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101.
102.
Dan E. Arking Kyndaron Reinier Wendy Post Jonathan Jui Gina Hilton Ashley O'Connor Ronald J. Prineas Eric Boerwinkle Bruce M. Psaty Gordon F. Tomaselli Thomas Rea Nona Sotoodehnia David S. Siscovick Gregory L. Burke Eduardo Marban Peter M. Spooner Aravinda Chakravarti Sumeet S. Chugh 《PloS one》2010,5(3)
Background
Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.Methodology/Principal Findings
We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002–07, population ∼1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5×10−8). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10−4 and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).Conclusions/Significance
A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study. 相似文献103.
104.
Stefan W. Metz Shaomin Tian Gabriel Hoekstra Xianwen Yi Michelle Stone Katie Horvath Michael J. Miley Joseph DeSimone Chris J. Luft Aravinda M. de Silva 《PLoS neglected tropical diseases》2016,10(10)
Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever. The virus is endemic in over 120 countries, causing over 350 million infections per year. Dengue vaccine development is challenging because of the need to induce simultaneous protection against four antigenically distinct DENV serotypes and evidence that, under some conditions, vaccination can enhance disease due to specific immunity to the virus. While several live-attenuated tetravalent dengue virus vaccines display partial efficacy, it has been challenging to induce balanced protective immunity to all 4 serotypes. Instead of using whole-virus formulations, we are exploring the potentials for a particulate subunit vaccine, based on DENV E-protein displayed on nanoparticles that have been precisely molded using Particle Replication in Non-wetting Template (PRINT) technology. Here we describe immunization studies with a DENV2-nanoparticle vaccine candidate. The ectodomain of DENV2-E protein was expressed as a secreted recombinant protein (sRecE), purified and adsorbed to poly (lactic-co-glycolic acid) (PLGA) nanoparticles of different sizes and shape. We show that PRINT nanoparticle adsorbed sRecE without any adjuvant induces higher IgG titers and a more potent DENV2-specific neutralizing antibody response compared to the soluble sRecE protein alone. Antigen trafficking indicate that PRINT nanoparticle display of sRecE prolongs the bio-availability of the antigen in the draining lymph nodes by creating an antigen depot. Our results demonstrate that PRINT nanoparticles are a promising platform for delivering subunit vaccines against flaviviruses such as dengue and Zika. 相似文献
105.
Chang YP Liu X Kim JD Ikeda MA Layton MR Weder AB Cooper RS Kardia SL Rao DC Hunt SC Luke A Boerwinkle E Chakravarti A 《American journal of human genetics》2007,80(2):253-264
Essential hypertension, defined as elevated levels of blood pressure (BP) without any obvious cause, is a major risk factor for coronary heart disease, stroke, and renal disease. BP levels and susceptibility to development of essential hypertension are partially determined by genetic factors that are poorly understood. Similar to other efforts to understand complex, non-Mendelian phenotypes, genetic dissection of hypertension-related traits employs genomewide linkage analyses of families and association studies of patient cohorts, to uncover rare and common disease alleles, respectively. Family-based mapping studies of elevated BP cover the large intermediate ground for identification of genes with common variants of significant effect. Our genomewide linkage and candidate-gene-based association studies demonstrate that a replicated linkage peak for BP regulation on human chromosome 1q, homologous to mouse and rat quantitative trait loci for BP, contains at least three genes associated with BP levels in multiple samples: ATP1B1, RGS5, and SELE. Individual variants in these three genes account for 2-5-mm Hg differences in mean systolic BP levels, and the cumulative effect reaches 8-10 mm Hg. Because the associated alleles in these genes are relatively common (frequency >5%), these three genes are important contributors to elevated BP in the population at large. 相似文献
106.
Jyotsna Shah Olivia Mark Helena Weltman Nicolas Barcelo Wai Lo Danuta Wronska Srinivas Kakkilaya Aravinda Rao Shalia T. Bhat Ruchi Sinha Sabah Omar Peter O’bare Manuel Moro Robert H. Gilman Nick Harris 《PloS one》2015,10(9)
Malaria is a responsible for approximately 600 thousand deaths worldwide every year. Appropriate and timely treatment of malaria can prevent deaths but is dependent on accurate and rapid diagnosis of the infection. Currently, microscopic examination of the Giemsa stained blood smears is the method of choice for diagnosing malaria. Although it has limited sensitivity and specificity in field conditions, it still remains the gold standard for the diagnosis of malaria. Here, we report the development of a fluorescence in situ hybridization (FISH) based method for detecting malaria infection in blood smears and describe the use of an LED light source that makes the method suitable for use in resource-limited malaria endemic countries. The Plasmodium Genus (P-Genus) FISH assay has a Plasmodium genus specific probe that detects all five species of Plasmodium known to cause the disease in humans. The P. falciparum (PF) FISH assay and P. vivax (PV) FISH assay detect and differentiate between P. falciparum and P. vivax respectively from other Plasmodium species. The FISH assays are more sensitive than Giemsa. The sensitivities of P-Genus, PF and PV FISH assays were found to be 98.2%, 94.5% and 98.3%, respectively compared to 89.9%, 83.3% and 87.9% for the detection of Plasmodium, P. falciparum and P. vivax by Giemsa staining respectively. 相似文献
107.
Donna M. Brown Tara C. Matise George Koike Jason S. Simon Eric S. Winer Sarah Zangen Michael G. McLaughlin Masahide Shiozawa O. Scott Atkinson James R. Hudson Jr. Aravinda Chakravarti Eric S. Lander Howard J. Jacob 《Mammalian genome》1998,9(7):521-530
The laboratory rat, Rattus novegicus, is a major model system for physiological and pathophysiological studies, and since 1966 more than 422,000 publications describe
biological studies on the rat (NCBI/Medline). The rat is becoming an increasingly important genetic model for the study of
specific diseases, as well as retaining its role as a major preclinical model system for pharmaceutical development. The initial
genetic linkage map of the rat contained 432 genetic markers (Jacob et al. 1995) out of 1171 developed due to the relatively
low polymorphism rate of the mapping cross used (SHR × BN) when compared to the interspecific crosses in the mouse. While
the rat genome project continues to localize additional markers on the linkage map, and as of 11/97 more than 3,200 loci have
been mapped. Current map construction is using two different crosses (SHRSP × BN and FHH × ACI) rather than the initial mapping
cross. Consequently there is a need to provide integration among the different maps. We set out to develop an integrated map,
as well as increase the number of markers on the rat genetic map.
The crosses available for this analysis included the original mapping cross SHR × BN reciprocal F2 intercross (448 markers),
a GH × BN intercross (205 markers), a SS/Mcw × BN intercross (235 markers), and a FHH/Eur × ACI/Hsd intercross (276 markers),
which is also one of the new mapping crosses. Forty-six animals from each cross were genotyped with markers polymorphic for
that cross. The maps appear to cover the vast majority of the rat genome. The availability of these additional markers should
facilitate more complete whole genome scans in a greater number of strains and provide additional markers in specific genomic
regions of interest.
Received: 3 December 1997 / Accepted: 20 February 1998 相似文献
108.
Dimitrios Avramopoulos Tara Cox Jan P. Kraus Aravinda Chakravarti Stylianos E. Antonarakis 《Human genetics》1993,90(5):566-568
We used single-strand conformation polymorphism (SSCP) to detect DNA polymorphisms in the 3 untranslated (3UT) region of the gene for cystathionine -synthase (CBS). A polymorphism due to a T-to-C substitution at nucleotide 549 of the 3UT region with heterozygosity of 46% has been identified. Genotypes for this polymorphism have been obtained in all of the informative CEPH families, and CBS has been placed in the linkage map of human chromosome 21. 相似文献
109.
Raghurama P Hegde Subrayashastry Aravinda Rajkishor Rai Ramesh Kaul Sarojini Vijayalakshmi R Balaji Rao Narayanaswamy Shamala Padmanabhan Balaram 《Journal of peptide science》2008,14(5):648-659
The crystal structures of two oligopeptides containing di-n-propylglycine (Dpg) residues, Boc-Gly-Dpg-Gly-Leu-OMe (1) and Boc-Val-Ala-Leu-Dpg-Val-Ala-Leu-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe (2) are presented. Peptide 1 adopts a type I'beta-turn conformation with Dpg(2)-Gly(3) at the corner positions. The 14-residue peptide 2 crystallizes with two molecules in the asymmetric unit, both of which adopt alpha-helical conformations stabilized by 11 successive 5 --> 1 hydrogen bonds. In addition, a single 4 --> 1 hydrogen bond is also observed at the N-terminus. All five Dpg residues adopt backbone torsion angles (phi, psi) in the helical region of conformational space. Evaluation of the available structural data on Dpg peptides confirm the correlation between backbone bond angle N-C(alpha)-C' (tau) and the observed backbone phi,psi values. For tau > 106 degrees, helices are observed, while fully extended structures are characterized by tau < 106 degrees. The mean tau values for extended and folded conformations for the Dpg residue are 103.6 degrees +/- 1.7 degrees and 109.9 degrees +/- 2.6 degrees, respectively. 相似文献
110.
The study of vertebrate pigmentary anomalies has greatly improved our understanding of melanocyte biology. One such disorder, Waardenburg syndrome (WS), is a mendelian trait characterized by hypopigmentation and sensorineural deafness. It is commonly subdivided into four types (WS1–4), defined by the presence or absence of additional symptoms. WS type 4 (WS4), or Shah‐Waardenburg syndrome, is also known as Hirschsprung disease Type II (HSCR II) and is characterized by an absence of epidermal melanocytes and enteric ganglia. Mutations in the genes encoding the endothelin type‐B receptor (EDNRB) and its physiological ligand endothelin 3 (EDN3) are now known to account for the majority of HSCR II patients. Null mutations in the mouse genes Ednrb and Edn3 have identified a key role for this pathway in the normal development of melanocytes and other neural crest‐derived lineages. The pleiotropic effects of genes in this pathway, on melanocyte and enteric neuron development, have been clarified by the embryologic identification of their common neural crest (NC) ancestry. EDNRB and EDN3 are transiently expressed in crest‐derived melanoblast and neuroblast precursors, and in the surrounding mesenchymal cells, respectively. The influence of EDNRB‐mediated signaling on the emigration, migration, proliferation, and differentiation of melanocyte and enteric neuron precursors, in vivo and in vitro has recently been the subject of great scrutiny. A major emergent theme is that EDN3‐induced signaling prevents the premature differentiation of melanocyte and enteric nervous system precursors and is essential between 10 and 12.5 days post‐coitum. We review the present understanding of pigment cell development in the context of EDNRB/EDN3 – a receptor‐mediated pathway with pleiotropic effects. 相似文献