Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

Objective To establish a lipid differentiation model of primary rat bone marrow mesenchymal stem cells(rBMSCs)in vitro using homocysteine(Hcy),and analyze the specific effects of Hcy on lipid and bone differentiation of BMSCs;to comprehensively explore the effects of mangiferin on lipid and bone differentiation of BMSCs,and further reveal the potential mechanism of mangiferin in the treatment of osteoporosis through the inter-vention of Hcy-induced BMSCs by different concentrations of mangiferin.Methods First,rBMSCs were extracted and isolated.The rBMSCs that were well-cultured to a certain generation were placed in culture medium containing different concentrations of Hcy(0.125,0.250,0.5,1,2,4 mmol/L)to establish lipid differentiation model of rBMSCs.Then,different concentrations of mangiferin(37.5,75,150 μmol/L)were applied to the experimental cells for intervention.After culture for a certain period of time,the cells were collected for the following tests:The accumulation of lipids in the cells was detected by semi-quantitative method of oil red 0 dye solution to evaluate the degree of lipid differentiation;The activity of alkaline phosphatase(ALP)was measured by pNPP method;The expression of bone morphogenetic protein-2(BMP-2)and type Ⅰ collagen(Col Ⅰ)were detected by western blot assay to evaluate the degree of bone differentiation.Results Mangiferin could significantly up-regulate the expression of BMP-2 and Col Ⅰ in vitro,increase the level of ALP,and promote bone differentiation of rBMSCs.Hcy promoted lipid differentiation of rBMSCs by increasing lipid accumulation,and down-regulated the expression of BMP-2 and Col Ⅰ,reduced the intracellular ALP level,thereby inhibiting bone differentiation of rBMSCs.How-ever,the above Hcy-related effects could be successfully reversed by mangiferin.Conclusion Mangiferin can sig-nificantly promote bone differentiation of rBMSCs in vitro,while Hcy can inhibit bone differentiation of rBMSCs and promote its lipid differentiation.Mangiferin has the ability to reverse this effect,indicating that mangiferin has certain potential in the treatment of osteoporosis-related diseases.

Purpose/Significance To analyze the current status of residents'health literacy levels in China in the context of new media environment,and to explore the pathways to continuously improve residents'health literacy.Method/Process The monitoring data of residents'health literacy from 2012 to 2022 are collected and an empirical research is carried out based on literature analysis.Result/Conclusion Although the health literacy level of Chinese residents shows a stable upward trend,there are still phenomena such as unbal-anced development and a gap between knowledge and action.In the new media environment,health information dissemination should use big data and artificial intelligence(AI)to implement accurate health information dissemination,optimize health behaviors,establish health information evaluation standards and systems,and strengthen the supervision of new media health information dissemination.

Objective To establish a lipid differentiation model of primary rat bone marrow mesenchymal stem cells(rBMSCs)in vitro using homocysteine(Hcy),and analyze the specific effects of Hcy on lipid and bone differentiation of BMSCs;to comprehensively explore the effects of mangiferin on lipid and bone differentiation of BMSCs,and further reveal the potential mechanism of mangiferin in the treatment of osteoporosis through the inter-vention of Hcy-induced BMSCs by different concentrations of mangiferin.Methods First,rBMSCs were extracted and isolated.The rBMSCs that were well-cultured to a certain generation were placed in culture medium containing different concentrations of Hcy(0.125,0.250,0.5,1,2,4 mmol/L)to establish lipid differentiation model of rBMSCs.Then,different concentrations of mangiferin(37.5,75,150 μmol/L)were applied to the experimental cells for intervention.After culture for a certain period of time,the cells were collected for the following tests:The accumulation of lipids in the cells was detected by semi-quantitative method of oil red 0 dye solution to evaluate the degree of lipid differentiation;The activity of alkaline phosphatase(ALP)was measured by pNPP method;The expression of bone morphogenetic protein-2(BMP-2)and type Ⅰ collagen(Col Ⅰ)were detected by western blot assay to evaluate the degree of bone differentiation.Results Mangiferin could significantly up-regulate the expression of BMP-2 and Col Ⅰ in vitro,increase the level of ALP,and promote bone differentiation of rBMSCs.Hcy promoted lipid differentiation of rBMSCs by increasing lipid accumulation,and down-regulated the expression of BMP-2 and Col Ⅰ,reduced the intracellular ALP level,thereby inhibiting bone differentiation of rBMSCs.How-ever,the above Hcy-related effects could be successfully reversed by mangiferin.Conclusion Mangiferin can sig-nificantly promote bone differentiation of rBMSCs in vitro,while Hcy can inhibit bone differentiation of rBMSCs and promote its lipid differentiation.Mangiferin has the ability to reverse this effect,indicating that mangiferin has certain potential in the treatment of osteoporosis-related diseases.

OBJECTIVE To study the protective effect of phenolic acid components from Salvia deserta Schang on the oxidative stress injury of human renal tubular epithelial cells HK -2 induced by high glucose and high fat . METHODS HK-2 cells were divided into control group ，model group ，canagliflozin group （positive control group ，15 μmol/L），purified product of phenolic acids from S. deserta Schang group （10.8 μg/mL），4 monomers group （salvianic acid ，protocatechuic aldehyde ，caffeic acid，rosmarinic acid ，50 μmol/L）. In addition to the control group ，cell injury model of high glucose and high fat was established in other groups （500 μmol/L palmitic acid+ 30 mmol/L glucose for 48 h）and cultured for 48 h. The cell apoptotic rate ，the contents of malondialdehyde （MDA）and glutathione （GSH），and the activity of superoxide dismutase （SOD）were detected in each group ； the expression levels of nuclear erythroid 2-related factor 2（Nrf2），Kelch-like ECH -associated protein 1（Keap1）protein，heme oxygenase-1（HO-1）and NADH ：quinone acceptor oxidoreductase 1（NQO1）were determined in above 5 groups（except for salvianic acid ，protocatechuic aldehyde ，caffeic acid ）. RESULTS Compared with control group ，the apoptotic rate of HK -2 cells in model group was increased significantly （P＜0.01）；the content of MDA was increased significantly （P＜0.01），while the content of GSH and the activity of SOD were decreased significantly ；protein expressions of Nrf 2，NQO1 and HO -1 2018D01C169） were significantly down -regulated（P＜0.01），while the protein expression of Keap 1 was up -regulated significantly （P＜0.01）. Compared with model group ， the apoptotic rate and the content of MDA were decreased significantly in administration groups（P＜0.01）；the content of GSH in administration groups and the activity of SOD in purified product of phenolic acids group，protocatechuic aldehyde group and rosmarinic acid group were increased significantly （P＜0.01）. The protein expressions of Nrf2，HO-1 and NQO 1 in purified product of phenolic acids group as well as the protein expression of Nrf 2 in rosmarinic acid group were up -regulated significantly （P＜0.01），while the protein expression of Keap 1 was down -regulated significantly in purified product of phenolic acids group and rosmarinic acid group （P＜0.01）. CONCLUSIONS The phenolic acids components from S. deserta Schang can relieve oxidative stress injury of renal tubular epithelial cells induced by high glucose and high fat ，the mechanism of which may be associated with activating Keap 1/Nrf2 signaling pathway and inhibiting oxidative stress response .

OBJECTIVE To in vestigate inhibitory effect s of gallic acid （GA）on human esophageal cancer TE- 1 cells in vitro and its potential mechanism. METHODS The effects of GA on the proliferation of TE- 1 cells were determined by MTT assay after treated with GA for 24 h and 48 h. Cell fluorescence counting （CCK-F）method and inverted fluorescence microscope were used to observe the changes in the number and morphology of TE- 1 cells after treated with GA. The change of cell migration ability was detected by scratch test. The effects of GA on the colony-forming ability of TE- 1 cells were tested by plate colony formation experiment. Cell apoptosis was detected by flow cytometry. Fluorescence probe （DCFH-DA）method was used to observe reactive oxygen species （ROS）production. Western blot assay was used to detect the expression of caspase- 3，caspase-9，Bcl-2，Bcl-2 associated X protein （Bax），cyclin D 1 and cyclin D 3. RESULTS GA significantly reduced the proliferation ability of TE- 1 cells in time and concentration dependent manner. the IC 50 of GA to TE- 1 cells were （281.22±26.81）μmol/L（24 h）and（220.90±31.15） μ mol/L（48 h），respectively. Compared with control group ，the cells in the administration group showed shrinkage ，sparse arrangement and nuclear pyknosis ，and the number of cells decreased significantly. Compared with control group ，the cell migration ability and colony formation ability were decreased significantly in administration groups （P＜0.01 or P＜0.05）. The apoptosis rates of TE- 1 cells were （6.21±0.32）％，（12.59±0.58）％ and（15.41±0.41）％ after treated with 100，300 and 500 μmol/L GA for 24 h，all of which were significantly higher than （5.29±0.28）％ of control group （P＜0.01 or P＜0.05）. Except for GA 100 μmol/L group，the level of ROS in other administration groups were significantly increased （P＜0.01 or P＜0.05）. Compared with control group，the expressions of Bcl- 2（only GA 200 μmol/L group），Bax（except for GA 100 μmol/L），caspase-3 and caspase- 9（except for GA 100 μmol/L）were increased significantly （P＜0.01 or P＜0.05），while the protein expressions of Bcl- 2（except GA 100， 200 μmol/L group），cyclin D 1 and cyclin D 3 were significantly decreased （P＜0.01 or P＜0.05）. CONCLUSIONS GA can inhibit the proliferation of esophageal cancer TE- 1 cells， E-mail：1209364115@qq.com restrict their migration ability and colony-forming ability ，and promote apoptosis. The mechanism may be related to the increase of ROS level ，up-regulation of the expressions of pro-apoptotic proteins caspase- 3，caspase-9 and Bax ，and down-regulation of the expressions of anti-apoptotic protein Bcl- 2，cyclin D1 and cyclin D 3.

Objective:To investigate the characteristics of event-related potentials(ERPs)P300 in the development of attention cognitive function of school-age children.Methods:A total of 180 school-age children were divided into 3 groups according to their ages (7-8 years old group with 48 cases, 9-10 years old group with 44 cases and 11-12 years old group with 48 cases). All of the participants completed an Oddball task, and their behavioral data, P3a and P3b components of ERPs were analyzed by SPSS 21.0.Results:(1)The differences of hit numbers(49(47.25, 50), 50(49, 50), 50(50, 50) ), correct reaction time((533.37±56.94) ms, (486.91±61.12) ms, (411.55±51.97) ms), and Omission errors (2(1, 4), 2(1, 3), 1(0, 2) ) among the three groups were statistically significant( F/χ 2=20.635, 54.477, 13.169, all P<0.01). (2)There was a main effect of age( F=3.884, P=0.023) and an interaction effect between age and condition( F=3.314, P=0.038) on the amplitude of P3a, while the main effect of condition was not significant( F=0.111, P=0.740). The amplitude of P3a component in 11-12 years old group ((11.02±6.00)μV) was significantly larger than that of 7-8 years old group ((7.36±4.48)μV) and 9-10 years old group ((7.76±5.17)μV, both P<0.05). However, there was no significant interaction effect between age and condition on P3a latency, P3b amplitude and latency ( P>0.05). Conclusion:P3a may be a sensitive indicator of cognitive function in school-age children, and the age of 11-12 years old is a sensitive period for the development of children's attention orientation and selection ability, which may be related to the development of brain network.

Objective To explore the changes of attention cognitive function by studying Oddball task behavior and event-related potentials(ERPs) in children with first-episode tic disorder(TD). Methods Oddball task was tested in 30 children with TD and 30 normal children,and their behavioral data and P3a/P3b components of ERPs were analyzed. Results Children with TD had a lower hitting number (49(48, 50)) than control group (50(49,50),P<0. 05). The main effect of group ( F=6. 047,P=0. 015) and the interaction effect between group and condition (F=4. 619,P=0. 034) on the amplitude of P3a were signifi-cant(P<0. 05). The amplitude of P3a component ((5. 91±4. 51)μV ) in TD group were smaller than that in the control group((9. 57±5. 80)μV)(P<0. 05). However,there was no significant interaction effect be-tween group and condition on P3a latency,P3b amplitude and latency (P>0. 05). Conclusion Attentional orienting is impaired in children with TD.

Objective To analyze the influence of ligaments surrounding sacroiliac joints (SIJs) on stability of SIJs by finite element method. Methods The finite element lumbar spine-pelvis-femur model was established. Based on this normal model, all SIJ ligaments in both sides were removed in turn, to establish models without iliolumbar ligaments, sacroiliac anterior ligaments, sacroiliac posterior ligament, sacrotuberous ligaments, sacrospinous ligaments, sacroiliac interosseous ligaments, respectively. The models were used to simulate physiological motions of the spine. The range of motion (ROM) and average stress on the left and right SIJs were analyzed and compared with the normal models. Results Compared with the normal SIJ model, no significant differences in the ROM of bilateral SIJs were found in the models without sacrotuberous ligaments, sacrospinous ligaments and sacroiliac posterior ligaments; for the model without acroiliacinterosseous ligaments, there was no significant difference in the ROM of the left SIJs under spinal right rotation and ROM of the right SIJs under spinal extension, but the ROM of bilateral SIJs increased significantly under the other spinal physiological activities. Under the physiological activities of the spine, the average stress of the SIJ surface in the left and right sides of the model without acroiliacinterosseous ligaments significantly decreased. Conclusions Of all the sacroiliac ligaments, the sacroiliac interosseous ligaments showed the maximum influences on the stability of SIJs. The research findings are helpful to investigate the mechanism of SIJ subluxation and provide certain theoretical basis for clinical treatment of SIJ subluxation.