20 results found
Watson S, Duff J, Bardi I, et al., 2019, Biomimetic electromechanical stimulation to maintain adult myocardial slices in vitro, Nature Communications, Vol: 10, ISSN: 2041-1723
Adult cardiac tissue undergoes a rapid process of dedifferentiation when cultured outside the body. The in vivo environment, particularly constant electromechanical stimulation, is fundamental to the regulation of cardiac structure and function. We investigated the role of electromechanical stimulation in preventing culture-induced dedifferentiation of adult cardiac tissue using rat, rabbit and human heart failure myocardial slices. Here we report that the application of a preload equivalent to sarcomere length (SL) = 2.2 μm is optimal for the maintenance of rat myocardial slice structural, functional and transcriptional properties at 24 h. Gene sets associated with the preservation of structure and function are activated, while gene sets involved in dedifferentiation are suppressed. The maximum contractility of human heart failure myocardial slices at 24 h is also optimally maintained at SL = 2.2 μm. Rabbit myocardial slices cultured at SL = 2.2 μm remain stable for 5 days. This approach substantially prolongs the culture of adult cardiac tissue in vitro.
Rajani RM, Quick S, Ruigrok SR, et al., 2018, Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats, Science Translational Medicine, Vol: 10, Pages: eaam9507-eaam9507, ISSN: 1946-6234
Black HA, Parry D, Atanur SS, et al., 2016, De novo mutations in autosomal recessive congenital malformations, GENETICS IN MEDICINE, Vol: 18, Pages: 1325-1326, ISSN: 1098-3600
Abdelmagid N, Bereczky-Veress B, Atanur S, et al., 2016, Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis, PLOS One, Vol: 11, ISSN: 1932-6203
Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines—generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89–174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11–2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.
Zhao L, Oliver E, Maratou K, et al., 2015, The zinc transporter, ZIP12, regulates the pulmonary vascular response to chronic hypoxia, Nature, Vol: 524, Pages: 356-360, ISSN: 0028-0836
The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1, 2, 3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
Wang J, Ma MCJ, Mennie AK, et al., 2015, Systems Biology With High-Throughput Sequencing Reveals Genetic Mechanisms Underlying the Metabolic Syndrome in the Lyon Hypertensive Rat, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 8, Pages: 316-326, ISSN: 1942-325X
Johnson MD, Mueller M, Adamowicz-Brice M, et al., 2014, Genetic Analysis of the Cardiac Methylome at Single Nucleotide Resolution in a Model of Human Cardiovascular Disease, PLOS GENETICS, Vol: 10, ISSN: 1553-7404
Baud A, Guryev V, Hummel O, et al., 2014, Genomes and phenomes of a population of outbred rats and its progenitors, Scientific Data, Vol: 1
Finding genetic variants that contribute to phenotypic variation is one of the main challenges of modern genetics. We used an outbred population of rats (Heterogeneous Stock, HS) in a combined sequence-based and genetic mapping analysis to identify sequence variants and genes contributing to complex traits of biomedical relevance. Here we describe the sequences of the eight inbred progenitors of the HS and the variants that segregate between them. We report the genotyping of 1,407 HS rats, and the collection from 2,006 rats of 195 phenotypic measures that are relevant to models of anxiety, type 2 diabetes, hypertension and osteoporosis. We make available haplotype dosages for the 1,407 genotyped rats, since genetic mapping in the HS is best carried out by reconstructing each HS chromosome as a mosaic of the progenitor genomes. Finally, we have deposited an R object that makes it easy to incorporate our sequence data into any genetic study of HS rats. Our genetic data are available for both Rnor3.4 and Rnor5.0 rat assemblies.
Ma MCJ, Atanur SS, Aitman TJ, et al., 2014, Genomic structure of nucleotide diversity among Lyon rat models of metabolic syndrome, BMC GENOMICS, Vol: 15, ISSN: 1471-2164
Vandrovcova J, Thomas ERA, Atanur SS, et al., 2013, The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia, GENETICS IN MEDICINE, Vol: 15, Pages: 948-957, ISSN: 1098-3600
Thomas ERA, Atanur SS, Norsworthy PJ, et al., 2013, Identification and biochemical analysis of a novel APOB mutation that causes autosomal dominant hypercholesterolemia., Mol Genet Genomic Med, Vol: 1, Pages: 155-161, ISSN: 2324-9269
Patients with autosomal dominant hypercholesterolemia (ADH) have a high risk of developing cardiovascular disease that can be effectively treated using statin drugs. Molecular diagnosis and family cascade screening is recommended for early identification of individuals at risk, but up to 40% of families have no mutation detected in known genes. This study combined linkage analysis and exome sequencing to identify a novel variant in exon 3 of APOB (Arg50Trp). Mass spectrometry established that low-density lipoprotein (LDL) containing Arg50Trp APOB accumulates in the circulation of affected individuals, suggesting defective hepatic uptake. Previously reported mutations in APOB causing ADH have been located in exon 26. This is the first report of a mutation outside this region causing this phenotype, therefore, more extensive screening of this large and highly polymorphic gene may be necessary in ADH families. This is now feasible due to the high capacity of recently available sequencing platforms.
Atanur SS, Garcia-Diaz A, Maratou K, et al., 2013, Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat., Cell
Pillai R, Waghulde H, Nie Y, et al., 2013, Isolation and high-throughput sequencing of two closely linked epistatic hypertension susceptibility loci with a panel of bicongenic strains, PHYSIOLOGICAL GENOMICS, Vol: 45, Pages: 729-736, ISSN: 1094-8341
Baud A, Hermsen R, Guryev V, et al., 2013, Combined sequence-based and genetic mapping analysis of complex traits in outbred rats, NATURE GENETICS, Vol: 45, Pages: 767-+, ISSN: 1061-4036
Hull RP, Srivastava PK, D'Souza Z, et al., 2013, Combined ChIP-Seq and transcriptome analysis identifies AP-1/JunD as a primary regulator of oxidative stress and IL-1 beta synthesis in macrophages, BMC GENOMICS, Vol: 14, ISSN: 1471-2164
Johnson MD, Mueller M, Game L, et al., 2012, Single Nucleotide Analysis of Cytosine Methylation by Whole-Genome Shotgun Bisulfite Sequencing
Unlike other methods to assess methylation, whole-genome shotgun bisulfite sequencing is used to generate quantitative genome-wide methylation profiles at single-nucleotide resolution. As described in this unit, this method allows for the quantitative measurement of methylation at each cytosine base by treatment of genomic DNA with sodium bisulfite followed by sequencing and alignment of the reads to a reference genome. Curr. Protoc. Mol. Biol. 99:21.23.1-21.23.28. © 2012 by John Wiley & Sons, Inc.
Morrissey C, Grieve IC, Heinig M, et al., 2011, Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat, PHYSIOLOGICAL GENOMICS, Vol: 43, Pages: 1207-1218, ISSN: 1094-8341
Atanur SS, Birol I, Guryev V, et al., 2010, The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance, GENOME RESEARCH, Vol: 20, Pages: 791-803, ISSN: 1088-9051
Patil DP, Atanur S, Dhotre DP, et al., 2009, Generation, annotation, and analysis of ESTs from midgut tissue of adult female Anopheles stephensi mosquitoes, BMC Genomics, Vol: 10, Pages: 386-386, ISSN: 1471-2164
Rangrez AY, Dayananda KM, Atanur S, et al., 2006, Detection of Conjugation Related Type Four Secretion Machinery in Aeromonas culicicola, PLoS ONE, Vol: 1, Pages: e115-e115
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