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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 919 records · Page 51
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Structures of drug-specific monoclonal antibodies bound to opioids and nicotine reveal a common mode of binding

Opioid-related fatal overdoses have reached epidemic proportions. Because existing treatments for opioid use disorders offer limited long-term protection, accelerating the development of newer approaches is critical. Monoclonal antibodies (mAbs) are an emerging treatment strategy that targets and sequesters selected opioids in the bloodstream, reducing drug distribution across the blood-brain barrier, thus preventing or reversing opioid toxicity. We previously identified a series of murine mAbs with high affinity and selectivity for oxycodone, morphine, fentanyl, and nicotine. To determine their binding mechanism, we used X-ray crystallography to solve the structures of mAbs bound to their respective targets, to 2.2 Å resolution or higher. Structural analysis showed a critical convergent hydrogen bonding mode that is dependent on a glutamic acid residue in the mAbs’ heavy chain and a tertiary amine of the ligand. Further, characterizing drug-mAb complexes represents a significant step toward rational antibody engineering and future manufacturing activities to support clinical evaluation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Impact of common clandestine structural modifications on synthetic cathinone “bath salt” pharmacokinetics

Since 2009, the synthetic cathinones (“bath salts”) have risen in popularity as drugs of abuse. However, there are a paucity of studies that have determined the impact of functional group modifications in the synthetic cathinone chemical structures on plasma and central nervous system (CNS) pharmacokinetics. In the present study, we investigated the in vivo plasma and CNS pharmacokinetics of three synthetic cathinones whose structures differ by lengthening of the α-alkyl chain: methylone (-CH{sub 3}), butylone (-CH{sub 2}CH{sub 3}), and pentylone (-CH{sub 2}CH{sub 2}CH{sub 3}). Male Sprague-Dawley rats were treated with a 20 mg/kg subcutaneous dose of the individual synthetic cathinone. Blood samples were obtained at specific times from a jugular vein cannula over an 8 hour period. Over a separate three-hour period, CNS samples were obtained using a microdialysis cannula surgically implanted into the lateral ventricle. In the plasma, pentylone, with the longest α-alkyl chain, displayed the highest C{sub max} and AUC{sub 0–∞}, and the longest t{sub 1/2.} Decreasing the α-alkyl chain length as in butylone and methylone significantly decreased the C{sub max}, AUC{sub 0–∞}, and t{sub 1/2}. The plasma pharmacokinetic values are consistent with the greater lipophilicity associated with α-alkyl side chain lengthening. Conversely, in the CNS, methylone and butylone displayed higher C{sub max} and AUC{sub 0–∞} values than pentylone. These contrary findings in the CNS and plasma demonstrate that lengthening of the α-alkyl chain of methylone, butylone, and pentylone yields differential pharmacokinetic properties in the CNS as compared to the plasma. - Highlights: • Adding α-methyl groups increase synthetic cathinone plasma C{sub max}, AUC{sub 0–∞,} t{sub 1/2.} • Adding α-methyl groups decrease synthetic cathinone CNS C{sub max}, AUC{sub 0–∞,} t{sub 1/2.} • The CNS has greater exposure to the synthetic cathinones as compared to the plasma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Common traffic routes for imported spermine and endosomal glypican-1-derived heparan sulfate in fibroblasts

Import of the polyamine spermine from the extracellular environment depends on the presence of cell surface heparan sulfate proteoglycans, such as glypican-1. This proteoglycan is internalized by endocytosis, releases its heparan sulfate chains in endosomes by a nitric oxide-, copper- and amyloid precursor protein-dependent mechanism, then penetrates the membrane and is transported to the nucleus and then to autophagosomes. This process is spontaneous or induced by ascorbate depending on the growth-state of the cell. Here, we have explored possible connections between the heparan sulfate traffic route and spermine uptake and delivery in wild-type and Tg2576 mouse fibroblasts. Cells were examined by deconvolution immunofluorescence microscopy. The antibodies used were specific for spermine, glypican-1-derived heparan sulfate, Rab7, nucleolin and a marker for autophagosomes. Endogenous immunostainable spermine was primarily associated with autophagosomes. When spermine synthesis was inhibited, imported spermine appeared in Rab7-positive endosomes. When ascorbate was added, heparan sulfate and spermine were transported to the nucleus where they colocalized with nucleolin. Spermine also appeared in autophagosomes. In a pulse-chase experiment, heparan sulfate and spermine were first arrested in late endosomes by actinomycin D treatment. During the chase, when arrest was abolished, heparan sulfate and spermine were both transported to the nucleus and targeted nucleolin. In amyloid precursor protein{sup -/-}-fibroblasts, ascorbate failed to induce release of heparan sulfate and spermine remained in the endosomes. We propose that cell surface glypican-1 carries spermine to the endosomes and that the released heparan sulfate carries spermine across the membrane into the cytosol and then to the nucleus.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Food–Energy–Water Crises in the United States and China: Commonalities and Asynchronous Experiences Support Integration of Global Efforts

Food, energy, and water (FEW) systems have been recognized as an issue of critical global importance. Understanding the mechanisms that govern the FEW nexus is essential to develop solutions and avoid humanitarian crises of displacement, famine, and disease. The U.S. and China are the world’s leading economies. Although the two nations are shaped by fundamentally different political and economic systems, they share FEW trajectories in several complementary ways. These realities place the U.S. and China in unique positions to engage in problem definition, dialogue, actions, and transdisciplinary convergence of research to achieve productive solutions addressing FEW challenges. By comparing the nexus and functions of the FEW systems in the two nations, this perspective aims to facilitate collaborative innovations that reduce disciplinary silos, mitigate FEW challenges, and enhance environmental sustainability. Finally, the review of experiences and challenges facing the U.S. and China also offers valuable insights for other nations seeking to achieve sustainable development goals.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Uranium Isotopic Fractionation Induced by U(VI) Adsorption onto Common Aquifer Minerals

Uranium groundwater contamination due to U mining and processing affects numerous sites globally. Bioreduction of soluble, mobile U(VI) to U(IV)-bearing solids is potentially a very effective remediation strategy. Uranium isotopes ( 238 U/ 235 U) have been utilized to track the progress of microbial reduction, with laboratory and field studies finding a ~1‰ isotopic fractionation, with the U(IV) product enriched in 238 U. However, the isotopic fractionation produced by adsorption may complicate the use of 238 U/ 235 U to trace microbial reduction. A previous study found that adsorption of U(VI) onto Mn oxides produced a -0.2‰ fractionation with the adsorbed U(VI) depleted in 238 U. In this paper, adsorption to quartz, goethite, birnessite, illite, and aquifer sediments induced an average isotopic fractionation of -0.15‰ with the adsorbed U(VI) isotopically lighter than coexisting aqueous U(VI). In bicarbonate-bearing matrices, the fractionation depended little on the nature of the sorbent, with only birnessite producing an atypically large fractionation. In the case of solutions with ionic strengths much lower than those of typical groundwater, less isotopic fractionation was produced than U(VI) solutions with greater ionic strength. Finally, studies using U isotope data to assess U(VI) reduction must consider adsorption as a lesser, but significant isotope fractionation process.

54 ENVIRONMENTAL SCIENCES↗