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 evaluate the effect of sleep deprivation on the expression of sirtuin 6 (SIRT6) in the cerebellum of immature mice.Methods:Fifty SPF healthy male C57BL/6 mice, aged 4 weeks, weighing 14-16 g, were divided into 2 groups ( n=25 each) using a random number table method: control group (Con group) and sleep deprivation group (SD group). The chronic sleep deprivation model was prepared by using the multi-platform water environment method, with 20 h of sleep deprivation per day for 10 consecutive days. After sleep deprivation, a balance beam experiment was performed to test the balance and coordination ability of mice. The mice were sacrificed after anesthesia and cerebellar lobular IV-VI (4-6 cb) tissues were taken for microscopic examination of the ultrastructure (with a transmission electron microscope) and for determination of the dendritic spine density of cerebellar 4-6cb Purkinje neurons (by Golgi staining), co-expression of SIRT6 and Calbindin D-28k (CbD-28k) and expression of glucose transporter Glut3 of cerebellar 4-6cb (by immunofluorescence staining). Results:Compared with group Con, the duration of passage through the balance beam was significantly prolonged, and the number of posterior foot slips was increased, the synaptic gap of cerebellar 4-6cb neurons was increased, the thickness of postsynaptic density was increased, the density of dendritic spines of Purkinje cells and the number of positive cells co-expressing SIRT6 and CbD-28k were decreased, and the expression of Glut3 was down-regulated in group SD ( P<0.05). Conclusions:The mechanism by which sleep deprivation decreases the abilities of balance and coordination is related to down-regulating SIRT6 expression in cerebellar Purkinje cells and decreasing neuronal glucose metabolism, thus damaging the synaptic plasticity of cerebellum in immature mice.

Objective To investigate the effect of reducing the image-guided X-ray field area on the accuracy of Cyberknife radiotherapy,in order to provide a feasible method for achieving patient protection optimization.Methods Firstly,the spine-tracking,fiducial tracking and lung-tracking radiotherapy plans were formulated for the simulation phantom,and then image-guided full-field localization and position pre-setting were carried out for the simulation phantom,and the spine-tracking,fiducial tracking and lung-tracking radiotherapy plans were executed for the simulation phantom using a reduced lead block field area,respectively.Secondly,the radiotherapy accuracy of different radiotherapy plans was verified by end-to-end(E2E)software using new EBT films of the same batch as the base film.Finally,the changes of the simulation phantom were compared in terms of position pre-presetting error,radiotherapy accuracy and lead block field area.Results The spine-tracking and fiducial tracking radiotherapy plans had the translation errors not higher than 0.1 mm and the rotation errors not higher than 0.1°,which were comparable to the fluctuated conventional Cyberknife image-guided locating;the spine-tracking,fiducial tracking and lung-tracking radiotherapy plans had the lead block field radiotherapy accu-racies being 0.71,0.18 and 1.06 mm,respectively,which met the clinical requirements for Cyberknife radiotherapy;the lead block field areas of the spine-tracking,fiducial tracking and lung-tracking radiotherapy plans were reduced to 19.75％,29.28％and 12.71％of the full field area,respectively,and the efficacy for field area optimization was significant.Conclusion It's feasible to involve a reduced image-guided X-ray field area in Cyberknife radiotherapy,which contributes to optimizing radiation protection for the patients.[Chinese Medical Equipment Journal,2024,45(11):49-53]

Objective To investigate the effects of microsurgical varicocelectomy on testicular function and sexual function in patients with varicocele.Methods The clinical data of 90 patients with varicocele admitted to our hospital were retrospectively analyzed,and the patients were divided into the laparoscopic group(received laparoscopic varicocelectomy)and the microscopic group(received microsurgical varicocelectomy)according to different surgical methods,with 45 cases in each group.The testicular function and sexual function related indexes including sperm density,normal sperm ratio,rate of sperm motility(grades a+b),forward motility sperm rate,international index of erectile function-5(IIEF-5)score,and the levels of testosterone,follicle-stimulating hormone,luteinizing hormone,and androgen levels before and 6 months after surgery in the two groups were compared.The incidence of complications and recurrence 6 months after surgery in the two groups were counted.Results Compared with those before surgery,the sperm density,forward motility sperm rate,rate of sperm motility(grades a+b),normal sperm ratio,IIEF-5 score,testosterone level,and androgen level 6 months after surgery of patients in the two groups were significantly increased(P<0.05),and the levels of luteinizing hormone and follicle-stimulating hormone were decreased(P<0.05).Compared with the laparoscopic group,the levels of follicle-stimulating hormone and luteinizing hormone,and incidence of complications 6 months after surgery of patients in the microscopic group were decreased(P<0.05),and the levels of testosterone and androgens,and IIEF-5 score 6 months after surgery were increased(P<0.05).There was no significant difference in the recurrence rate between the two groups(P>0.05).Conclusion Microsurgical varicocelectomy can improve the testicular function and sexual function of patients with varicocele,with a low incidence of complications.

Objective: To describe the distribution characteristics of hypertension among adult twins in the Chinese National Twin Registry (CNTR) and to provide clues for exploring the role of genetic and environmental factors on hypertension. Methods: A total of 69 220 (34 610 pairs) of twins aged 18 and above with hypertension information were selected from CNTR registered from 2010 to 2018. Random effect models were used to describe the population and regional distribution of hypertension in twins. To estimate the heritability, the concordance rates of hypertension were calculated and compared between monozygotic twins (MZ) and dizygotic twins (DZ). Results: The age of all participants was (34.1±12.4) years. The overall self-reported prevalence of hypertension was 3.8%(2 610/69 220). Twin pairs who were older, living in urban areas, married, overweight or obese, current smokers or ex-smokers, and current drinkers or abstainers had a higher self-reported prevalence of hypertension (P<0.05). Analysis within the same-sex twin pairs found that the concordance rate of hypertension was 43.2% in MZ and 27.0% in DZ, and the difference was statistically significant (P<0.001). The heritability of hypertension was 22.1% (95%CI: 16.3%- 28.0%). Stratified by gender, age, and region, the concordance rate of hypertension in MZ was still higher than that in DZ. The heritability of hypertension was higher in female participants. Conclusions: There were differences in the distribution of hypertension among twins with different demographic and regional characteristics. It is indicated that genetic factors play a crucial role in hypertension in different genders, ages, and regions, while the magnitude of genetic effects may vary.
Adult ; Female ; Humans ; Male ; Alcohol Drinking ; Diseases in Twins/genetics* ; Hypertension/genetics* ; Twins, Dizygotic/genetics* ; Twins, Monozygotic/genetics*

Objective: To describe the distribution characteristics of hyperlipidemia in adult twins in the Chinese National Twin Registry (CNTR) and explore the effect of genetic and environmental factors on hyperlipidemia. Methods: Twins recruited from the CNTR in 11 project areas across China were included in the study. A total of 69 130 (34 565 pairs) of adult twins with complete information on hyperlipidemia were selected for analysis. The random effect model was used to characterize the population and regional distribution of hyperlipidemia among twins. The concordance rates of hyperlipidemia were calculated in monozygotic twins (MZ) and dizygotic twins (DZ), respectively, to estimate the heritability. Results: The age of all participants was (34.2±12.4) years. This study's prevalence of hyperlipidemia was 1.3% (895/69 130). Twin pairs who were men, older, living in urban areas, married,had junior college degree or above, overweight, obese, insufficient physical activity, current smokers, ex-smokers, current drinkers, and ex-drinkers had a higher prevalence of hyperlipidemia (P<0.05). In within-pair analysis, the concordance rate of hyperlipidemia was 29.1% (118/405) in MZ and 18.1% (57/315) in DZ, and the difference was statistically significant (P<0.05). Stratified by gender, age, and region, the concordance rate of hyperlipidemia in MZ was still higher than that in DZ. Further, in within-same-sex twin pair analyses, the heritability of hyperlipidemia was 13.04% (95%CI: 2.61%-23.47%) in the northern group and 18.59% (95%CI: 4.43%-32.74%) in the female group, respectively. Conclusions: Adult twins were included in this study and were found to have a lower prevalence of hyperlipidemia than in the general population study, with population and regional differences. Genetic factors influence hyperlipidemia, but the genetic effect may vary with gender and area.
Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; China/epidemiology* ; Diseases in Twins/genetics* ; Hyperlipidemias/genetics* ; Metabolic Diseases ; Twins, Dizygotic ; Twins, Monozygotic/genetics*

Humans ; Otitis Media, Suppurative ; Chronic Disease ; Biofilms ; Otitis Media

Objective:To investigate the predictive role of dynamic changes of plasma biomarkers in patients with viral and mycoplasma community-acquired pneumonia (CAP).Methods:From January 2020 to June 2020, 141 patients with viral and mycoplasma CAP in People's Hospital of Ningxia Hui Autonomous Region were enrolled. Pneumonia severity index (PSI) scores [grade Ⅰ-Ⅱ(PSI score ≤ 70), grade Ⅲ (PSI score 71-90) and grade Ⅳ-Ⅴ(PSI score ≥ 91)], serum amyloid A (SAA), hypersensitive C-reactive protein (hs-CRP), procalcitonin (PCT), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) on the 1 day after admission were compared between the different pathogens (viral and mycoplasma) or different disease severity. The change in level of SAA, hs-CRP on the third day (Δ 3 d = 1 d-3 d) were compared among different disease outcome groups (patients were divided into improved group, stable group and exacerbation group based on PSI scores or lung CT images on the third day). The change in the level of SAA, hs-CRP on the seventh day (Δ 7 d = 1 d-7 d) were compared among different disease prognosis groups (patients were divided into survival group and death group based on 28-day survival data). The receiver operating characteristic curve (ROC) were drawn to evaluate the value of SAA in the evaluation of disease and prediction prognosis. Results:The level of SAA in mycoplasma group (43 cases) was significantly higher than that in virus group (98 cases) on the 1 day after admission. There were no significant differences in other plasma biomarkers between the two groups. The more severe the illness, the higher the SAA level on the 1 day after admission. The trends of other plasma biomarkers in the two groups were consistent with SAA. The levels of SAA in the patients with exacerbation of the virus group and mycoplasma group (12 cases, 9 cases) were significantly higher than those of the improved group (57 cases, 26 cases) and the stable group (29 cases, 8 cases). SAA increased gradually in the exacerbation group, decreased gradually in the improved group, and slightly increased in the stable group. ΔSAA 3 d were differences among three groups. The change trend of hs-CPR was consistent with SAA. The level of SAA in the death group was higher than that in the survival group on the seventh day. SAA increased in the death group and decreased in survival group with time from hospital admission. There were differences according to ΔSAA 7 d between death group and survival group. The change trend of hs-CPR was consistent with SAA. ROC curve showed that the value of SAA was better than hs-CRP in assessing the severity of patients on admission day, and the area under ROC curve (AUC) was respectively 0.777 [95% confidence interval (95% CI) was 0.669-0.886], 0.729 (95% CI was 0.628-0.830). The value of ΔSAA 3 d was better than SAA on the third day predicting disease trends, and AUC was respectively 0.979 (95% CI was 0.921-1.000), 0.850 (95% CI was 0.660-1.000). hs-CRP on the third day and Δhs-CRP 3 d had no predictive value. Both SAA on the seventh day and ΔSAA 7 d have predictive value for prognosis. AUC was respectively 0.954 (95% CI was 0.898-0.993) and 0.890 (95% CI was 0.689-1.000). SAA on the seventh day and ΔSAA 7 d were better than hs-CRP on the seventh day. Δhs-CRP 7 d have no predictive value. Conclusions:SAA is a sensitive and valuable indicator for CAP patients with viruses and mycoplasma. Dynamic monitoring of SAA can evaluate the patient's progression, prognosis, and assist diagnosis and treatment.

Objective: To describe the distribution characteristics of type 2 diabetes in twins in Chinese National Twin Registry (CNTR), provide clues and evidence for revealing the influence of genetic and environmental factors for type 2 diabetes. Methods: Of all twins registered in the CNTR during 2010-2018, a total 18 855 twin pairs aged ≥30 years with complete registration information were included in the analysis. The random effect model was used to describe the population and area distribution characteristics and concordance of type 2 diabetes in twin pairs. Results: The mean age of the subjects was (42.8±10.2) years, the study subjects included 10 339 monozygotic (MZ) twin pairs and 8 516 dizygotic (DZ) twin pairs. The self-reported prevalence rate of type 2 diabetes was 2.2% in total population and there was no sighificant difference between MZ and DZ. Intra-twin pairs analysis showed that the concordance rate of type 2 diabetes was 38.2% in MZ twin pairs, and 16.0% in DZ twin pairs, the difference was statistically significant (P<0.001). The concordance rate of type 2 diabetes in MZ twin parts was higher than that in DZ twin pairs in both men and women, in different age groups and in different areas (P<0.05). Further stratified analysis showed that in northern China, only MZ twin pairs less than 60 years old were found to have a higher concordance rate of type 2 diabetes compared with DZ twin pairs (P<0.05). In southern China, the co-prevalence rate in male MZ twin pairs aged ≥60 years was still higher than that in DZ twin pairs (P<0.05). Conclusion: The twin pairs in this study had a lower self-reported prevalence of type 2 diabetes than the general population. The study results suggested that genetic factors play a role in type 2 diabetes prevalence in both men and women, in different age groups and in different areas, however, the effect might vary.
Adult ; China/epidemiology* ; Diabetes Mellitus, Type 2/genetics* ; Diseases in Twins/genetics* ; Female ; Humans ; Male ; Middle Aged ; Registries ; Twins, Dizygotic ; Twins, Monozygotic/genetics*

Objective: To describe the distribution characteristics of coronary heart disease in adult twins recruited from Chinese Twin Registry (CNTR), and provide clues and evidence for the effect of genetic and environmental influences on coronary heart disease. Methods: By using the data of CNTR during 2010-2018, a total of 34 583 twin pairs aged ≥18 years who completed questionnaire survey and had related information were included in the current study to analyze the population and area distribution characteristics of coronary heart disease. Random effect models were used to compare the differences between groups. The concordane rate of coronary heart disease were calculated respectively in monozygotic (MZ) twin pairs and dizygotic (DZ) twin pairs to estimate the heritability. Results: The twin pairs included in this analysis were aged (34.2±12.4) years. The overall prevalence rate of coronary heart disease in twin pairs was 0.7%. Twin pairs who were women, older, obese and lived in northern China had higher prevalence of coronary heart disease (P<0.05). Intra-pair analysis in the same-sex twin pairs found that the concordane rate of coronary heart disease was higher in MZ twin pairs (25.3%) than in DZ twins (7.4%), and the difference was statistically significant (P<0.001). The overall heritability of coronary heart disease was 19.3% (95%CI: 11.8%-26.8%). Stratified by gender, age and area, the concordane rate was still higher in MZ twin pairs than in DZ pairs. Participants who were women, aged 18-30 years or ≥60 years and lived in northern China had a higher heritability of coronary heart disease. Conclusion: The distribution of coronary heart disease in twin pairs differed in populations and areas. The prevalence of coronary heart disease was affected by genetic factors, but the effect varied with age, gender and area.
Adolescent ; Adult ; China/epidemiology* ; Coronary Disease/genetics* ; Diseases in Twins/genetics* ; Female ; Humans ; Male ; Twins, Dizygotic ; Twins, Monozygotic/genetics*