Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology RESEARCH

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests tha...
Source: Genome Research - Category: Genetics & Stem Cells Authors: Tags: RESEARCH Source Type: research

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Authors: Rombauts A, Abelenda-Alonso G, Cuervo G, Gudiol C, Carratalà J Abstract INTRODUCTION: Despite adequate antibiotic coverage, community-acquired pneumonia (CAP) remains a leading cause of hospitalization and mortality worldwide. It induces both a local pulmonary and a systemic inflammatory response, particularly significant in severe cases. The intensity of the dysregulated host response varies from patient to patient and has a negative impact on survival and other outcomes. AREAS COVERED: This comprehensive review summarizes the pathophysiological aspects of the inflammatory response in CAP, brie...
Source: Expert Review of Anti-Infective Therapy - Category: Infectious Diseases Tags: Expert Rev Anti Infect Ther Source Type: research
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Source: European Journal of Pediatrics - Category: Pediatrics Source Type: research
In this study, we explored its health effects on the female offspring of mice that had been exposed during pregnancy. We found that exposure of pregnant mice to nitenpyram resulted in decreased levels of serum triglycerides, total cholesterol, and glucose in female offspring, and additional research uncovered gut microbiota disturbances, accompanied by abnormal fecal metabolic profiles. Based on Pearson correlation analysis, we found that decreased abundance of Lactobacillus may play the most critical role, and changes in gut bacterial purine metabolism, BCAAs metabolism, and the TCA cycle are all closely related to the ab...
Source: Chemosphere - Category: Chemistry Authors: Tags: Chemosphere Source Type: research
Publication date: December 2020Source: Journal of Functional Foods, Volume 75Author(s): Jian Zhang, Xiaohang Fu, Wenhui Li, He Li, Zhiwei Ying, Xinqi Liu, Liduan Yin
Source: Journal of Functional Foods - Category: Nutrition Source Type: research
Authors: Ebrahimi-Zadehlou P, Najafpour A, Mohammadi R Abstract PURPOSE: It is compulsory to make a tension-free, end-to-end repair in transected injuries. However, when it comes to longer defects, placement of an autograft or nerve conduits is required. The present study was designed to assess regenerative potential of silymarin nanoparticles loaded into chitosan conduit on peripheral nerve regeneration in a transected sciatic nerve model in rat. METHODS: In NML group left sciatic nerve was exposed through a gluteal muscle incision and after careful hemostasis skin was closed. In TSC group left sciatic nerve w...
Source: Neurological Research - Category: Neurology Tags: Neurol Res Source Type: research
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Source: European Archives of Oto-Rhino-Laryngology - Category: ENT & OMF Source Type: research
Authors: Gualtieri B, Marzano AV, Grando S Abstract In this review, we recap current knowledge about non-desmoglein autoantigens in atypical forms of autoimmune pemphigus. More than 50 keratinocyte proteins, including adhesion molecules, receptors and enzymes as well as mitochondrial proteins can be targeted, leading to alterations in numerous intracellular signaling pathways. Patients with pemphigus herpetiformis feature various combinations of antibodies to desmogleins 1 and 3 and desmocollins 1-3. Pemphigus vulgaris patients who do not have antibodies to desmogleins develop typical clinical and histological feat...
Source: Giornale Italiano di Dermatologia e Venereologia - Category: Dermatology Tags: G Ital Dermatol Venereol Source Type: research
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Source: The Tohoku Journal of Experimental Medicine - Category: Research Authors: Tags: Tohoku J Exp Med Source Type: research
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Source: RSC - Soft Matter latest articles - Category: Chemistry Authors: Source Type: research
AbstractIntroductionWith multiple proven benefits, statin therapy has become the most critical advance in stroke prevention. We aimed to evaluate the risk factors and the effect of poor adherence or statin interruption on the clinical outcomes of ischemic stroke.MethodsThis prospective cohort study included patients admitted with acute ischemic stroke between 2014 and 2018. Consecutive patients were distinguished into subgroups according to the adherence and withdrawal of statin. All participants were followed for 24  months. The outcomes included stroke recurrence, major cardiovascular events, all-cause mortality, an...
Source: Neurological Sciences - Category: Neurology Source Type: research
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