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.

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.

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.

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.

[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.

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.

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.

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.

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.

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.

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.

Is childhood maltreatment associated with murderous ideation and behaviors in adolescents in China?

Previous research has revealed associations between childhood maltreatment (CM) and adverse health behaviors. However, little is known about the relationship between CM and adolescent murderous ideation and behaviors. A total of 5726 middle and high school students completed the Childhood Trauma Questionnaire-Short Form and the Murderous Ideation and Behaviors Questionnaire. The findings revealed that the prevalence rates for murderous ideation, plans, preparation, and attempts were 9.9%, 2.8%, 1.3%, and 0.6%, respectively. The results of multinomial logistic regression models indicated that adolescents who experienced CM were more likely to exhibit murderous ideation and behaviors, with adjusted odds ratios (AORs) ranging from 2.55 to 22.31. Additionally, a significant dose-response relationship was found between the number of CM types experienced and murderous ideation and behaviors (AORs ranging from 1.52 to 2.45). The odds of participants who had experienced three or five types of CM were significantly associated with murderous ideation and behaviors, with AORs ranging from 4.55 to 28.30 and from 5.26 to 85.45, respectively. The findings highlighted that adolescents who engaged in murderous ideation and behaviors were more likely to have a personal history of CM and revealed a dose-response relationship between the number of CM types and murderous ideation and behaviors.

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.

Raman and FTIR spectroscopic studies on two hydroxylated tung oils (HTO) bearing conjugated double bonds.

Tung oil (TO) was used as a model compound to study two hydroxylated tung oils (HTO), prepared from TO by either aminolysis (HTO-am) or alcoholysis (HTO-al). Main bands in Raman and FTIR spectra were initially assigned based on the detailed analysis of the compound spectra before and after exposure to elevated temperature (200°C). The effect of heat treatment in air on spectral bands, and especially on the changes associated with double bonds, were then investigated. In the present work, changes in spectral bands due to heat treatment were compared with those revealed in the previous work of others. The results show that the conjugated triene structure of TO has been retained during alcoholysis and aminolysis, to yield the HTOs studied; yet the change of the triene structure caused by heating is different among the three samples; the H-bonding strength between OH and CO in HTO-am is higher than that in HTO-al; the changes in HTO vOH and vCO bands in FTIR caused by the present heat treatment were significant; for TO, there is a big difference between changes in spectra as caused by thermal exposure, compared to those caused by ageing under UV light or exposure to a catalyst. The present work has laid additional groundwork for further study of the reactions of such triply conjugated double bond structures under different ageing conditions.

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.

miR­132 in atrial fibrillation directly targets connective tissue growth factor.

Atrial fibrillation (AF) is the most frequently occurring, persistent cardiac arrhythmia, and the hallmark of AF­dependent structural remodeling is atrial fibrosis. Connective tissue growth factor (CTGF) is important in the process of fibrosis. The association between miRNA and CTGF in AF­dependent fibrosis remains to be elucidated. The present study aimed to determine if microRNA (miR)­132 was able to regulate CTGF with an anti­fibrotic effect in AF. A total of ten dogs or patients were assigned to control (n=4) and AF groups (n=6). The left atrium of dogs or right atrial appendage of patients was observed. Following this, cardiac fibroblasts of adult rats were treated with or without angiotensin II (Ang II). Furthermore, cardiac fibroblasts were transfected with miR­132 mimics, inhibitor or negative control. The expression of miR­132 and CTGF were analyzed by reverse transcription­quantitative polymerase chain reaction or western blotting. These analyses demonstrated that miR­132 expression was decreased and CTGF increased in the human and canine models with AF. The expression of miR­132 and CTGF protein levels were upregulated in Ang II stimulated cardiac fibroblasts of adult rats. Furthermore, when miR­132 was introduced into cardiac fibroblasts, the expression of miR­132 increased significantly whereas the expression of CTGF decreased. Inverse results were observed when cardiac fibroblasts were transfected with miR­132 inhibitor. The luciferase reporter assay was then performed to confirm that miR­132 may suppress CTGF expression by binding to its 3'­untranslated region. In conclusion, miR­132 may target CTGF in regulating fibrosis in Ang II­treated cardiac fibroblasts. These findings may aid in providing potential therapeutic targets in the treatment of AF.

Further triple integral approach to mixed-delay-dependent stability of time-delay neutral systems.

This paper studies the asymptotic stability for a class of neutral systems with mixed time-varying delays. Through utilizing some Wirtinger-based integral inequalities and extending the convex combination technique, the upper bound on derivative of Lyapunov-Krasovskii (L-K) functional can be estimated more tightly and three mixed-delay-dependent criteria are proposed in terms of linear matrix inequalities (LMIs), in which the nonlinearity and parameter uncertainties are also involved, respectively. Different from those existent works, based on the interconnected relationship between neutral delay and state one, some novel triple integral functional terms are constructed and the conservatism can be effectively reduced. Finally, two numerical examples are given to show the benefits of the proposed criteria.

Global fast dynamic terminal sliding mode control for a quadrotor UAV.

A control method based on global fast dynamic terminal sliding mode control (TSMC) technique is proposed to design the flight controller for performing the finite-time position and attitude tracking control of a small quadrotor UAV. Firstly, the dynamic model of the quadrotor is divided into two subsystems, i.e., a fully actuated subsystem and an underactuated subsystem. Secondly, the dynamic flight controllers of the quadrotor are formulated based on global fast dynamic TSMC, which is able to guarantee that the position and velocity tracking errors of all system state variables converge to zero in finite-time. Moreover, the global fast dynamic TSMC is also able to eliminate the chattering phenomenon caused by the switching control action and realize the high precision performance. In addition, the stabilities of two subsystems are demonstrated by Lyapunov theory, respectively. Lastly, the simulation results are given to illustrate the effectiveness and robustness of the proposed control method in the presence of external disturbances.

Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors.

Blockade of aberrant Wnt signaling is an attractive therapeutic approach in multiple cancers. We developed and performed a cellular high-throughput screen for inhibitors of Wnt secretion and pathway activation. A lead structure (GNF-1331) was identified from the screen. Further studies identified the molecular target of GNF-1331 as Porcupine, a membrane bound O-acyl transferase. Structure-activity relationship studies led to the discovery of a novel series of potent and selective Porcupine inhibitors. Compound 19, GNF-6231, demonstrated excellent pathway inhibition and induced robust antitumor efficacy in a mouse MMTV-WNT1 xenograft tumor model.