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Title: Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals

Authors:
; ; ; ; ; ; ;
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1338628
Grant/Contract Number:
SC0005430
Resource Type:
Journal Article: Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 4; Related Information: CHORUS Timestamp: 2017-06-25 03:45:40; Journal ID: ISSN 0027-8424
Publisher:
Proceedings of the National Academy of Sciences
Country of Publication:
United States
Language:
English

Citation Formats

McKinlay, Colin J., Vargas, Jessica R., Blake, Timothy R., Hardy, Jonathan W., Kanada, Masamitsu, Contag, Christopher H., Wender, Paul A., and Waymouth, Robert M.. Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. United States: N. p., 2017. Web. doi:10.1073/pnas.1614193114.
McKinlay, Colin J., Vargas, Jessica R., Blake, Timothy R., Hardy, Jonathan W., Kanada, Masamitsu, Contag, Christopher H., Wender, Paul A., & Waymouth, Robert M.. Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals. United States. doi:10.1073/pnas.1614193114.
McKinlay, Colin J., Vargas, Jessica R., Blake, Timothy R., Hardy, Jonathan W., Kanada, Masamitsu, Contag, Christopher H., Wender, Paul A., and Waymouth, Robert M.. Mon . "Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals". United States. doi:10.1073/pnas.1614193114.
@article{osti_1338628,
title = {Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals},
author = {McKinlay, Colin J. and Vargas, Jessica R. and Blake, Timothy R. and Hardy, Jonathan W. and Kanada, Masamitsu and Contag, Christopher H. and Wender, Paul A. and Waymouth, Robert M.},
abstractNote = {},
doi = {10.1073/pnas.1614193114},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 4,
volume = 114,
place = {United States},
year = {Mon Jan 09 00:00:00 EST 2017},
month = {Mon Jan 09 00:00:00 EST 2017}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1073/pnas.1614193114

Citation Metrics:
Cited by: 6works
Citation information provided by
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  • Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors.more » In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver. - Highlights: • Utilized a graded CR model in male mice • The mRNA profiles of xenobiotic processing genes (XPGs) in liver were investigated. • CR up-regulates many phase-II enzymes. • CR tends to feminize the mRNA profiles of XPGs.« less
  • Metamphetamine’s widepread abuse and concerns that it may increase Parkinson’s disease led us to assess if the reported loss of dopamine transporters (DAT) in methamphetamine abusers (MA) reflected damage to dopamine neurons. Using PET with [ 11C]cocaine to measure DAT, and with [ 11C]raclopride to measure dopamine release (assessed as changes in specific binding of [ 11C]raclopride between placebo and methylphenidate), which was used as marker of dopamine neuronal function, we show that MA (n=16), tested during early detoxification, had lower DAT (20-30%) but overall normal DA release in striatum (except for a small decrease in left putamen), when comparedmore » to controls (n=15). In controls, DAT were positively correlated with DA release (higher DAT associated with larger DA increases), consistent with DAT serving as markers of DA terminals. In contrast, MA showed a trend for a negative correlation (p=0.07) (higher DAT associated with lower DA increases), consistent with reduced DA re-uptake following DAT downregulation. MA who remained abstinent nine-months later (n=9) showed significant increases in DAT (20%) but methylphenidate-induced dopamine increases did not change. In contrast, in controls, DAT did not change when retested 9 months later but methylphenidate-induced dopamine increases in ventral striatum were reduced (p=0.05). Baseline D2/D3 receptors in caudate were lower in MA than in controls and did not change with detoxification, nor did they change in the controls upon retest. The loss of DAT in the MA, which was not associated with a concomitant reduction in dopamine release as would have been expected if DAT loss reflected DA terminal degneration; as well as the recovery of DAT after protracted detoxification, which was not associated with increased dopamine release as would have been expected if DAT increases reflected terminal regeneration, indicate that the loss of DAT in these MA does not reflect degeneration of dopamine terminals.« less
  • In eukaryotic cells, pre-mRNAs are transcribed in the nucleus, processed by 5' capping, 3'-polyadenylation, and splicing, and exported to the cytoplasm for translation. To examine the nuclear mRNA transport mechanism, intron-deficient mRNAs of truncated {beta}-globin and EGFP were synthesized, fluorescently labeled in vitro, and injected into the nucleus of living Xenopus A6 cells. The trajectories of single mRNA molecules in the nucleus were visualized using video-rate confocal microscopy. Approximately half the mRNAs moved by Brownian motion in the nucleoplasm, except the nucleoli, with an apparent diffusion coefficient of 0.2 {mu}m{sup 2}/s, about 1/150 of that in water. The slow diffusionmore » could not be explained by simple diffusion obeying the Stokes-Einstein equation, suggesting interactions of the mRNAs with nuclear components. The remaining mRNAs were stationary with an average residence time of about 30 s, comparable to the time required for mRNA diffusion from the site of synthesis to nuclear pores.« less
  • Cysteamine (300 mg/kg) administered subcutaneously depletes pancreatic somatostatin to 36% of control levels, but does not alter pancreatic insulin or glucagon content. Although perfusion of pancreata from normal animals with glucose (300 mg/dl) markedly stimulated somatostatin release, pancreata from cysteamine-treated animals failed to secrete somatostatin in response to glucose. Cysteamine treatment was without effect on insulin and glucagon release under the conditions tested. The isolated perfused pancreas from the cysteamine-treated rat provides a model for further investigations into regulation of islet hormone release in the absence of stimulated somatostatin release.
  • Translated from Prib. Tekh. Eksp.; 16: No. 4, 31-32(1973). Various constructions of charge transporters and charging systems of an electrostatic generator were investigated. Results are presented of investigations on the contact and corona method of depositing and removing charges from the tape. Several types of tapes are considered. The advantages of the contact method of depositing and removing charges are demonstrated. (auth)