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 explore the value of contrast-enhanced ultrasound(CEUS)in the assessment of diabetic microangiopademia through evaluating microcirculation perfusion of triceps surae muscle by CEUS.Method Totally 51 patients with type 2 diabetes mellitus(T2DM)admitted in our hospital between August 2020 and January 2023 were collected,including 15 pure T2DM patients and 36 T2DM patients complicated with microcirculatory disturbance(T2DM+CM).Each patient's hemoglobin A1c(HbA1c)and homeostatic model assessment for insulin resistance(HOMA-IR)were recorded.After getting enhanced intensity(PI-BI)and regional peak time(TTP-AT)by CEUS,comparative analysis between groups was conducted.Results The levels of HbA1c and HOMA-IR in T2DM+CM group were higher than those in pure T2DM group(P<0.05).TTP-AT in T2DM+CM group were longer than that in pure T2DM group of all muscles musculi gastrocnemii(MG),laterale musculi gastrocnemi(LG),soleus(SOL)and triceps surae muscle's junction region)(P<0.05).The TTP-AT of SOL was longest in both groups,followed by LG,and MG(P<0.05).The PI-BI had no significant difference among MG,LG and SOL in pure T2DM group.The PI-BI of MG was higher than that of SOL in the T2DM+CM group(P<0.05).TTP-AT of triceps surae muscle's junction region had significant positive association with both HbA1c and HOMA-IR(P<0.05).Conclusion The TTP-AT of triceps surae muscle measured by CEUS is a new indicator for evaluating microangiopathopathy in T2DM patients.

Objective To investigate the antagonistic effect of ω-3PUFAs on cognitive impairment in MK-801-induced schizophrenia (SZ) rats and its mechanism.Methods Rat model of schizophrenia was induced by MK-801.Morris water maze was used to detect the change of cognitive function in rats.The number of neonatal neurons in hippocampus was detected by Brdu staining.CREB,p-CREB,BDNF,TrkB and p-TrkB levels were detected by Weston Blot.Results MK-801 induced schizophrenia-like cognitive impairment (the escape latency in the water maze test was (6.51±3.10)s for Ctr group,(15.27±6.20)s for Mod group;acrossing times was (4.63±1.06) times for Ctr group,(2.00±1.15) times for Mod group),reduced the number of neonatal neurons in hippocampus (the relative level of neonatal neuron number per unit area,Mod/Ctr was 0.656±0.066) and impaired the CREB/BDNF/TrkB pathway (the relative level of gray value,Mod/Ctr:CREB was 0.393±0.065,p-CREB was 0.591±0.015,BDNF was 0.716±0.115,TrkB was 0.787±0.029,p-TrkB was 0.586±0.013).ω-3PUFAs improved the CREB/BDNF/TrkB pathway activity by increasing CREB and TrKB level and their phosphorylation (the relative level of gray value,Pre/Ctr:CREB was 1.139±0.111,p-CREB was 0.845±0.243,BDNF was 0.864±0.133,TrkB was 0.916±0.022,p-TrkB was 0.952±0.047),and then recovered the number of neonatal neurons in hippocampus (the relative level of neonatal neuron number per unit area,Pre/ Ctr was 1.183±0.101),thereby reduced the cognitive dysfunction in schizophrenia rats(the escape latency in the water maze was (7.44±4.55)s for Pre;acrossing times was (3.86±1.68) times for Pre).Conclusion ω-3PUFAs can relieve the MK-801-induced schizophrenia-like cognitive impairment.

To investigate the changes of aortic stiffness and its influencing factors in patients with chronic kidney diseases (CKD).Eightyfour patients with CKD from Department of Nephrology, Zhejiang Provincial People's Hospital were divided into the dialysis group (CKD stage 5,=48) and non-dialysis group (CKD stage 3-5,=36). Clinical data, biochemical parameters and echocardiography findings were collected. SphygmoCor pulse wave analysis system was used to obtain pulse wave analysis (PWA) parameters including central aortic systolic blood pressure (CSP), central pulse pressure (CPP), augmented pressure (AP), augmentation index (AIX), and heart rate 75-adjusted augmentation index (HR75AIX). The influencing factors of aortic stiffness were analyzed by spearman correlation analysis and multiple regression analysis.CSP, CPP, AP, AIX and HR75AIX in dialysis patients had no significant differences compared with those in non-dialysis group (all>0.05). Spearman correlation analysis showed that CSP was positively correlated with systolic blood pressure, diastolic blood pressure, cholesterol, low-density lipoprotein cholesterol, left atrial diameter (LA),left ventricular systolic diameter (LVDs), left ventricular diastolic diameter (LVDd), and negatively correlated with calcium and hemoglobin levels. CPP was positively correlated with systolic blood pressure, age, LA, LVDd, and negatively correlated with diastolic blood pressure and hemoglobin levels. AP was positively correlated with systolic blood pressure, age, LA, LVDd, and negatively correlated with hemoglobin levels. AIX was positively correlated with systolic blood pressure, age, sodium, and negatively correlated with phosphorus levels. HR75AIX was positively correlated with systolic blood pressure, sodium, cholesterol, and negatively correlated with hemoglobin and albumin levels. Multiple regression analysis showed that higher systolic blood pressure was the independent risk factor for CSP (β=0.944,<0.01); lower diastolic blood pressure (β=0.939,<0.01) and higher systolic blood pressure (β=-1.010,<0.01) were the independent risk factors for CPP; older age (β=0.237,<0.01) and higher systolic blood pressure (β=0.200,<0.01) were the independent risk factors for AP; higher systolic blood pressure (β=0.163 and 0.115,<0.05 and<0.01) and higher sodium (β=0.646 and 0.625, all<0.05) were independent risk factors for both AIX and HR75AIX.No significant correlation is observed between aortic stiffness and CKD of different stages. Control blood pressure and restrict sodium intake may be effective means of delaying arterial stiffness in patients with CKD.
Age Factors ; Aorta ; pathology ; Blood Pressure ; physiology ; Cholesterol ; Dialysis ; Female ; Heart Atria ; Humans ; Male ; Middle Aged ; Regression Analysis ; Renal Insufficiency, Chronic ; complications ; Risk Factors ; Sodium, Dietary ; adverse effects ; Vascular Stiffness ; physiology

Objective This epidemiologic survey aims to investigate the changes in prevalence and risk factors for non-alcoholic fatty liver disease (NAFLD)in the elderly people who are living within Pudong San-lin region.Methods We retrospectively analyzed annual physical check-up data in 2012 and 2014 for elderly people living in this region (aged≥70years).Demographic variables including age,sex,blood pressure,body mass index (BMI)were recorded.Serum fasting glucose level was determined and liver and kidney function were assessed.Abdominal echo-Doppler examination was performed.NAFLD was diagnosed according to Chinese guideline on management of NAFLD (revised version).Results Among 2127 sub-jects with physical check-up in 2012,the occurrence rate of NAFLD was 27.46% (23.02% and 31.02%for men and women,respectively).Type 2 diabetes was detected in 224 subjects and 33.93% of them de-veloped NAFLD (26.73% and 39.84% for males and females,respectively).Among 1771 subjects who received physical check-up in 2014,the occurrence rate of NAFLD increased up to 32.29%,with NAFLD rate being 29.97% and 34.19% for men and women,respectively.In 185 subjects with type 2 diabetes, 49.19% developed NAFLD (47.56% and 50.49% for men and women,respectively).Thus,compared with the findings during physical check-up in 2012,the occurrence rate of NAFLD was significantly in-creased during physical check-up in 2014 for both male and female subjects of overall and diabetic popula-tions (P <0.05 for all comparisons).Further analysis showed that for 185 diabetic patients who had phys-ical check-up in 2014,systolic and diastolic blood pressures,BMI,and serum levels of fasting glucose lev-el,alanine aminotransferase,aspartate aminotransferase,total cholesterol,and triglyceride were significant-ly higher in patients with NAFLD than in those without NAFLD (all P <0.05).Multivariate regression a-nalysis revealed that BMI,total cholesterol and triglyceride levels were independent risk factors for occur-rence of NAFLD in diabetic patients.Conclusions This epidemiologic survey demonstrates a significant increase in the occurrence rate of NAFLD for the elderly people (especially with type 2 diabetes).Hyper-lipidemia,obesity,and hypertension are major risk factors for NAFLD in diabetic patients.

Objective: To investigate the changes of aortic stiffness and its influencing factors in patients with chronic kidney diseases ( CKD) .Methods:Eighty-four patients with CKD from Department of Nephrology , Zhejiang Provincial People ’ s Hospital were divided into the dialysis group ( CKD stage 5 , n=48 ) and non-dialysis group ( CKD stage 3 -5 , n =36 ) . Clinical data , biochemical parameters and echocardiography findings were collected .SphygmoCor pulse wave analysis system was used to obtain pulse wave analysis ( PWA ) parameters including central aortic systolic blood pressure ( CSP ) , central pulse pressure ( CPP ) , augmented pressure ( AP ) , augmentation index ( AIX ) , and heart rate 75 -adjusted augmentation index ( HR75 AIX ) .The influencing factors of aortic stiffness were analyzed by spearman correlation analysis and multiple regression analysis .Results: CSP, CPP, AP, AIX and HR75 AIX in dialysis patients had no significant differences compared with those in non-dialysis group (all P>0.05).Spearman correlation analysis showed that CSP was positively correlated with systolic blood pressure , diastolic blood pressure , cholesterol , low-density lipoprotein cholesterol , left atrial diameter ( LA ) , left ventricular systolic diameter ( LVDs ) , left ventricular diastolic diameter ( LVDd ) , and negatively correlated with calcium and hemoglobin levels . CPP was positively correlated with systolic blood pressure , age, LA, LVDd, and negatively correlated with diastolic blood pressure and hemoglobin levels . AP was positively correlated with systolic blood pressure, age, LA, LVDd, and negatively correlated with hemoglobin levels .AIX was positively correlated with systolic blood pressure , age, sodium, and negatively correlated with phosphorus levels .HR75AIX was positively correlated with systolic blood pressure , sodium , cholesterol , and negatively correlated with hemoglobin and albumin levels .Multiple regression analysis showed that higher systolic blood pressure was the independent risk factor for CSP (β=0.944, P<0.01);lower diastolic blood pressure (β=0.939, P<0.01) and higher systolic blood pressure (β=-1.010, P<0.01) were the independent risk factors for CPP; older age (β=0.237, P <0.01) and higher systolic blood pressure (β=0.200,P<0.01) were the independent risk factors for AP; higher systolic blood pressure (β=0 .163 and 0 .115 , P<0 .05 and P<0.01 ) and higher sodium (β=0.646 and 0.625, all P <0.05 ) were independent risk factors for both AIX and HR 75 AIX.Conclusions: No significant correlation is observed between aortic stiffness and CKD of different stages .Control blood pressure and restrict sodium intake may be effective means of delaying arterial stiffness in patients with CKD .

We wished to select a cold-adapted genotype G1P[8] ZTR-68 rotavirus (China southwest strain) in MA104 cells for possible use as a live vaccine. ZTR-68 was recovered originally from children with diarrhea. The virus was cultivated at 37 degrees C at the first passage. Then, the cultivation temperature was decreased stepwise by 3 degrees C per eight passages. In total, the virus was passaged 32 times, and cultivation was terminated at 28 degrees C. Biological characteristics of the virus were analyzed during serial passages. There was no difference between the migration patterns of genomic dsRNA segments according to polyacrylamide gel electrophoresis of original and cold-adapted viruses. Infectious and red cell-agglutination titers of cold-adapted virus were lower than those of the parent virus. Also, the virus formed small-size plaques with irregular shapes at 31 degrees C and 28 degrees C. These results suggested that a genetically stable attenuated virus can be obtained through serial cold-adapted passages. Thus, an alternative strategy is provided by cold-adaption for development of attenuated live rotavirus vaccines.
Adaptation, Physiological ; China ; Cold Temperature ; Diarrhea ; virology ; Female ; Genotype ; Humans ; Infant ; Male ; Rotavirus ; genetics ; growth & development ; isolation & purification ; physiology ; Serial Passage ; Virus Cultivation ; Virus Replication

Objective: To determine the effect of polygona-polysaccharose (PP) on learning and memory ability in rats with Alzheimer’s disease (AD). Methods: Forty ifve Sprague-Dawley rats were assigned into 3 groups. Rats in the sham-operated group were injected with normal saline. Rats in the Aβ group were injected with Aβ1-42. Rats in the PP group were injected with 16% PP solution for 45 days consecutively. hTe Morris water maze was used to investigate the ability of learning and memory in the rats. hTe effect of Aβ and PP on the hippocampus cells was observed by HE and Congo red staining of methanol. Results: Rats in the sham-operated group had no obvious morphological change; and morphology of rats in the PP group was basicaly normal. The layer of pyramidal cells in the Aβ group was decreased. hTe cells appeared sparse and irregular and became smaller. Karyopyknosis and vacuolardegeneration cells were also found. More positive staining materials aggradated in the Aβ group compared with the PP group by Congo red staining (P<0.05). Conclusion: Aβ infusion into the hippocampus results in the impairment of the neuronal degeneration in the rats, which shows similar characterizations of AD. PP can reduce the deposition of Aβ in the hippocampus.

Anatomy experimental teaching for nursing students in higher vocational college should reflect the actuality of nursing work,strengthen anatomical structure knowledge related with nursing procedures,help solve the difficuhies in nursing operation.We reformed on experimental item,experiment teaching content,design of experiment teaching procedure and making of experiment teaching specimens,etc.We also created situational teaching scene and combine anatomical structure with nursing ideas thus to make the students master the knowledge of anatomy,which can meet the clinical nursing operation related requirements.Therefore,basic medical education must make students use what they learn and closely correlated with its profession and clinical application.

Objective To investigate the relationship between the risk stratification of cardiovascular diseases and the outcome of 64-slice helical computed tomography (MSCT) coronary angiography. Methods A total of 470 cases suspected to have coronary heart disease were enrolled.They all received 64-slice MSCT coronary angiography, and they were divided into groups according to the range of disease, degree of calcium scoring, degree of stenosis and characteristic of plaque. Among them, 80 patients underwent both MSCT and selective coronary angiography (CAG) at one time, and they were grouped according to the range of disease and degree of stenosis. All the 470 cases were classified as five levels according to the risk stratification of cardiovascular diseases. The lesions of coronary artery in different risk stratifications were observed, and the correlations were analyzed.Results In the 80 patients who underwent both MSCT and selective CAG, there were no significant differences in the range of coronary artery diseases(χ2=3.631, P=0.067) and coronary arterystenosis (χ2=1.639, P=0.200) between MSCT and CAG. Along with the increased level of the risk stratification, there were the more ranges of the coronary artery diseases (λvery high risk. multi-vessel disease=1.09,λhigh risk. double-vessel disease=0.91, λlow-risk. single-vessel disease=1.07)and the more degrees of coronary artery stenosis(λvery high risk. severe stenosis=0.96,λhigh risk. moderate stenosis=1.03,λlow-risk. mild stenosis=0.78). The degrees of calcium scoring in different risk stratifications of cardiovascular diseases showed significantly differences (F=256.20,123.76,62.50, 98. 24,52.36,P＜0.01). There was the highest percentage of soft plaque in very high risk patients.Higher percentages of fiber plaque, calcified plaque and mixed plaque were found in moderate risk and low risk patients(λvery high risk. soft plaque=1.01,λlow-risk. calcium plaques=1.17). Conclusions The 64-slice MSCT coronary angiography could provide a basis for assessing risk stratification of cardiovascular diseases. The complicated coronary artery disease, moderate-severe calcification, more severe stenosis, higher percentage of soft plaque are found in the very high risk patients. The lower level of the risk stratification is found in patients with the less range of the coronary artery disease and less severe degree of the coronary artery calcification and stenosis. The calcified plaque and mixed plaque are found in moderate risk and low risk patients.