into blank group， model group， positive control group 1 （Estazolam tablets 0.5 mg/kg），control group 2 （Shumian capsule 0.6 g/kg）， Compound zaoren granule low-dose， medium-dose and high-dose groups （2.5， 5， 10 g/kg）， with 7 mice in each group. The insomnia model was established by chronic unpredictable mild stress combined with 4-chloro-DL- phenylacetic acid. The behavioral changes of mice were investigated through open field test and pentobarbital sodium synergistic hypnosis experiment， as well as the pathomorphology of mice hypothalamus tissue was observed by HE staining. The metabonomics analysis and multivariate statistical analysis of serum in mice were performed by UHPLC-Q-TOF-MS/MS， and the differential metabolites were screened out； the metabolic pathway analysis was conducted based on MetaboAnalyst 5.0 database. RESULTS Compared with blank group， the total travelling distance， the number of entering the central region and the moving distance in the central region of the model group were significantly reduced （P＜0.05）， the proportion of total rest time was significantly increased （P＜0.05）， the sleep duration of mice was significantly shortened （P＜0.05）， and hypothalamic nerve cells damaged and severely vacuolated. Compared with model group， the total travelling distance of Compound zaoren granule low-dose and medium-dose groups were increased significantly and the proportions of total rest time of those groups were decreased significantly （P＜0.05）， and the sleep duration of mice in Compound zaoren granule high-dose group was prolonged significantly （P＜0.05）； the hypothalamic nerve cells of mice in each administration group recovered to varying degrees， and the hypothalamus histiocytes of mice in the Compound zaoren granules high-dose group were closer to those in the blank group. A total of 18 differential metabolites （such as phenylalanine， taurine， norvaline， methionine） and 4 important amino acid metabolic pathways （L-phenylalanine， tyrosine and tryptophan biosynthesis； taurine and hypotaurine metabolism； L-phenylalanine metabolism； cysteine and methionine metabolism） were identified through metabolomics analysis. CONCLUSIONS Compound zaoren granules can normalize the disordered metabolism in vivo by regulating differential metabolites such as phenylalanine， taurine， and four amino acid metabolic pathways， so as to improve insomnia.