[Association between family history of diabetes and incident diabetes of adults: a prospective study].

Objective: To evaluate the association betweew family history of diabetes and incident diabetes of adults. Methods: A total of 49 266 participants in the China Kadoorie Biobank (CKB) study from Wuzhong district of Suzhou city were included in the analysis, after the exclusion of those with heart disease, stroke, cancer and diabetes at baseline survey. The person-year of follow-up was calculated from the date on completion of baseline survey to the date on any firstly-occurred event, i.e., diabetes incidence, death, loss of follow-up, or December 31, 2013. Cox regression model was used to estimate the hazards ratios of the association between family history of diabetes and incident diabetes. Results: During 348 677 person-years of the follow-up (median 7.08 years), a total of 423 men and 791 women were diagnosed as having diabetes. Compared to those without diabetic family history, participants with family history of diabetes showed a higher risk of diabetes, with a HR (95%CI) of 1.90 (1.57-2.29), and the risk increased with the number of relatives suffering from diabetes (Pfor trend<0.05). The family history of maternal type, sibling type, and sibling and parental type had a statistically significant association with the risk of diabetes. The adjusted HR (95%CI) was 2.03 (1.45-2.77), 2.07 (1.56-2.68) and 2.39 (1.14-4.34), respectively. Modification effects of tobacco smoking, alcohol drinking, body mass index and physical activity on the association between diabetic family history and risk of diabetes were not observed in the study (Pfor interaction >0.05). Conclusions: Diabetic family history is associated with the increased incident diabetes, and the risk increased with the number of relatives suffering from diabetes.

[A prospective study on association between sleep duration and the risk of chronic obstructive pulmonary disease in adults in Suzhou].

Objective: To investigate the prospective association of sleep duration with the development of chronic obstructive pulmonary disease (COPD) in adults in Suzhou. Methods: The study used the data of 53 269 participants aged 30-79 years recruited in the baseline survey from 2004 to 2008 and the follow-up until December 31, 2017 of China Kadoorie Biobank (CKB) conducted in Wuzhong District, Suzhou. After excluding participants with airflow limitation, self-reported chronic bronchitis/emphysema/coronary heart disease history at the baseline survey and abnormal or incomplete data, a total of 45 336 participants were included in the final analysis. The association between daily sleep duration and the risk for developing COPD was analyzed by using a Cox proportional hazard regression model, and the hazard ratio (HR) values and their 95%CI were calculated. The analysis was stratified by age, gender and lifestyle factors, and cross-analysis was conducted according to smoking status and daily sleep duration. Results: The median follow-up time was 11.12 years, with a total of 515 COPD diagnoses in the follow-up. After adjusting for potential confounders, multifactorial Cox proportional hazard regression analysis showed that daily sleep duration ≥10 hours was associated with higher risk for developing COPD (HR=1.42, 95%CI: 1.03-1.97). The cross analysis showed that excessive daily sleep duration increased the risk for COPD in smokers (HR=2.49, 95%CI: 1.35-4.59, interaction P<0.001). Conclusion: Longer daily sleep duration (≥10 hours) might increase the risk for COPD in adults in Suzhou, especially in smokers.

[Mediating effect of physical activity on association between sedentary leisure-time and obesity indexes among hypertensive individuals].

Objective: To explore the mediating effect of physical activity on association between sedentary leisure-time and obesity indexes among hypertensive individuals. Methods: After excluding of those with a prior history of heart disease, stroke and cancer, a total of 20 178 hypertensive participants in the China Kadooire Biobank (CKB) study from Wuzhong district of Suzhou city were included. Mediating effect analysis was used to analyze the mediating effect of physical activity (PA) on correlation between sedentary leisure-time and body fat percentage (BFP), waist circumference (WC) and body mass index (BMI). Results: After adjusted for age, gender, smoking status, alcohol consumption, education levels, intake frequencies of meat and intake frequencies of fresh fruit, sedentary leisure-time (SLT) was negatively correlated with PA (ß=-0.246, P<0.001), but positively associated with BFP (ß=0.061, P<0.001), WC (ß=0.087, P<0.001) and BMI (ß=0.071, P<0.001). After including the mediator variable PA, the direct effect of SLT on obesity index was still significant. PA was negatively correlated with BFP, WC and BMI (ß=-0.052, -0.083 and -0.028, respectively, P<0.001). Analysis of mediating effect indicated that the association of SLT with BFP, WC and BMI were partly mediated by PA, the proportion of mediating effect was 20.820%, 23.421% and 9.915%. Stratified by gender, PA had mediating effect on SLT and all obesity indexes in women, while only on SLT and BFP and WC in men. Conclusions: There is a significant mediating effect of PA on correlation between SLT and obesity indexes among hypertensive individuals. Hypertensive patients should increase the level of physical activity and reduce sedentary behavior to achieve a profounder healthy effect.

[Relationship between sleep status and the risk of diabetes in adults].

Objective: To explore the relationship between sleep status and the risk of diabetes in adults. Methods: The baseline data of 53 260 subjects who were aged 30-79 years and had been enrolled into China Kadoorie Biobank (CKB) study from Suzhou, Jiangsu province were analyzed. Multiple logistic regression models were used to investigate the association between sleep status and diabetes after adjusting for potential confounders. Results: Among 53 260 subjects, 5.3% had diabetes. The proportions of difficultly falling asleep, early morning arousal and snoring frequently was 7.2%, 10.0% and 29.5%, respectively. There were 22.6% of subjects reporting sleep duration ≤6 hours. After controlling for possible confounders, the subjects with difficulty falling sleep (OR=1.63 for male, 95%CI: 1.30-2.05; OR=1.48 for female, 95%CI: 1.27-1.73), early morning arousal (OR=1.37 for male, 95%CI: 1.12-1.68; OR=1.31 for female, 95%CI: 1.14-1.51) or snoring frequently (OR=1.16 for male, 95%CI: 1.00-1.34; OR=1.39 for female, 95%CI: 1.23-1.57) had a higher risk of diabetes. Using hypnotics regularly was associated with the risk of diabetes in females (OR=1.42, 95%CI: 1.06-1.92). Compared with 8 hours sleep duration daily, shorter sleep duration (≤6 hours) was associated with risk of diabetes in both males (OR=1.37, 95%CI: 1.17-1.60) and females (OR=1.24, 95%CI: 1.08-1.41). No statistical significant association was found between longer sleep duration (≥9 hours) and the risk of diabetes. Conclusion: Sleep problems, including difficulty falling asleep, early morning arousal, snoring frequently and shorter sleep duration, were associated with the risk of diabetes, but no statistical significant association was observed between longer sleep duration and the risk of diabetes.

Failure to activate interleukin 1beta-converting enzyme-like proteases and to cleave retinoblastoma protein in drug-resistant cells.

We previously found that retinoblastoma (RB) is cleaved at the initiation of apoptotic execution. Here we report that when an HL-60 cell line resistant to cytosine arabinoside (Ara-C) was exposed to this anticancer drug, neither RB cleavage nor apoptosis was detected. Consistent with that, processing of interleukin 1beta-converting enzyme (ICE) and CPP32 (an ICE-like protease) was also prevented in these cells. In contrast, treatment of the HL-60-Ara-C-resistant cells with etoposide induced all of these apoptotic events. Furthermore, the etoposide-induced RB cleavage was inhibited by a specific tetrapeptide ICE-like inhibitor. Our results demonstrate that activation of the RB cleavage enzyme, an ICE-like protease, is required for overcoming drug resistance.

Enhancer sharing in a plasmid model containing the alpha-fetoprotein and albumin promoters.

It has been proposed that the alpha-fetoprotein (AFP) enhancers also regulate the adjacent albumin gene, since the -10 kbp albumin enhancer is inactive in a number of cell lines that express albumin. In transfection experiments, the AFP enhancers strongly stimulate the albumin promoter in cells that silence the AFP promoter. These observations led us to develop a plasmid model of AFP-albumin gene switching, in which the albumin and AFP promoters would compete for the three AFP enhancers. However, when AFPCAT + ALBgal genes were combined with the AFP enhancers in one plasmid, both genes were driven at full activity. There was no change in the relative promoter expression over a wide range of transfected DNA concentrations, demonstrating that relative promoter activity was independent of DNA concentration and of promoter concentration, and that neither promoter was limiting the expression of the other. In contrast, a control plasmid containing two albumin promoters showed mutual inhibition, indicating the expected promoter competition. The albumin and AFP promoters noncompetitively shared the three enhancers on this plasmid, resulting in high levels of transcription from both promoters.

Bcl-2- and CrmA-inhibitable dephosphorylation and cleavage of retinoblastoma protein during etoposide-induced apoptosis.

Cell numbers are regulated by a balance between proliferation and apoptosis (programmed cell death). Recent evidence suggests that proteins regulating cell proliferation also mediate apoptosis. Therefore, cellular fate might be determined by cross talk between regulators of cell cycle progression and apoptosis. Previously, we had found that during DNA damage-induced apoptosis, retinoblastoma protein (RB), an important G1/S regulator and tumor suppressor, became dephosphorylated and then immediately cleaved into p48 and p68 fragments. Here, we report that expression of the Bcl-2 oncoprotein, an inhibitor of caspases (interleukin 1 -converting enzyme-like proteases), blocked RB dephosphorylation, RB cleavage and apoptosis in etoposide-treated human Jurkat T cells. In addition, expression of the cowpox virus CrmA protein, a direct inhibitor of caspases, also inhibited both RB changes and apoptosis. Taken together, our findings demonstrate important roles for caspases in the processes of etoposide-induced RB dephosphorylation, RB proteolysis and apoptosis.

The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function.

We have constructed novel chimeric receptors, GAL-ER and GAL-GR, consisting of the DNA-binding domain of the yeast transcription factor GAL4 joined to the C-terminal region containing the hormone-binding domain of either the human estrogen (hER) or human glucocorticoid (hGR) receptor. Stimulation of transcription by GAL-ER and GAL-GR from GAL4-responsive reporter genes was hormone dependent, and the activation function has been localized to the hER or hGR region. Both chimeric receptors recognized GAL4-responsive elements only in the presence of hormone or anti-hormone, yet solely the hormone was capable of stimulating transcription. These and additional results suggest that the hormone plays at least a dual role. First, the hormone, or anti-hormone, is responsible for receptor "transformation" allowing the recognition of responsive DNA elements. Second, the hormone, but not the anti-hormone, can induce a transcription activation function present in the region that contains the hormone-binding domain.

Functional domains of the human estrogen receptor.

Two domains of the human estrogen receptor, responsible for hormone binding (region E) and tight nuclear binding (region C), are essential for the receptor to activate efficiently the transcription of estrogen-responsive genes. Region D, which joins the DNA- and hormone-binding domains, can be altered without affecting activation. Deletion of the N-terminal domain (region A/B) has no effect on activation of a reporter gene containing a vitellogenin estrogen-responsive element (ERE) and the HSV-tk promoter, whereas it severely impairs activation of the human pS2 gene promoter. Deletion of most or all of the hormone-binding domain leads to only about 5% constitutive transcriptional activity, yet these mutants appear to bind efficiently to an ERE in vivo. Apparently, region C recognizes the ERE of target genes, and the hormone-binding domain plays an essential role for efficient activation of transcription.

The yeast UASG is a transcriptional enhancer in human HeLa cells in the presence of the GAL4 trans-activator.

The yeast trans-activator protein GAL4, when expressed in HeLa cells, stimulates transcription from several class B (II) eukaryotic promoters containing GAL4 binding sites either as the full UASG or as synthetic 17-mers. The characteristics of this activation are indistinguishable from those of the SV40 enhancer. Transcription was similarly stimulated from either complex promoter regions containing multiple upstream elements or from a simple promoter region composed of only a TATA box. Addition of a 17-mer GAL4 binding site to the SV40 enhancer resulted in a synergistic enhancement of transcription in the presence of GAL4. Furthermore, chimeras of the human estrogen receptor DNA binding domain and either GAL4 or GCN4 activating "acidic" regions can activate a promoter region controlled by an estrogen-responsive enhancer. Together, these data indicate that the molecular mechanisms responsible for transcriptional enhancement have been conserved from yeast to man.

Mechanism of interferon action III--significance of pppA2'p5'A2'p5'A in the antiviral action of interferon.

This paper is to evidence that the antiviral effect of pppA2'P5'A2'P5'A(2'-5'P3A3) could cover a wide spectrum of viruses, the RNA viruses such as influenza H3N2/77, influenza H1N1/77, ECHO11, rhino, Sendai, Sindbis and VSV, and the DNA viruses such as herpes (type I). In addition, the antiviral effect of 2'-5'P3A3 on ECHO11 virus, as compared with other viruses, is more efficient than that of IFN. It seems likely that 2'-5'P3A3 plays an important role in the antiviral action of IFN. After comparing the action of 2'-5'P3A3 with interferon (IFN), it has appeared that the action of 2'-5'P3A3 is something parallel to that of IFN for most viruses. For a few viruses, however, considerable differences have been observed.