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[Pharmacological Treatments for Alcohol consumption Withdrawal].
AIMS In long QT syndrome (LQTS) patients, modifier genes modulate the arrhythmic risk associated with a disease-causing mutation. Their recognition can improve risk stratification and clinical management, but their discovery represents a challenge. We tested whether a cellular-driven approach could help to identify new modifier genes and especially their mechanism of action. METHODS AND RESULTS We generated human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) from two patients carrying the same KCNQ1-Y111C mutation, but presenting opposite clinical phenotypes. We showed that the phenotype of the iPSC-CMs derived from the symptomatic patient is due to impaired trafficking and increased degradation of the mutant KCNQ1 and wild-type human ether-a-go-go-related gene. In the iPSC-CMs of the asymptomatic (AS) patient, the activity of an E3 ubiquitin-protein ligase (Nedd4L) involved in channel protein degradation was reduced and resulted in a decreased arrhythmogenic substrate. Two single-nucleotide variants (SNVs) on the Myotubularin-related protein 4 (MTMR4) gene, an interactor of Nedd4L, were identified by whole-exome sequencing as potential contributors to decreased Nedd4L activity. Correction of these SNVs by CRISPR/Cas9 unmasked the LQTS phenotype in AS cells. Importantly, the same MTMR4 variants were present in 77% of AS Y111C mutation carriers of a separate cohort. Thus, genetically mediated interference with Nedd4L activation seems associated with protective effects. CONCLUSION Our finding represents the first demonstration of the cellular mechanism of action of a protective modifier gene in LQTS. It provides new clues for advanced risk stratification and paves the way for the design of new therapies targeting this specific molecular pathway. © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.The hematopoietic system is sensitive to radiation. In this research, new aryl sulfone derivatives (XH-201 and XH-202) containing a nitrogen heterocycle were designed and synthesized and their radio-protective efficacies with regard to the hematopoietic system were evaluated. XH-201 administration significantly increased the survival rate of mice after 8.0 Gy total body irradiation (TBI). The results showed that XH-201 treatment not only increased the white blood cells, platelets counts and the percentage of hematopoietic progenitor cells and hematopoietic stem cells in mice exposed to 4.0 Gy TBI but also decreased DNA damage, as determined by flow cytometric analysis of histone H2AX phosphorylation. In addition, our data demonstrated that XH-201 decreased the mitochondrial reactive oxygen species (ROS) levels in hematopoietic cells. Overall, these data suggest that XH-201 is beneficial for the protection of the hemoatopoietic system against radiation-induced injuries. © The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.Forensic entomologists usually estimate the minimum postmortem interval (PMImin) using the time required for the oldest immature insects found on the corpse to grow to its development stage and age at the time of discovery. The sheep blow fly Lucilia sericata (Meigen, 1826) is a carrion fly found nearly worldwide, and important in forensics. We studied the development time of L. sericata from egg to adult at constant temperatures of 16, 19, 22, 25, 28, 31, and 34°C, and found that the times required are 913.2 ± 19.4, 588.8 ± 35.8, 459.8 ± 15.2, 373.2 ± 15.3, 308.0 ± 9.7, 272.5 ± 9.2, and 267.5 ± 10.5 h, respectively. We established three development models to infer the age of the immature insect isomegalen diagram, isomorphen diagram, and thermal summation model. click here In addition, a regression analysis was performed on the relationship between body length and total development time from hatching to dispersing. The thermal summation constant during the development of L. sericata is 6023.2 degree hours and development threshold temperature is 9.19°C. The results of this experiment provide a basis for the use of L. sericata in the estimation of PMImin. © The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America.All rights reserved. For permissions, please e-mail [email protected] Recent studies suggest that microRNAs (miRNAs) can participate in depression pathogenesis by altering a host of genes that are critical in corticolimbic functioning. The present study focuses on examining whether alterations in the miRNA network in the amygdala are associated with susceptibility or resiliency to develop depression-like behavior in rats. METHODS Amygdala-specific altered miRNA transcriptomics were determined in a rat depression model following next-generation sequencing method. Target prediction analyses (cis- and trans) and qPCR-based assays were performed to decipher the functional role of altered miRNAs. miRNA-specific target interaction was determined using in vitro transfection assay in neuroblastoma cell line. miRNA-specific findings from the rat in vivo model were further replicated in postmortem amygdala of major depressive disorder (MDD) subjects. RESULTS Changes in miRNome identified 17 significantly upregulated and 8 significantly downregulated miRNAs in amygdala of learnswitching mechanism could be active between miR-128-3p and RNA binding protein Arpp21 to gain control over their target genes such as Lef1. CONCLUSION Our study suggests that in amygdala a specific set of miRNAs may play an important role in depression susceptibility, which could potentially be mediated through Wnt signaling. © The Author(s) 2020. Published by Oxford University Press on behalf of CINP.BACKGROUND AND AIMS Carnivorous plants can enhance photosynthetic efficiency in response to prey nutrient uptake but the underlying mechanisms of increased photosynthesis are largely unknown. Here we investigated photosynthesis in the pitcher plant Nepenthes x ventrata in response to different prey-derived and root mineral nutrition to reveal photosynthetic constrains. METHODS Nutrient-stressed plants were irrigated with full inorganic solution or fed with four different insects wasps, ants, beetles and flies. Full dissection of photosynthetic traits was achieved by means of gas exchange, chlorophyll fluorescence and immunodetection of photosynthesis-related proteins. Leaf biochemical and anatomical parameters together with mineral composition, N and C isotopic discrimination of leaves and insects were also analysed. KEY RESULTS Mesophyll diffusion was the major photosynthetic limitation for nutrient-stressed Nepenthes x ventrata, while biochemistry was the major photosynthetic constriction after nutrient application.
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