Excessive Dpp signaling induces cardial apoptosis through dTAK1 and dJNK during late embryogenesis of Drosophila

<p>Abstract</p> <p>Background</p> <p>To identify genes involved in the heart development of <it>Drosophila</it>, we found that embryos lacking <it>raw </it>function exhibited cardial phenotypes. <it>raw </it>was initially identified as a dorsal open group gene. The dorsal open phenotype was demonstrated to be resulted from the aberrant expression of <it>decapentaplegic </it>(<it>dpp</it>), a member of the tumor growth factor beta (TGF-β), signaling pathway. Despite the role of <it>dpp </it>in pattering cardioblasts during early embryogenesis of <it>Drosophila </it>have been demonstrated, how mutation in <it>raw </it>and/or excessive <it>dpp </it>signaling involves in the differentiating heart of <it>Drosophila </it>has not been fully elaborated at late stages.</p> <p>Results</p> <p>We show that <it>raw </it>mutation produced a mild overspecification of cardial cells at stage 14, but these overproduced cells were mostly eliminated in late mutant embryos due to apoptosis. Aberrant <it>dpp </it>signaling is likely to contribute to the cardial phenotype found in <it>raw </it>mutants, because expression of <it>dpp </it>or constitutively activated <it>thickven </it>(<it>tkv^CA</it>), the type I receptor of Dpp, induced a <it>raw</it>-like phenotype. Additionally, we show that <it>dpp </it>induced non-autonomous apoptosis through TGFβ activated kinase 1 (<it>TAK1</it>), because mis-expression of a dominant negative form of <it>Drosophila TAK1 </it>(<it>dTAK1^DN</it>) was able to suppress cell death in <it>raw </it>mutants or embryos overexpressing <it>dpp</it>. Importantly, we demonstrated that <it>dpp </it>induce its own expression through <it>dTAK1</it>, which also leads to the hyperactivation of <it>Drosophila </it>JNK (DJNK). The hyperactivated DJNK was attributed to be the cause of Dpp/DTAK1-induced apoptosis because overexpression of a dominant negative DJNK, <it>basket </it>(<it>bsk^DN</it>), suppressed cell death induced by Dpp or DTAK1. Moreover, targeted overexpression of the anti-apoptotic P35 protein, or a dominant negative proapoptotic P53 (P53^DN) protein blocked Dpp/DTAK1-induced apoptosis, and rescued heart cells under the <it>raw </it>mutation background.</p> <p>Conclusions</p> <p>We find that ectopic Dpp led to DJNK-dependent cardial apoptosis through the non-canonical TGF-β pathway during late embryogenesis of <it>Drosophila</it>. This certainly will increase our understanding of the pathogenesis of cardiomyopathy, because haemodynamic overload can up-regulate TGF-β and death of cardiomyocytes is observed in virtually every myocardial disease. Thus, our study may provide possible medical intervention for human cardiomyopathy.</p

Interleukin 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients

AbstractAlcoholic liver cirrhosis is a severe form of alcohol-related liver damage. More than 95% of heavy drinkers develop a fatty liver, but only 35% of them develop cirrhosis. We postulate that genetic factors may play a role in this difference. Genetic polymorphisms of the cytokine genes may influence Kupffer cells cytokine genes expression. In this study, we evaluated the promoter polymorphisms of interleukin (IL) 1β, IL 6, IL 10, and tumor necrosis factor alpha (TNFα) and aimed to clarify the association between the polymorphisms and the disease. Forty alcoholic patients with liver cirrhosis and 64 healthy volunteers were included in our investigation. Genotyping on IL 1β –511 T>C, IL 6 –572 G>C, IL 10 –819 C>T, IL 10 –1082 G>A, and TNFα –308 G>A was done. Another 36 patients with recurrent alcoholic pancreatitis were included as an additional control group. Genotyping on IL 10 –819 C>T and IL 10 –1082 G>A was done. The polymorphisms on IL 1 and IL 6 showed no significant association. The p value for TNFα –308 G>A was 0.028 in comparison with healthy volunteers. Although the p value was less than 0.05, it did not reach significance after Bonferroni correction. The p values for IL 10 –819 C>T and IL 10 –1082 G>A were respectively 0.031 and 0.026 in healthy volunteers and 0.028 and 0.023 in the alcoholic pancreatitis group. The results also did not reach significance after Bonferroni correction. Among the participants with the GCC haplotype, healthy volunteers had p = 0.027 (p < 0.05) and an odds ratio (OR) of 0.124 [confidence interval (95%) CI, 0.015–0.997], whereas the alcoholic pancreatitis group had p = 0.023 (p < 0.05) and an OR of 0.106 (95% CI, 0.012–0.912). The odds ratio of people having one ATA haplotype was 6.233 (95% CI, 0.739–52.547) in healthy volunteers and 6.588 (95% CI, 0.727–59.679) in the alcoholic pancreatitis group; the corresponding rate was 10.521 (95% CI, 1.252–88.440) and 12.833 (95% CI 1.408–117.008) for people with two ATA haplotypes. The p values in these groups were 0.031 (p < 0.05) and 0.028 (p < 0.05), respectively. The presence of a GCC haplotype could have protective effect against alcoholic liver disease, whereas the presence of an ATA haplotype could predispose carriers to the disease. The IL 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients

Applying Hybrid PSO to Optimize Directional Overcurrent Relay Coordination in Variable Network Topologies

In power systems, determining the values of time dial setting (TDS) and the plug setting (PS) for directional overcurrent relays (DOCRs) is an extremely constrained optimization problem that has been previously described and solved as a nonlinear programming problem. Optimization coordination problems of near-end faults and far-end faults occurring simultaneously in circuits with various topologies, including fixed and variable network topologies, are considered in this study. The aim of this study was to apply the Nelder-Mead (NM) simplex search method and particle swarm optimization (PSO) to solve this optimization problem. The proposed NM-PSO method has the advantage of NM algorithm, with a quicker movement toward optimal solution, as well as the advantage of PSO algorithm in the ability to obtain globally optimal solution. Neither a conventional PSO nor the proposed NM-PSO method is capable of dealing with constrained optimization problems. Therefore, we use the gradient-based repair method embedded in a conventional PSO and the proposed NM-PSO. This study used an IEEE 8-bus test system as a case study to compare the convergence performance of the proposed NM-PSO method and a conventional PSO approach. The results demonstrate that a robust and optimal solution can be obtained efficiently by implementing the proposal

Electrical tuning of robust layered antiferromagnetism in MXene monolayer

A-type antiferromagnetism, with an in-plane ferromagnetic order and the interlayer antiferromagnetic coupling, owns inborn advantages for electrical manipulations but is naturally rare in real materials except in those artificial antiferromagnetic heterostructures. Here, a robust layered antiferromagnetism with a high N\'eel temperature is predicted in a MXene Cr$_2$CCl$_2$ monolayer, which provides an ideal platform as a magnetoelectric field effect transistor. Based on first-principles calculations, we demonstrate that an electric field can induce the band splitting between spin-up and spin-down channels. Although no net magnetization is generated, the inversion symmetry between the lower Cr layer and the upper Cr layer is broken via electronic cloud distortions. Moreover, this electric field can be replaced by a proximate ferroelectric layer for nonvolatility. The magneto-optic Kerr effect can be used to detect this magnetoelectricity, even if it is a collinear antiferromagnet with zero magnetization