Gestational bisphenol A exposure advances puberty onset in female offspring: Critical time window identification.

Increasing evidence shows that the early onset of puberty in female offspring may be caused by maternal prenatal exposure to bisphenol A (BPA) during pregnancy; however, the critical time window of maternal prenatal BPA exposure remains unknown. Here, we identify the critical time window of gestational BPA exposure that induces early onset of puberty in female offspring. Pregnant CD-1 mice were gavaged with BPA (8 mg/kg) daily during the early gestational stage (GD1-GD6), middle gestational stage (GD7-GD12) or late gestational stage (GD13-GD18). We show that maternal BPA exposure during the early and middle gestational stages could advance the vaginal opening time and increase the serum levels of kisspeptin-10 and GnRH in the female offspring at PND 34. Mechanistically, maternal BPA exposure during early and middle gestation could significantly increase CpG island methylation in the Eed gene promoters but reduce the mRNA expression of Eed in the hypothalamus tissues of the female offspring. In conclusion, the critical period of maternal BPA exposure-induced early onset of puberty in female offspring is early and middle gestation; this BPA-induced early onset of puberty might be partly attributed to epigenetic programming of the Eed gene in the hypothalamus. This study provides important insights regarding the relationship and the mechanisms between BPA and offspring pubertal development.

Histone Deacetylase 1 Depletion Alleviates Coronary Heart Disease Via the MicroRNA-182-Mediated Transforming Growth Factor ß/Smad Signaling Pathway.

ABSTRACT: Histone deacetylase (HDAC) determines the acetylation status of histones, thereby regulating gene expression. HDAC inhibitors have been demonstrated to suppress cardiomyocyte growth in vitro and in vivo. We assessed here whether HDAC1 exerts an aggravating effect on coronary heart disease (CHD). Epigenetic probe array revealed that HDAC1 was overexpressed in patients with CHD. HDAC1 was then downregulated in rat cardiomyocytes, and microRNA microarray analysis was performed to detect downstream targets of HDAC1, followed by chromatin immunoprecipitation validation. HDAC1 inhibited miR-182 expression through deacetylation. miR-182 was poorly expressed in patients with CHD. Using enzyme-linked immunosorbent assay, Reverse transcription-quantitative PCR, hematoxylin-eosin staining, terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling assay, and immunohistochemistry, we observed that HDAC1 downregulation promoted cardiac function, restored lipid levels, reduced myocardial injury markers and inflammatory factors, and alleviated myocardial tissue damage and apoptosis in CHD rats. By contrast, miR-182 downregulation exacerbated injury in rats in the presence of HDAC1 knockdown. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes of miR-182 were mainly enriched in the transforming growth factor (TGF)-ß/Smad pathway. Western blot also validated that HDAC1/miR-182 modulated the TGF-ß/Smad pathway activity. Our results demonstrated that HDAC1 repressed miR-182 and activated the TGF-ß/Smad pathway to promote CHD.

Donepezil Prevents ox-LDL-Induced Attachment of THP-1 Monocytes to Human Aortic Endothelial Cells (HAECs).

Oxidized low-density lipoprotein (ox-LDL)- induced endothelial insults plays an important role in the pathogenesis of atherosclerosis. Donepezil is a well-known acetylcholinesterase inhibitor with its primary application being the treatment of Alzheimer's disease. More recently, there has been increased interest in donepezil as an antiatherosclerosis treatment as it possesses a host of relevant and potentially beneficial properties. In the present study, we found that donepezil could reduce the expression of lectin-type oxidized low-density lipoprotein receptor-1 (LOX-1) in human aortic endothelial cells (HAECs). We found that donepezil could suppress the expression of intercellular adhesion molecule-1 (ICAM-1), which recruits monocytes to adhere to the endothelium, by more than half. Another key finding of our study is that donepezil could reduce the expression of tumor necrosis factor receptor-α (TNF-α) and interleukin-6 (IL-6) by more than half at both the mRNA and protein transcriptional levels. Donepezil also reduced the expression of tissue factor (TF), which is considerably upregulated in atherosclerotic lesions, by more than half. Finally, we turned our attention to the early growth response protein-1 (Egr-1) for its potential role in mediating the effects of donepezil. Through our Egr-1 overexpression experiment, we found that overexpression of Egr-1 almost completely abolished the effects of donepezil described above. Thus, the effects of donepezil are likely mediated through downregulation of Egr-1. These findings provide evidence that donepezil may exert protective effects against atherosclerosis.

[Dietary literacy questionaire for school-age children's daily diet providers and its reliability and validity].

OBJECTIVE: Development of dietary literacy questionnaire for school-age children's diet providers and evaluation of its reliability and validity. METHODS: Based on the main theoretical basis of dietary literacy definition, a pool of dietary literacy questionnaires for school-age children's daily diet providers was prepared by expert group discussion through the Delphi method. The initial scale was formed by method such as expert panel discussions. A stratified cluster sampling method was used to investigate the daily dietary providers of 1137 urban and rural children in Hefei in November 2018. The t-test and Pearson correlation coefficient were used to analyze the decision value, correlation analysis and internal consistency analysis. The structural equation model was constructed to evaluate the structural validity of the questionnaire. One week after the interval, 90 school-age children's daily diet providers using random sampling were retested, and the test-retest reliability was analyzed. The reliability of the questionnaire was evaluated using Cronbach'α, Guttman coefficient, and structural validity. Further analysis of the differences in the educational level of children's diet providers and the scores of urban and rural questionnaires. RESULTS: A total of 1043 valid questionnaires were returned. 894(85. 7%) were children's parents and 128(12. 3%) were children's grandparents or maternal grandparents. After expert group discussion, the questionnaire preliminarily identified four first-level indicators to provide attitudes, actions, skills and environment for daily dietary providers about children's meals. The average authority coefficient of experts was 0. 87. The study finally retained 30 items, including the four dimensions of attitudes, actions, skills and environment provided by the daily diet providers of school-age children to the children's diet. The cumulative variance contribution rate was 52. 470%. The Cronbach' α coefficient of the questionnaire was 0. 874, the split-half reliability was 0. 813, and the test-retest reliability was 0. 878. Structural equation model fitting index: χ~2/df=2. 28, RMSEA=0. 042, NFI=0. 841, GFI=0. 927, AGFI=0. 912, RFI=0. 821, IFI=0. 904, TLI=0. 891, CFI=0. 903. In addition, the differences in scores of different education levels, urban and rural questionnaires and different dietary behaviors of children were statistically significant(P<0. 05), and the questionnaires had good discriminant validity. CONCLUSION: The reliability and validity of the dietary literacy questionnaire for school-age children's daily diet providers is good, and it can provide reference for evaluating the dietary quality of school-age children's dietary providers.

Is involvement in school bullying associated with increased risk of murderous ideation and behaviours among adolescent students in China?

BACKGROUND: School bullying is a destructive behaviour common among adolescents that can sometimes escalate to criminal activity. This study aimed to examine the association between four types of school bullying (i.e., physical, verbal, relational, and cyber) and murderous ideation and behaviours (i.e., ideation, plans, preparation, and attempts) among adolescent students. METHODS: Data were collected from 5726 middle and high school students using self-administered questionnaires in December 2013. The participants were selected using a 3-stage random cluster-sampling strategy. The participants were asked about the frequency of their bullying experiences in the past two months and the frequencies of their murderous ideation and behaviours in the past six months. Multivariate logistic regressions were performed to explore the association between school bullying and murderous ideation and behaviours. RESULTS: Each type of school bullying perpetration was associated with murderous ideation and behaviours, as was each type of bullying victimization. Students who experienced more types of school bullying perpetration and victimization were more likely to report murderous ideation and behaviours. Moreover, the number of types of bullying perpetration and victimization had a dose-response association with murderous ideation and behaviours (aOR min = 1.45, aOR max = 2.72), as did the frequency of involvement in bullying perpetration and victimization (aOR min = 1.33, aOR max = 2.00). Being a bully-victim was a risk factor for murderous ideation and behaviours (aOR min = 3.88, aOR max = 7.24). CONCLUSIONS: Each type of school bullying was associated with an increased risk for murderous ideation and behaviours among adolescents. Dose-response relationships between the frequency of bullying and number of bullying types experienced and murderous ideation and behaviours were found in this study. Future studies are warranted to confirm our findings and explore the mechanisms underlying the relationship between school bullying and murderous ideation and behaviours.

[Effects of on-pump beating-heart coronary artery bypass grafting for left-main patients].

OBJECTIVE: To explore the value of on-pump beating-heart coronary artery bypass grafting (OnP-BH CABG) for left-main patients with coronary heart disease through a comparative study with conventional coronary artery bypass grafting (CCABG). METHODS: The clinical data were retrospectively analyzed for 66 patients of OnP-BH and 48 control cases undergoing CCABG from January 2009 to January 2012 at Department of Cardiac Surgery, People's Hospital of Zhengzhou University. RESULTS: OnP-BH group had a better clinical outcome than CCABG group. There were obvious statistical difference in cardiopulmonary bypass (CPB) time, mean ventilation time, intensive care unit stay and recovery time of plasma cardiac troponin I (OnP-BH group vs CCABG group:(89 ± 25) vs (117 ± 28) min, (15 ± 14) vs (27 ± 19) h, (57 ± 27) vs (79 ± 34) h, (6.2 ± 1.8) vs (7.0 ± 2.4) d, all P < 0.05). The data of preoperative cTnI showed no significant difference between two groups (P > 0.05) .However, after CPB, significant intergroup difference existed in the level of cTnI (µg/L) OnP-BH group vs CCABG group: (0.5 h after CPB: (0.132 ± 0.022) vs (0.265 ± 0.014) , 1 h after CPB: (0.341 ± 0.027) vs (0.572 ± 0.046) , 1 h after operation: (0.641 ± 0.036) vs (0.932 ± 0.047) , 6 h after operation: (1.212 ± 0.765) vs (1.627 ± 0.542) and 24 h after operation: (1.496 ± 0.263) vs (1.734 ± 0.328) , all P < 0.05). CONCLUSIONS: On-pump beating-heart coronary artery bypass grafting is a feasible surgical approach for left-main patients. And it has a low risk and causes less myocardial damage.

Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases.

Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren's syndrome and mixed connective tissue disease.

MicroRNA-155 inhibition attenuates myocardial infarction-induced connexin 43 degradation in cardiomyocytes by reducing pro-inflammatory macrophage activation.

Background: Degradation of pro-inflammatory macrophage-mediated connexin 43 (Cx43) plays an important role in post-myocardial infarction (MI) arrhythmogenesis, microRNA (miR)-155 produced by macrophages has been shown to mediate post-MI effects. We hypothesized that miR-155 inhibition attenuated MI-induced Cx43 degradation by reducing pro-inflammatory macrophage activation. Methods: MI was induced by permanent ligation of the left anterior descending coronary artery in male C57BL/6 mice. Lipopolysaccharide (LPS)-stimulated mice bone marrow-derived macrophages (BMDMs) and hypoxia-induced neonatal rat cardiomyocytes (NRCMs) were used in vitro models. qRT-PCR, Western-blot and immunofluorescence were used to analyze relevant indicators. Results: The expression levels of miR-155, interleukin-1 beta (IL-1ß), and matrix metalloproteinase (MMP)7 were higher in MI mice and LPS-treated BMDMs than in the sham/control groups, treatment with a miR-155 antagomir reversed these effects. Moreover, miR-155 inhibition reduced ventricular arrhythmias incidence and improved cardiac function in MI mice. Cx43 expression was decreased in MI mice and hypoxia-exposed NRCMs, and hypoxia-induced Cx43 degradation in NRCMs was reduced by application of conditioned medium from LPS-induced BMDMs treated with the miR-155 antagomir, but increased by conditioned medium from BMDMs treated with a miR-155 agomir. Importantly, NRCMs cultured in conditioned medium from LPS-induced BMDMs transfected with small interfering RNA against IL-1ß and MMP7 showed decreased hypoxia-mediated Cx43 degradation, and this effect also was diminished by BMDM treatment with the miR-155 agomir. Additionally, siRNA-mediated suppressor of cytokine signaling 1 (SOCS1) knockdown in LPS-induced BMDMs promoted Cx43 degradation in hypoxia-exposed NRCMs, and the effect was reduced by the miR-155 inhibition. Conclusions: MiR-155 inhibition attenuated post-MI Cx43 degradation by reducing macrophage-mediated IL-1ß and MMP7 expression through the SOCS1/nuclear factor-κB pathway.

[Study on the solid state transformation of PET/nano-CaCO3 composites by variable temperature FTIR spectroscopy].

Solid state transformation of crude poly (ethylene terephthalate)(PET) and PET/nano-CaCO3 (MPET) composites were studied by variable temperature FTIR spectroscopy during the heating process from 40 to 250 degrees C. The effects of nanometer calcium carbonate(nano-CaCO3) on the solid state transformation and crystal correlation bands of MPET composites were analyzed by the curves of the ratio of 1 342 and 1 410 cm(-1) absorbency(A1 342/A1 410) with temperature increasing, and together with DSC curves in the same condition. The results showed that the crystallization degrees of crude PET and MPET are obviously different in this condition by adding nano-CaCO3 particles as inhomogeneous nucleating agents.

Improved Sliding Mode Control for Finite-Time Synchronization of Nonidentical Delayed Recurrent Neural Networks.

This brief further explores the problem of finite-time synchronization of delayed recurrent neural networks with the mismatched parameters and neuron activation functions. An improved sliding mode control approach is presented for addressing the finite-time synchronization problem. First, by employing the drive-response concept and the synchronization error of drive-response systems, a novel integral sliding mode surface is constructed such that the synchronization error can converge to zero in finite time along the constructed integral sliding mode surface. Second, a suitable sliding mode controller is designed by relying on Lyapunov stability theory such that all system state trajectories can be driven onto the predefined sliding mode surface in finite time. Moreover, it is found that the presented control approach can be conveniently verified and does not need to solve any linear matrix inequality (LMI) to guarantee the finite-time synchronization of delayed recurrent neural networks. Finally, three numerical examples are exploited to demonstrate the effectiveness of the presented control approach.

Interaction effects of co-consumption of fast food and sugar-sweetened beverages on psychological symptoms: Evidence from a nationwide survey among Chinese adolescents.

BACKGROUND: Although fast food and sugar-sweetened beverages (SSBs) consumption have been closely linked to childhood and adolescent obesity, the data regarding their co-consumption and relationship to mental health remains controversial. METHODS: A multi-centered population-based survey was conducted among Chinese adolescents from grades 7 to 12. Data about participants' consumption of fast foods and SSBs were obtained from self-reported questionnaires. Psychological symptoms were assessed using the Multi-dimensional Sub-health Questionnaire of Adolescents (MSQA). The association between co-consumption of fast food and SSBs and psychological symptoms was assessed using quantile regression analysis, adjusting for covariates. RESULTS: Approximately one-fifth of the 14,500 participants reported psychological symptoms. The regression coefficient (ß) value increased as the quantile of fast food, SSBs, and co-consumption increased in the quantile regression model, and the model had an excellent goodness-of-fit (F = 192.51, p < 0.001). In the interaction model, fast food and SSBs in combination were associated with greater odds of psychological symptoms (aOR = 1.90, 95% CI: 1.69, 2.12). The synergy index, relative excess risk of interaction, and attributable proportions were 1.86 (95% CI: 1.17, 2.96), 0.4 (95% CI: 0.20, 0.63), and 0.22 (95% CI: 0.11, 0.33), respectively. LIMITATIONS: Information bias is inevitable in self-reported data among participants. The ability to assess causal relationships is reduced by a cross-sectional study design. CONCLUSIONS: Our findings suggest that co-consumption of fast food and SSBs was cross-sectionally associated with mental health problems among adolescents.

Sensitive periods for the effect of bullying victimization on suicidal behaviors among university students in China: The roles of timing and chronicity.

OBJECTIVE: To examine whether timing and chronicity of bullying victimization (BV) play a significant role in linking exposure to BV to suicidal behaviors in university students. METHODS: A multistage stratification sampling method was used to select a sample of 4034 university students (18-23 years, mean age 20.38±1.35 years, 41.9% female). We used latent class analysis and developmental-stage-based characterizations of BV timing and chronicity to explore the sensitive periods for the effect of BV on suicidal behaviors. RESULTS: The prevalence rates of suicidal ideation, plans and attempts among our study participants were 9.9%, 3.0% and 1.3%, respectively. BV during primary school (OR = 2.12, 95% CI: 1.55-2.90) and secondary school (OR = 2.65, 95% CI: 1.80-3.90) was associated with suicidal ideation among university students. We identified four classes of life-course BV experiences (low BV, 73.8%; moderate BV, 18.6%; secondary school BV, 4.4% and persistent BV, 3.2%). Persistent BV was associated with 2.50 times (95% CI: 1.56-3.98), 2.98 times (95% CI: 1.48-6.02), and 6.13 times (95% CI: 2.48-15.14) higher risk of suicide ideation, plans, and attempts, respectively. Both moderate BV (OR = 1.75, 95% CI: 1.35-2.26) and secondary school BV (OR=2.01, 95% CI: 1.29-3.12) were positively correlated with suicidal ideation. Furthermore, there was a dose-response relationship between the number of periods of BV and suicidal behaviors. LIMITATIONS: This study was a cross-sectional study based on self-reported measures, especially BV experiences in each school stage. CONCLUSIONS: This study identifies sensitive periods for the effect of BV on suicidal behaviors among university students in China.

Discovery of pyrimidine benzimidazoles as Src-family selective Lck inhibitors. Part II.

A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src-family kinases (SFKs). These type II inhibitors were optimized using a cellular Lck-dependent proliferation assay and are capable of inhibiting Lck at single-digit nanomolar concentrations. This scaffold is likely to serve a valuable template for developing potent inhibitors of a number of SFKs.

The impact of swimming training on physiological and psychological indicators in individuals of different age groups: a cross-sectional study

Swimming training is a kind of aquatic exercise that has been shown to be beneficial to physical fitness at any age. This study aimed to determine how mental and physical aspects of swimming affect aerobic and anaerobic capacity describes the physiologicaland psychological effects of swimming training at different ages. This studyexamines how swimming impacts youthful and elderly cardio-respiratory fitness, muscular strength, flexibility, and body composition. A correlation and stepwise regression analysis was performed on the information gathered from a RESTQ-76 sport questionnaire, aHeart Rate Variability (HRV) test, and the efforts of swimmers to improve their aerobic and anaerobic swimming performance. We also investigate the benefits that swimming has on lowering stress, boosting self-esteem, and improving mental health for people of varying ages. We useSPSS version 17.0 was used for the statistical analysis. An examination of the relevant research reveals that swimmers of all ages enjoy significant advantages as a result of their training, including enhancements to their physical and mental health. In that case, they can be able to tailor swimming programs to match the changing physiological and psychological needs of their swimmers. Findings from this study add to a growing body of evidence that open-water swimming is perceived to have positive effects on participants' mental and physical health regardless of age and can be used to inform co-created policy formation to advance outdoor recreation possibilities that are safer, healthier, and more sustainable about this expanding outside activity (AU)

Association between different stages of precollege school bullying and murder-related psychological behaviors among college students in Anhui Province, China.

Little is known about the relationship between precollege school bullying and murder-related psychological behaviors. The present study aims to examine that relationship in Chinese college students using a cross-sectional study. Self-report data were collected from 4034 college students in Anhui Province using a proportional stratified cluster sampling method. Four types of school bullying (i.e., physical, verbal, relational, and cyber) with bullies and victims and two periods (i.e., primary and secondary) were measured. The prevalence rates of murderous ideation, plans, preparation, and attempts were 6.9%, 2.5%, 1.8%, 1.4%, respectively. Different stages of precollege cyber bullying were associated with murder-related psychological behaviors for both bullies (primary: AORs = 2.78 to 15.67; secondary: AORs = 2.43 to 9.99; both periods: AORs = 2.26 to 14.04) and victims (primary: AORs = 2.87 to 16.57; secondary: AORs = 1.89 to 4.49; both periods: AORs = 3.68 to 21.48). A dose-response relationship was found, such that college students with a bullying perpetration index of two types and more were more likely to have murder-related psychological behaviors than those who were not bullied. Notably, both primary and secondary school bullying, especially cyber forms, were more likely to be associated with murder-related psychological behaviors. Therefore, it is necessary to develop school bullying preventive measures beginning in primary school.

The association between childhood physical disability or long-term health problems and depression among adolescents in China: Mediating effect of childhood maltreatment.

BACKGROUND: Increasing evidence has suggested that childhood maltreatment might mediate the association between physical disability or chronic illness and depression among adolescents. We sought to identify whether childhood maltreatment mediated the relationship between physical disability or long-term health problems and depression in Chinese adolescents. METHOD: A total of 5726 middle and high school students aged 12-18 years old were chosen to participant in this study. Participants completed the self-reported questionnaire on childhood physical or long-term health problems, childhood maltreatment and depression. RESULTS: The results showed that there were significant differences of childhood maltreatment, depression between adolescents with childhood physical disability or long-term health problems and those without. Physical abuse, sexual abuse, emotional abuse, physical neglect and emotional neglect mediated the association between childhood physical disability or long-term health problems and depression accounting for 8.7%, 20.6%, 14.5%, 16.3% and 14.7% of the total effect of physical disability or long-term health problems on depression in each single mediator model respectively, whereas the indirect effect of emotional abuse and sexual abuse in the association between physical disability or long-term health problems and depression explained 15.6% and 8.0% of the total effect in a multiple mediation model respectively. CONCLUSION: Childhood physical disability or long-term health problems was associated with the increased risk for depression, and the associations between childhood physical disability and long-term health problems and depression were partially mediated by childhood maltreatment experiences. Childhood maltreatment exposure should be considered to prevent depression among adolescents with childhood physical disability or long-term health problems.

Analysis of multiple H-bond interactions in self-assembly between polyurethane with pendent carboxyl and poly(4-vinylpyridine).

As an extension study, FTIR and molecular simulation methods were combined in the present paper to analyze the H-bond interactions resulting from multiple donors and acceptors that have led to self-assembly based on segmented polyurethane with carboxyl (PUc) and poly(4-vinylpyridine) (P4VP) in our previous work. Of them, FTIR was used to analyze the H-bonding types and interactions as well as their changes before and after self-assembly; molecular mechanics (MM/COMPASS) was used to study the effect of possible conformations on the H-bonds involved and analyze the most probable H-bond patterns; quantum mechanics (QM/B3LYP) was used to help confirm the experimental FTIR band assignments and calculate the H-bond energy. It was found that two types of H-bonds exist, namely, COOH...P4VP (type I) and (OCO)NH...P4VP (type II), based on OH and NH as the strong donors in the interaction between PUc and P4VP. Strong evidence has been obtained for a type II H-bond, which is the specialty in PUc/P4VP assembly. The type I and type II H-bonding energies are -11.293 and -7.150 kcal/mol, respectively. The forming probability of the type I H-bond accounts for 95.87%, while that of the type II H-bond is 4.13%, showing the primary driving force for the assembly based on PUc and P4VP is still the H-bond between COOH and P4VP, yet the H-bonds based on NH and pyridyl in P4VP cannot be ignored.

Discovery of pyrimidine benzimidazoles as Lck inhibitors: part I.

A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src kinase family. Highly efficient parallel syntheses were devised to prepare analogues for SAR studies. A number of these 4-amino-6-benzimidazole-pyrimidines exhibited single-digit nanomolar IC(50)s against Lck in biochemical and cellular assays. These 4-amino-6-benzimidazole-pyrimidines represent a new class of tyrosine kinase inhibitors.

Improved Stability Criterion for Recurrent Neural Networks With Time-Varying Delays.

In this brief, the problem of delay-dependent stability of recurrent neural networks with time-varying delays is studied. A newly augmented Lyapunov-Krasovskii functional (LKF) that considers the information of the nonzero lower bound of time-varying delays is developed. Moreover, the information of the delayed state terms is not considered as elements of augmented vectors when constructing the LKF. An improved stability criterion with the framework of linear matrix inequalities is derived by employing the integral inequality and reciprocally convex combination. With the comparison to the existing ones, the developed stability criterion for neural networks has less conservatism and complexity. Finally, two widely used numerical examples are given to show the effectiveness and superiority of the obtained stability criterion.

Role of Sprouty1 (Spry1) in the pathogenesis of atrial fibrosis.

Atrial fibrosis is the hallmark of atrial fibrillation (AF) dependent structure remodeling. Besides, sprouty 1 (Spry1) plays a key role in the process of fibrosis. In this study, we investigated whether Spry1 could regulate TGF-ß1 in atrial fibrosis. Ten dogs or patients were assigned to control (n=4) and AF group (n=6). The left atrium of dogs or right atrial appendage of patients was taken. After that, cardiac fibroblasts were treated with or without angiotensin II (Ang II). Furthermore, cardiac fibroblasts were transfected with lentivirus of Spry1 over-expression vector, Spry1 shRNA or negative control (NC). And the protein expression of Spry1 and TGF-ß1 was analyzed by western blot and immunohistochemistry. The results showed that TGF-ß1 was highly expressed while Spry1 was lowly expressed in the models of human and canine with AF. Besides, the protein expression of TGF-ß1 was up-regulated and Spry1 was down-regulated in Ang II stimulated cardiac fibroblasts. Furthermore, when Spry1 was knockdown in Ang II-induced cardiac fibroblasts, the cell proliferation and the TGF-ß1 protein expression increased significantly, while Spry1 over-expression showed inverse results. Our results demonstrated that Spry1 may target TGF-ß1 in regulating fibrosis. These findings may provide possible therapeutic targets in atrial fibrosis.