Institution
Research Triangle Park
Nonprofit•Durham, North Carolina, United States•
About: Research Triangle Park is a nonprofit organization based out in Durham, North Carolina, United States. It is known for research contribution in the topics: Population & Environmental exposure. The organization has 24961 authors who have published 35800 publications receiving 1684504 citations. The organization is also known as: RTP.
Topics: Population, Environmental exposure, Receptor, Poison control, Agonist
Papers published on a yearly basis
Papers
More filters
••
TL;DR: The results demonstrate no clear quantitative or qualitative correlation between inhibition of DNA polymerases, particularly mitochondrial DNA polymerase gamma, and the inhibition of mitochondrial DNA synthesis in Molt-4 cell culture, and indicate that inhibition of isolated DNA polymerasing may not be predictive of in vitro or in vivo toxicity.
Abstract: Inhibition constants were determined for 16 nucleoside analog triphosphates against human DNA polymerases alpha, beta, gamma, and epsilon, and 7 nucleoside analogs were examined as inhibitors of mitochondrial DNA synthesis in human Molt-4 cells in culture. The results demonstrate no clear quantitative or qualitative correlation between inhibition of DNA polymerases, particularly mitochondrial DNA polymerase gamma, and the inhibition of mitochondrial DNA synthesis in Molt-4 cell culture. Furthermore, the data indicate that inhibition of isolated DNA polymerases may not be predictive of in vitro or in vivo toxicity. Finally, it is not clear whether inhibition of mitochondrial DNA synthesis will be an accurate predictor of the potential in vivo toxicity of antiviral nucleoside analogs.
346 citations
••
TL;DR: The primary cause of lethality appears to be failure of the embryonic component of the placenta to vascularize and form the labyrinthine spongiotrophoblast, which may be related to ARNT's known role in hypoxic induction of angiogenesis.
346 citations
••
TL;DR: Results suggest that phylogenetic relationships are correlated with habitat, indicating the occurrence of geographical races within these groups, which is of practical importance for Solanum genome evolution studies.
Abstract: We explored genetic variation by sequencing a selection of 84 tomato accessions and related wild species representative of the Lycopersicon, Arcanum, Eriopersicon and Neolycopersicon groups, which has yielded a huge amount of precious data on sequence diversity in the tomato clade. Three new reference genomes were reconstructed to support our comparative genome analyses. Comparative sequence alignment revealed group-, species- and accession-specific polymorphisms, explaining characteristic fruit traits and growth habits in the various cultivars. Using gene models from the annotated Heinz 1706 reference genome, we observed differences in the ratio between non-synonymous and synonymous SNPs (dN/dS) in fruit diversification and plant growth genes compared to a random set of genes, indicating positive selection and differences in selection pressure between crop accessions and wild species. In wild species, the number of single-nucleotide polymorphisms (SNPs) exceeds 10 million, i.e. 20-fold higher than found in most of the crop accessions, indicating dramatic genetic erosion of crop and heirloom tomatoes. In addition, the highest levels of heterozygosity were found for allogamous self-incompatible wild species, while facultative and autogamous self-compatible species display a lower heterozygosity level. Using whole-genome SNP information for maximum-likelihood analysis, we achieved complete tree resolution, whereas maximum-likelihood trees based on SNPs from ten fruit and growth genes show incomplete resolution for the crop accessions, partly due to the effect of heterozygous SNPs. Finally, results suggest that phylogenetic relationships are correlated with habitat, indicating the occurrence of geographical races within these groups, which is of practical importance for Solanum genome evolution studies.
345 citations
••
TL;DR: Allosteric inhibition of RXR results from a rotation of the RXR AF-2 helix that places it in contact with the RAR coactivator-binding site, allowing RXR ligands to bind and promote the binding of a second LXXLL motif from the same SRC-1 molecule.
Abstract: Retinoic-acid receptor-α (RAR-α) and peroxisome proliferator-activated receptor-γ (PPAR-γ) are members of the nuclear-receptor superfamily that bind to DNA as heterodimers with retinoid-X receptors (RXRs)1,2. PPAR–RXR heterodimers can be activated by PPAR or RXR ligands3, whereas RAR–RXR heterodimers are selectively activated by RAR ligands only, because of allosteric inhibition of the binding of ligands to RXR by RAR4,5. However, RXR ligands can potentiate the transcriptional effects of RAR ligands in cells6. Transcriptional activation by nuclear receptors requires a carboxy-terminal helical region, termed activation function-2 (AF-2) (refs 7,8,9), that forms part of the ligand-binding pocket and undergoes a conformational change required for the recruitment of co-activator proteins, including NCoA-1/SRC-1 (refs 10,11,12,13,14,15,16,17). Here we show that allosteric inhibition of RXR results from a rotation of the RXR AF-2 helix that places it in contact with the RAR coactivator-binding site. Recruitment of an LXXLL motif of SRC-1 to RAR in response to ligand displaces the RXR AF-2 domain, allowing RXR ligands to bind and promote the binding of a second LXXLL motif from the same SRC-1 molecule. These results may partly explain the different responses of nuclear-receptor heterodimers to RXR-specific ligands.
345 citations
••
TL;DR: In this paper, a report summarizes the deliberations of a multidisciplinary committee, sponsored by the Pharmaceutical Research and Manufacturers of America, on current "best practices" within the U.S. pharmaceutical industry in assessing the role of drug metabolites as potential mediators of the toxicity of new drug products.
344 citations
Authors
Showing all 25006 results
Name | H-index | Papers | Citations |
---|---|---|---|
Douglas G. Altman | 253 | 1001 | 680344 |
Lewis C. Cantley | 196 | 748 | 169037 |
Ronald Klein | 194 | 1305 | 149140 |
Daniel J. Jacob | 162 | 656 | 76530 |
Christopher P. Cannon | 151 | 1118 | 108906 |
James B. Meigs | 147 | 574 | 115899 |
Lawrence Corey | 146 | 773 | 78105 |
Jeremy K. Nicholson | 141 | 773 | 80275 |
Paul M. Matthews | 140 | 617 | 88802 |
Herbert Y. Meltzer | 137 | 1148 | 81371 |
Charles J. Yeo | 136 | 672 | 76424 |
Benjamin F. Cravatt | 131 | 666 | 61932 |
Timothy R. Billiar | 131 | 838 | 66133 |
Peter Brown | 129 | 908 | 68853 |
King K. Holmes | 124 | 606 | 56192 |