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: Carvalho Vasconcelos R, Ferreira C, de Araújo EM, Motta F, Bomio M, de Araújo Júnior RF, Paiva DFF, Pirih FQ, da Silva JSP, Chan AB, Cruz LJ, Ishii M, de Medeiros CACX, Coelho Bernardo Guerra G, de Araújo AA Abstract The aim of this study was to characterize and evaluate zirconia/hydroxyapatite in a critical size calvarial defect model in rats. Zirconia/hydroxyapatite (80/20) scaffold was characterized by X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM). Critical size (8 mm) calvarial defects were created in wistar rats (n=48) and divided into four groups (90 days)...
Source: American Journal of Translational Research - Category: Research Tags: Am J Transl Res Source Type: research
CONCLUSION: Higher MS values were related with lower WC in adults. More evidence from longitudinal studies with high methodological rigor is needed to elucidate the relationship between MS and CVD among adults. PMID: 32660293 [PubMed - as supplied by publisher]
Source: The Physician and Sportsmedicine Online - Category: Sports Medicine Tags: Phys Sportsmed Source Type: research
Authors: Kiontke S, Göbel T, Brych A, Batschauer A Abstract DASH (Drosophila, Arabidopsis, Synechocystis, human)-type cryptochromes (cry-DASHs) form one subclade of the cryptochrome/photolyase family (CPF). CPF members are flavoproteins that act as DNA-repair enzymes (DNA-photolyases), or as UV-A/blue light photoreceptors (cryptochromes). In mammals, cryptochromes are essential components of the circadian clock feed-back loop. Cry-DASHs are present in almost all major taxa and were initially considered as photoreceptors. Later studies demonstrated DNA-repair activity that was, however, restricted to UV-lesions...
Source: Biological Chemistry - Category: Chemistry Tags: Biol Chem Source Type: research
Authors: Rout A, Tantry US, Novakovic M, Sukhi A, Gurbel PA Abstract INTRODUCTION: Achieving reperfusion immediately after acute myocardial infarction improves outcomes; despite this, patients remain at a high risk for mortality and morbidity at least for the first year after the event. Ischemia-reperfusion injury (IRI) has a complex pathophysiology and plays an important role in myocardial tissue injury, repair, and remodeling. AREAS COVERED: In this review, the authors discuss the various mechanisms and their pharmacological agents currently available for reducing myocardial ischemia-reperfusion injury (IRI)....
Source: Expert Opinion on Pharmacotherapy - Category: Drugs & Pharmacology Tags: Expert Opin Pharmacother Source Type: research
Conditions:   Rupture, Aortic;   Aneurysm, Abdominal Aortic;   Aneurysm, Ruptured Intervention:   Device: Endovascular repair of ruptured abdominal aortic aneurysm (EVAR) with Medtronic Endurant Sponsors:   Kostantinos Papazoglou;   Medtronic;   Aristotle University Of Thessaloniki Recruiting
Source: - Category: Research Source Type: clinical trials
Condition:   SARS-CoV-2 Intervention:   Drug: Standard of Care (SOC) and Colchicine+Rosuvastatin Sponsor:   Yale University Not yet recruiting
Source: - Category: Research Source Type: clinical trials
Publication date: Available online 15 July 2020Source: Journal of Vascular and Interventional RadiologyAuthor(s): David J.S. Zucker, Aaron Smith, Ravi N. Srinivasa, Eric H. Yang, Murray H. Kwon, John M. Moriarty
Source: Journal of Vascular and Interventional Radiology - Category: Radiology Source Type: research
AbstractIntroduction and hypothesisPelvic organ prolapse (POP) treatment has become more common in the world ’s health care systems, and the demand for pelvic floor disorder rehabilitation has been projected to increase by 35% between 2010 and 2030. Restitution procedures vary, but after the US Food and Drug Administration (FDA) notifications, the global use of mesh in vaginal surgeries has significantly decreased. The aim of this study is to show trends in urogynecological surgeries in Poland.MethodsRetrospective analysis was performed of data obtained between 2009 and 2017 from the National Health Fund Information ...
Source: International Urogynecology Journal - Category: OBGYN Source Type: research
Abstract Mitochondria-derived reactive oxygen species (mROS) are produced at a variety of sites and affect the function of bio-molecules. The anti-oxidant system from both mitochondria and cytosol tightly coordinate to maintain the redox balance of cells and reduce damage from mROS. Mitochondrial DNA (mtDNA) are highly susceptible to mROS, and are easily oxidized to accumulate DNA modifications. Frequent oxidative damages in mtDNA have been associated with neurological degeneration, inflammasomes, tumorigenesis, and malignant progression. Among mitochondrial DNA repair pathways, the base excision repair pathway ha...
Source: Journal of Biosciences - Category: Biomedical Science Authors: Tags: J Biosci Source Type: research
Background: Stroke accounts for approximately as 5.0% of disability-adjusted years of life and 10.0% of all deaths worldwide. Secondary stroke prevention in surviving individuals, which includes the use of statins, reduces atherothrombotic stroke recurrence, complications and mortality. The present study aimed to characterize the Brazilian population with stroke history and estimate the prevalence of statin use as secondary prevention.Methods: This is a population-based cross-sectional study conducted in Brazilian urban areas.
Source: Journal of Stroke and Cerebrovascular Diseases - Category: Neurology Authors: Source Type: research
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