Objective · To design and synthesize a series of benzenesulfonamide derivatives, test their inhibitory activity to CDK2-cyclinA2 kinase, and investigate the structure-activity relationship. Methods · Virtual screening was executed via computer-aided drug design according to the ATP binding site in CDK2-cyclinA2 protein crystal. A series of benzenesulfonamide derivatives were designed and synthesized on the basis of the interaction modes between the lead compound and the CDK2-cyclinA2. The biological evaluation of compounds was made through the CDK2-cyclinA2 in-vitro kinase activity detection system. Results · Twenty-nine new benzenesulfonamide compounds were prepared, and their inhibitory activity to CDK2-cyclinA2 was elicited. WZ-026 had the highest inhibitory parameter, which half maximal inhibitory concentration (IC50) was 3.81 μmol/L. Conclusion · By multipurpose utilization of virtual screening, chemical synthesis, and biological activity test, a benzenesulfonamide compound WZ-026 was found, which has great inhibitory activity towards CDK2-cyclinA2. Preliminary structure-activity relationship of compounds was obtained.

Objective To explore whether the peritoneal cooling was better than other cooling methods on protection neuron damage of the hippocampus CA1 after cardiopulmonary resuscitation (CPR) in New Zealand rabbits.Methods Forty eight adult New Zealand rabbits were induced ventricular fibrillation by AC current and were resuscitated after cardiac arrest for 5 minutes.The rabbits were randomly divided into four groups according to the way of cooling methods,nomothermia group ( NT),peritoneal cooling group (PC),surface cooling group (SC) and local cooling group (LC).The changes of tympanic membrane temperature were recorded in each animal and blood plasma concentrations of electrolyte were tested in each group at different time points after restore of spontaneous circulation (ROSC).Brain tissue were removed,the numbers of vigorous and apoptotic neurons in the hippocampus CA1 area were counted after ROSC at 72h.One-way ANOVA or Mann-Whitney rank was used to determine the statistical significance between two groups.LSD-t test for multiple comparisons,R × C test for ROSC comparisons,a two-tailed value of P ＜0.05 was considered statistically significant. Results Hypothermia was rapidly induced in PC after ROSC,and the time of arriving at target temperature was (26 ±7) min in PC,(60 ±9) min in SC,(69 ± 12) min in LC respectively; in the maintain hypothermia period,the tympanic membrane temperature was maintained at 33～ 35 ℃ in each group exception nomothermia group (NT).There were no differences with main electrolyte,acid-abase liquid balance and renal function between each group at each time point after ROSC.The numbers of vigorous neurons in hippocampus CA1 area were ( 37.07 ± 6.43 ) /40 × in NT group,(35.13 ± 6.97) /40 × in LC group,(55.76 ± 10.13 ) /40 × in PC group,and (50.70 ± 7.38 ) /40 × in SC group (PC:NT,P＜0.01,SC:NT,P＜0.01,PC:SC,P=0.043,PC:LC,P＜0.01,LC:NT,P=0.52).The numbers of apoptotic neurons were (44.07 ±6.09) /40 × in NT group,(29.88 ±4.81 ) /40× in PC group,( 33.55 ± 5.67 ) /40 × in SC group and ( 42.27 ± 5.20 ) /40 × in LC group respectively (PC:NT,P ＜0.01,SC:NT,P ＜0.01,PC:LC,P ＜0.01,SC:LC,P ＜0.01,PC:SC,P=0.026,LC:NT,P =0.364 ).Conclusions The new peritoneal cooling method could rapidly induce and maintain hypothermia,and it had better protections on neurons in hippocampus CA1 than surface cooling and local cooling method after ROSC in New Zealand rabbits.

Objective To evaluate the effect of percutaneous coronary intervention (PCI) or thrombolysis,in patients with return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA),in the presence of ST-elevation myocardial infarction (STEMI).We demonstrated the benefits of the two therapies on ROSC patients in hospital discharge and neurological recovery,and clarified the importance of ROSC,so as to guide the treatments for OHCA in the presence of STEMI.Methods It was performed a meta-analysis of clinical studies located in PUBMED and MEDLINE databases from January 1995 to October 2011.OHCA patients with ROSC were as our study objects,the hospital discharge and neurological recovery rates,of patients with and without PCI or thrombolysis,were assessed in patients with ROSC after OHCA in the presence of STEMI.In the same Cohort Study,between received and rejected PCI,or between received and rejected thrombolysis in OHCA patients with ROSC as treated group and control group,using Review Manager 5.1 software to analyze,respectively.Furthermore,we also compared the differences in hospital discharge and neurological recovery rates between patient groups who received PCI or thrombolysis by Pearson x2 analysis.Results The meta-analysis showed that the rate of hospital discharge improved with both PCI (odds ratio [OR],1.65 ; 95％ confidence interval [CI],1.05-2.59,P ＜ 0.01)and thrombolysis (OR,2.03 ; 95％ CI,1.24-3.34,P ＜ 0.01) in patients with ROSC after OHCA,in the presence of STEMI.We also found that there were not significant differences between with PCI and with thrombolysis in the rate of hospital discharge (63.00％ vs.65.19％,P =0.548) and neurological recovery (88.62％ vs.91.25％,P =0.351) for the patients with ROSC after OHCA (P ＞0.05).Conclusions In patients with ROSC after OHCA in the presence of STEMI,both PCI and thrombolysis improved hospital discharge rates.Furthermore,there were similar efficacy in hospital discharge and neurological recovery rates between with PCI and with thrombolysis.

Objective To characterize the clinical features of patients with cardiac amyloidosis (CA).Methods Totally 42 patients with CA admitted to Guangdong General Hospital since 2008 were included and retrospectively analyzed in the present study.CA was confirmed by abdomen and endocardium biopsy examination.Clinical manifestations,electrocardiogram and echocardiography were collected for the evaluation.Results Several clinic features are common in CA.In the present study,37 cases (88.1％) presented with chest tightness,dyspnea,20 cases(47.6％) with chest pain,27 cases(64.3％) with right heart failure,27 cases (64.3％) with fatigue,and 30 cases (71.4％) with renal insufficiency and proteinuria.Electrocardiogram (ECG) showed that 32 of the patients (76.2％) were with low voltage in limb leads,29 cases (69％) of them were with poor R wave progression in precordial leads,17 cases (40.5％) with ST-T change,28 cases(66.7％) with pseudo-necrotic Q wave and 36 cases (85.7％) with various kinds of arrhythmia.Echocardiography indicated that all of the subjects (100％) were with different degrees of left ventricular posterior wall or ventricular septal thickness,and left atrial hypertrophy with different degree of myocardial grain appearance or ground-glass opacity.Thirty-six cases (85.7％) were with pericardial effusion,and 27 cases (64.3％) were with abnormal left ventricular eject function.Conclusion For those who were with unexplained clinical cardiac insufficiency,renal insufficiency,myocardial hypertrophy,but normal of ventricular size in echocardiography and low voltage on ECG limb leads,a tissue biopsy from abdomen,labial glands or endocardium should be considered in the diagnosis of CA.

Objective Using twins methods to explore the influence of genetic and environmental factor on Intelligence develop-ment of children and adolescent twins .Methods It was 190 pair of twins aged 6 to 18 who lived in Chongqing were recruited ,DNA were extracted from buccal mucosa and venous blood samples to identify zygosity .The intelligence was investigated by using the Wechsler Intelligence Scale for Children(C-WISC) ,the intrapair correlation coefficients of twins were compared and calculate the genetic degrees .Results The total IQ of children aged 6 to 18 heritability were 0 .63 ,Verbal IQ were 0 .44 ,Performance IQ were 0 .57 .The total IQ heritability of children aged 10 to 14 and 15 to 18 years(0 .78 ,0 .79) were higher than that of those aged from 6 to 9 years(0 .018) .Conclusion This study suggested the intelligence of children aged 6 to 18 affected by genetic and environment , and the older ,the more influence of genetic on intelligence development .

Objective To explore the influence of genetic and environmental factors on emotional and behavioral problems in children and adolescents using twins quantitative method. Methods One hundred fifty-six twins pairs, aged from 6 to 18, were included in the present study. The parental version of the strengths and difficulties questionnaire (SDQ)was used to evaluate their emotional and behavioral problems. The DNA test of twin zygosity was conducted using DNA extracted from buccal mucosa or venous blood samples. The influence of genetic and environmental factors on emo-tional and behavioral problems was analyzed using structural equation modeling(SEM). Results Shared environment and special environment had impact on emotional symptoms and their contribution to the total variance of emotional symp- tom was 0.42 and 0.58, respectively. Prosocial behavior was mainly affected by shared environment and the contribution of shared environment to the total variance of prosocial behavior was 0.89. Genetic factors had greater influence on hyperac-tivity/attention deficit and the contribution of genetic factors to the total variance was 0.62. Shared environment had more influence on conduct disorder and the contribution of shared environment to total variance was 0.56. Heredity, shared envi-ronment and special environment had impact on peer problems and their contribution to the total variance was 0.24, 0.33 and 0.43, respectively. Conclusion In child and adolescent period, emotional symptoms are only affected by environ-ment, while behavior problems are affected by the combination of heredity and environment. Different behavior problems are affected by different genetic and environmental factors.

OBJECTIVETo explore the influence of genetic and environmental factors on the executive function of twin children.

METHODSThe executive function of 122 twin pairs from Chongqing (aged from 6 to 18 years) were investigated with the perseverative errors of the Wisconsin Card Sorting Test. Structural equation modeling was performed to evaluate the effects of the additive genetic factors (A), dominance genetic latent factors (D) and individual specific environmental factors (E) on the executive functions.

RESULTSThe effects of D and E on perseverative errors were 0. 77 (95%CI: 0.65-0.84) and 0.23 (95%CI: 0.16-0.35), respectively. The probability of perseverative errors showed a significant negative correlation with family functioning and with the total GHQ-12 scores of the fathers and mothers (r:-0.335, -0.335, and -0.219, respectively, P<0.01). Perseverative errors were not significantly correlated with the parenting styles and stress life events.

CONCLUSIONPerseverative errors are influenced by a common dominance genetic latent factor and individual specific environmental factors, but the role of environmental factors such as family functioning and parental health can not be ignored.

Objective We retrospectively analyzed the causes,diagnosis,clinical characteristics,treatment and prognosis of 17 patients with rhabdomyolysis.Methods Rhabdomyolysis cases diagnosed from January 2005 to March 2014 in our department were included.Results A total of 17 rhabdomyolysis patients (male 13,mean age (60.4 ± 15.7)years) were analyzed.Four cases had coronary heart disease combined with hypertension,hyperlipaemia,atrial fibrillation,10 cases had dilated cardiomyopathy combined with coronary heart disease,hyperlipaemia,atrial fibrillation,8 cases had atrial fibrillation combined with hypertension,coronary heart disease,hyperlipaemia,1 patient had pulmonary embolism combined with hyperlipaemia,1 patient had aortic dissection combined with hypertension,10 hypertension patients were combined with coronary heart disease,hyperlipaemia,atrial fibrillation,aortic dissection and 1 patient with ventricular tachycardia was combined with depression.Various degrees of liver and kidney dysfunction,reduced hemoglobin and myoglobinuria were found in all patients.Fever was found in 7 cases,relevant neurological signs in 5 cases.Digestive tract discomfort and muscle weakness or muscle pain symptoms were seen in all patients during hospitalization.All cases underwent renal replacement therapy and respirator was used in 14 patients to support breathing.Post therapy,10 cases improved but 7 cases died.All 17 patients had history of statin use.Conclusion Statin may be the major cause of rhabdomyolysis in these patients,and the mortality of rhabdomyolysis is high despite various therapy stratigies.

Objective:Based on the specific cleavage and non-specific "trans-cleavage" activities of the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein(CRISPR/Cas13), we established a visually amplification-free rapid detection technique of 2019-nCoV nucleic acid. This technique is easily processed with a low detection limit and good specificity.Methods:According to the 2019-nCoV gene sequence, specific CRISPR RNAs were screened and designed by bioinformatics analysis, and then synthesized as universal signal-strained RNA transcription targets in vitro to establish and optimize the reaction system. Moreover, the 2019-nCoV pseudoviral nucleic acid was used as a standard substance to evaluate the detection limit. A total of 65 positive samples were collected from various 2019-nCoV variants, while 48 negative samples included other clinically common respiratory pathogens, such as influenza A virus, influenza B virus, human parainfluenza virus, Klebsiella pneumonia, etc. All samples were tested by quantitative PCR (qPCR), digital PCR, and the method established in this study. The sensitivity and specificity of the newly established method were analyzed and evaluated. Results:With the newly established technique, the detection time for 2019-nCoV nucleic acid could be minimized to 6 minutes. In addition, the detection limit was 14 copies/μl when assisted by the displaying instrument, whereas it increased to 28 copies/μl with the naked eye. This technique had a sensitivity and specificity of 98.5% (66/67) and 100% (46/46) respectively, showing no statistically significant difference compared to the gold standard qPCR( P=1). Conclusions:This study has successfully established a CRISPR/Cas13a-based visually rapid detection technique for 2019-nCoV nucleic acid. This technique offers the advantages of a simple process, convenient operation, low environmental operating requirements, a detection limit close to qPCR, and a strong potential for on-site testing applications.

SIRT6 belongs to the conserved NAD⁺-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD⁺. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC₅₀ of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.