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Biology subjects

Rao, A. S.

Publications and source records attributed to Rao, A. S..

3 recordsLinked to original sources

Systematic Review of Aptamer Sequence Reporting in the Literature Reveals Widespread Unexplained Sequence Alterations

Aptamers have been the subject of more than 144,000 papers to date. However, there has been a growing concern that errors in reporting aptamer research limit the reliability of these reagents for research and other applications. These observations noting inconsistencies in the use of our RNA anti-lysozyme aptamer served as an impetus for our systematic review of the reporting of aptamer sequences in the literature. Our detailed examination of literature citing the RNA anti-lysozyme aptamer revealed that 93% of the 61 publications reviewed reported unexplained altered sequences with 86% of those using DNA variants. The ten most cited aptamers were examined using a standardized methodology in order to categorize the extent to which the sequences themselves were apparently improperly reproduced, both in the literature and presumably in experiments beyond their discovery. Our review of 800 aptamer publications spanned decades, multiple journals, and research groups, and revealed that 44% of the papers reported unexplained sequence alterations. We identified ten common categories of sequence alterations including deletions, substitutions, additions, among others. The robust data set we have produced elucidates a source of irreproducibility and unreliability in our field and can be used as a starting point for building evidence-based best practices in publication standards to elevate the rigor and reproducibility of aptamer research.

synthetic biology↗

A novel regulatory element upstream of TNFAIP3 promoter may be influenced by SLE risk variants

Almost all of Genome Wide Association Studies (GWAS) hits come from non-coding DNA elements. Data from chromatin interaction analyses suggest a long-range interaction with a putative enhancer upstream of TNFAIP3. Disrupting the enhancer may impair TNFAIP3 expression and enhance SLE risk. Two variants, rs10499197 and rs58905141 carried on the SLE risk haplotype are situated near this enhancer and could affect its function. Cloning the regulatory region surrounding rs10499197 into an expression plasmid containing a CRISPR-Cas9 backbone, and then performing a genome editing assay, we found that the variant is located near an enhancer. And any changes to the SNP region might impair enhancer and its ability to regulate TNFAIP3 expression.

bioinformatics↗

Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke

PCSK9 inhibitors are a potent new therapy for hypercholesterolemia and have been shown to decrease risk of coronary heart disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large well-phenotyped biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. We tested association of the PCSK9 loss-of-function variant rsll591147 (R46L) in a hypothesis-driven 11 phenotype set and a hypothesis-generating 278 phenotype set in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery (n = 225K) and replication (n = 112K). In addition to the known association with lipid levels (OR 0.63) and coronary heart disease (OR 0.73), the T allele of rs11591147 showed a protective effect on ischemic stroke (OR 0.61, p = 0.002) but not hemorrhagic stroke in the hypothesis-driven screen. We did not observe an association with type 2 diabetes, cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. In the phenome-wide screen, the variant was associated with a reduction in metabolic disorders, ischemic heart disease, coronary artery bypass graft operations, percutaneous coronary interventions and history of angina. A single variant analysis of UKB data using TreeWAS, a Bayesian analysis framework to study genetic associations leveraging phenotype correlations, also showed evidence of association with cerebral infarction and vascular occlusion. This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke, and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to low density lipoprotein cholesterol and atherosclerosis, suggesting that other effects are either small or absent.

genetics↗