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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 1,027 records · Page 57
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

A Semi‐Automated, High‐Throughput Approach for the Synthesis and Identification of Highly Photo‐Cytotoxic Iridium Complexes

Abstract The discovery of new compounds with pharmacological properties is usually a lengthy, laborious and expensive process. Thus, there is increasing interest in developing workflows that allow for the rapid synthesis and evaluation of libraries of compounds with the aim of identifying leads for further drug development. Herein, we apply combinatorial synthesis to build a library of 90 iridium(III) complexes (81 of which are new) over two synthesise‐and‐test cycles, with the aim of identifying potential agents for photodynamic therapy. We demonstrate the power of this approach by identifying highly active complexes that are well‐tolerated in the dark but display very low nM phototoxicity against cancer cells. To build a detailed structure–activity relationship for this class of compounds we have used density functional theory (DFT) calculations to determine some key electronic parameters and study correlations with the experimental data. Finally, we present an optimised semi‐automated synthesise‐and‐test protocol to obtain multiplex data within 72 hours.

Kench, Timothy↗
DOE OSTI2014

Rate Coefficients of C1 and C2 Criegee Intermediate Reactions with Formic and Acetic Acid Near the Collision Limit: Direct Kinetics Measurements and Atmospheric Implications

Rate coefficients are directly determined for the reactions of the Criegee intermediates (CI) CH2OO and CH3CHOO with the two simplest carboxylic acids, formic acid (HCOOH) and acetic acid (CH3COOH), employing two complementary techniques: multiplexed photoionization mass spectrometry and cavity-enhanced broadband ultraviolet absorption spectroscopy. The measured rate coefficients are in excess of 1 1010 cm3 s 1 , several orders of magnitude larger than those suggested from many previous alkene ozonolysis experiments and assumed in atmospheric modeling studies. These results suggest that the reaction with carboxylic acids is a substantially more important loss process for CIs than is presently assumed. Implementing these rate coefficients in global atmospheric models shows that reactions between CI and organic acids make a substantial contribution to removal of these acids in terrestrial equatorial areas and in other regions where high CI concentrations occur such as high northern latitudes, and implies that sources of acids in these areas are larger than previously recognized.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

Accelerated Chemical Reactions and Organic Synthesis in Leidenfrost Droplets

Abstract Leidenfrost levitated droplets can be used to accelerate chemical reactions in processes that appear similar to reaction acceleration in charged microdroplets produced by electrospray ionization. Reaction acceleration in Leidenfrost droplets is demonstrated for a base‐catalyzed Claisen–Schmidt condensation, hydrazone formation from precharged and neutral ketones, and for the Katritzky pyrylium into pyridinium conversion under various reaction conditions. Comparisons with bulk reactions gave intermediate acceleration factors (2–50). By keeping the volume of the Leidenfrost droplets constant, it was shown that interfacial effects contribute to acceleration; this was confirmed by decreased reaction rates in the presence of a surfactant. The ability to multiplex Leidenfrost microreactors, to extract product into an immiscible solvent during reaction, and to use Leidenfrost droplets as reaction vessels to synthesize milligram quantities of product is also demonstrated.

Bain, Ryan M.↗
DOE OSTI2017

Reaction Acceleration in Thin Films with Continuous Product Deposition for Organic Synthesis

Thin film formats are used to study the Claisen-Schmidt base-catalyzed condensation of 6-hydroxy-1-indanone with substituted benzaldehydes and to compare the reaction acceleration relative to the bulk. Relative acceleration factors initially exceeded 10 3 and were on the order of 10 2 at steady state, although the confined volume reaction was not electrostatically driven. Substituent effects were muted compared to those in the corresponding bulk and microdroplet reactions and it is concluded that the rate-limiting step at steady state is reagent transport to the interface. Conditions were found that allowed product deposition from the thin film to occur continuously as the reaction mixture was added and as the solvent evaporated. Yields of 74% and production rates of 98 mgh –1 were reached in a very simple experimental system that could be multiplexed to greater scales.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

A Semi‐Automated, High‐Throughput Approach for the Synthesis and Identification of Highly Photo‐Cytotoxic Iridium Complexes

Abstract The discovery of new compounds with pharmacological properties is usually a lengthy, laborious and expensive process. Thus, there is increasing interest in developing workflows that allow for the rapid synthesis and evaluation of libraries of compounds with the aim of identifying leads for further drug development. Herein, we apply combinatorial synthesis to build a library of 90 iridium(III) complexes (81 of which are new) over two synthesise‐and‐test cycles, with the aim of identifying potential agents for photodynamic therapy. We demonstrate the power of this approach by identifying highly active complexes that are well‐tolerated in the dark but display very low nM phototoxicity against cancer cells. To build a detailed structure–activity relationship for this class of compounds we have used density functional theory (DFT) calculations to determine some key electronic parameters and study correlations with the experimental data. Finally, we present an optimised semi‐automated synthesise‐and‐test protocol to obtain multiplex data within 72 hours.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Benchmark Dose Analysis of DNA Damage Biomarker Responses Provides Compound Potency and Adverse Outcome Pathway Information for the Topoisomerase II Inhibitor Class of Compounds

Genetic toxicology data have traditionally been utilized for hazard identification to provide a binary call for a compound's risk. Recent advances in the scientific field, especially with the development of high‐throughput methods to quantify DNA damage, have influenced a change of approach in genotoxicity assessment. The in vitro MultiFlow® DNA Damage Assay is one such method which multiplexes γH2AX, p53, phospho‐histone H3 biomarkers into a single‐flow cytometric analysis (Bryce et al., [2016]: Environ Mol Mutagen 57:546–558). This assay was used to study human TK6 cells exposed to each of eight topoisomerase II poisons for 4 and 24 hr. Using PROAST v65.5, the Benchmark Dose approach was applied to the resulting flow cytometric datasets. With “compound” serving as covariate, all eight compounds were combined into a single analysis, per time point and endpoint. The resulting 90% confidence intervals, plotted in Log scale, were considered as the potency rank for the eight compounds. The in vitro MultiFlow data showed a maximum confidence interval span of 1Log, which indicates data of good quality. Patterns observed in the compound potency rank were scrutinized by using the expert rule‐based software program Derek Nexus, developed by Lhasa Limited. Compound sub‐classification and structural alerts were considered contributory to the potencies observed for the topoisomerase II poisons studied herein. The Topo II poison Adverse Outcome Pathway was evaluated with MultiFlow endpoints serving as Key Events. The step‐wise approach described herein can be considered as a foundation for risk assessment of compounds within a specific mode of action of interest. Environ. Mol. Mutagen. 2020. © 2020 Wiley Periodicals, Inc.

Wheeldon, Ryan P.↗
DOE OSTI2019

Introduction of a bounded penalty function in contact‐assisted simulations of protein structures to omit false restraints

Contact‐assisted simulations, the contacts being predicted or determined experimentally, have become very important in the determination of the structures of proteins and other biological macromolecules. In this work, the effect of contact‐distance restraints on the simulated structures was investigated with the use of multiplexed replica exchange simulations with the coarse‐grained UNRES force field. A modified bounded flat‐bottom restraint function that does not generate a gradient when a restraint cannot be satisfied was implemented. Calculations were run with (i) a set of four small proteins, with contact restraints derived from experimental structures, and (ii) selected CASP11 and CASP12 targets, with restraints as used at prediction time. The bounded penalty function largely omitted false contacts, which were usually inconsistent. It was found that at least 20% of correct contacts must be present in the restraint set to improve model quality with respect to unrestrained simulations. © 2019 Wiley Periodicals, Inc.

Lubecka, Emilia A.↗
DOE OSTI2020

Reaction mechanisms of a cyclic ether intermediate: Ethyloxirane

Oxiranes are a class of cyclic ethers formed in abundance during low-temperature combustion of hydrocarbons and biofuels, either via chain-propagating steps that occur from unimolecular decomposition of β -hydroperoxyalkyl radicals ( β -˙QOOH) or from reactions of HOÓ with alkenes. Ethyloxirane is one of four alkyl-substituted cyclic ether isomers produced as an intermediate from n -butane oxidation. While rate coefficients for β -˙QOOH → ethyloxirane + ÓH are reported extensively, subsequent reaction mechanisms of the cyclic ether are not. As a result, chemical kinetics mechanisms commonly adopt simplified chemistry to describe ethyloxirane consumption by convoluting several elementary reactions into a single step, which may introduce mechanism truncation error—uncertainty derived from missing or incomplete chemistry. Here we provide fundamental insight on reaction mechanisms of ethyloxirane in support of ongoing efforts to minimize mechanism truncation error. Reaction mechanisms are inferred from the detection of products during chlorine atom-initiated oxidation experiments using multiplexed photoionization mass spectrometry conducted at 10 Torr and temperatures of 650 K and 800 K. To complement the experiments, calculations of stationary point energies were conducted using the ccCA-PS3 composite method on ˙R + O 2 potential energy surfaces for the four ethyloxiranyl radical isomers, which produced barrier heights for 24 reaction pathways. In addition to products from ˙QOOH → cyclic ether + ÓH and ˙R + O 2 → conjugate alkene + HOÓ, both of which were significant pathways and are prototypical to alkane oxidation, other species were identified from ring-opening of both ethyloxiranyl and ˙QOOH radicals. The latter occurs when the unpaired electron is localized on the ether group, causing the initial ˙QOOH structure to ring-open and form a resonance-stabilized ketohydroperoxide-type radical. The present work provides the first analysis of ethyloxirane oxidation chemistry, which reveals that consumption pathways are complex and may require an expansion of submechanisms to increase the fidelity of chemical kinetics mechanisms.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Isomer-Dependent Reaction Mechanisms of Cyclic Ether Intermediates: cis -23-Dimethyloxirane and trans -23-Dimethyloxirane.

Oxiranes are a class of cyclic ethers formed in abundance during low-temperature combustion of hydrocarbons and biofuels, either via chain-propagating steps that occur from unimolecular decomposition of β-hydroperoxyalkyl radicals (β-˙QOOH) or from reactions of HÒO with alkenes. The cis- and trans-isomers of 2,3-dimethyloxirane are intermediates of n-butane oxidation, and while rate coefficients for β-˙QOOH → 2,3-dimethyloxirane + OH are reported extensively, subsequent reaction mechanisms of the cyclic ethers are not. As a result, chemical kinetics mechanisms commonly adopt simplified chemistry to describe the consumption of 2,3-dimethyloxirane by convoluting several elementary reactions into a single step, which may introduce mechanism truncation error—uncertainty derived from missing or incomplete chemistry. The present research examines the isomerdependence of 2,3-dimethyloxirane reaction mechanisms in support of ongoing efforts to minimize mechanism truncation error. Reaction mechanisms are inferred via the detection of products from Cl-initiated oxidation of both cis-2,3-dimethyloxirane and trans-2,3-dimethyloxirane using multiplexed photoionization mass spectrometry (MPIMS). The experiments were conducted at 10 Torr and temperatures of 650 K and 800 K. To complement the experiments, the enthalpies of stationary points on the ˙R + O 2 surfaces were computed at the ccCA-PS3 level of theory. In total, 28 barrier heights were computed on the 2,3-dimethyloxiranylperoxy surfaces. Two notable aspects are low-lying pathways that form resonance-stabilized ketohydroperoxide-type radicals caused by ˙QOOH ring-opening when the unpaired electron is localized adjacent to the ether group, and cis-trans isomerization of ˙R and ˙QOOH radicals, via inversion, which enable reaction pathways otherwise restricted by stereochemistry. Several species were identified in the MPIMS experiments from ring opening of 2,3-dimethyloxiranyl radicals. Neither of the two conjugate alkene isomers prototypical of ˙R + O 2 reactions were detected. Products were also identified from decomposition of ketohydroperoxide-type radicals. The present work provides the first analysis of 2,3-dimethyloxirane oxidation chemistry and reveals that consumption pathways are complex and require the expansion of submechanisms in chemical kinetics mechanisms.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2015

Enhancing Bottom-up and Top-down Proteomic Measurements with Ion Mobility Separations

Proteomic measurements with greater throughput, sensitivity and additional structural information enhance the in-depth characterization of complex mixtures and targeted studies with additional information and higher confidence. While liquid chromatography separation coupled with mass spectrometry (LC-MS) measurements have provided information on thousands of proteins in different sample types, the additional of another rapid separation stage providing structural information has many benefits for analyses. Technical advances in ion funnels and multiplexing have enabled ion mobility separations to be easily and effectively coupled with LC-MS proteomics to enhance the information content of measurements. Finally, herein, we report on applications illustrating increased sensitivity, throughput, and structural information by utilizing IMS-MS and LC-IMS-MS measurements for both bottom-up and top-down proteomics measurements.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Flying Blind, or Just Flying Under the Radar? The Underappreciated Power of De Novo Methods of Mass Spectrometric Peptide Identification

Mass spectrometry-based proteomics is a popular and powerful method for precise and highly multiplexed protein identification. The most common method of analyzing untargeted proteomics data is called database searching, where the database is simply a collection of protein sequences from the target organism, derived from genome sequencing. Experimental peptide tandem mass spectra are compared to simplified models of theoretical spectra calculated from the translated genomic sequences. However, in several interesting application areas, such as forensics, archaeology, venomics and others, a genome sequence may not be available, or the correct genome sequence to use is not known. In these cases, de novo peptide identification can play an important role. De novo peptide identification infers peptide sequence directly from the tandem mass spectrum without reference to a sequence database, usually using graph-based or machine learning algorithms. In this review, we provide a basic overview of de novo peptide identification methods and applications, briefly covering de novo algorithms and tools, and focusing in more depth on recent applications from venomics, metaproteomics, forensics, and characterization of antibody drugs.

proteomics, mass spectrometry, forensics, de novo ↗
DOE OSTI2018

Autonomous Magnetic Microrobots by Navigating Gates for Multiple Biomolecules Delivery

The precise delivery of biofunctionalized matters is of great interest from the fundamental and applied viewpoints. In spite of significant progress achieved during the last decade, a parallel and automated isolation and manipulation of rare analyte, and their simultaneous on-chip separation and trapping, still remain challenging. In this work, a universal micromagnet junction for self-navigating gates of microrobotic particles to deliver the biomolecules to specific sites using a remote magnetic field is described. In the proposed concept, the nonmagnetic gap between the lithographically defined donor and acceptor micromagnets creates a crucial energy barrier to restrict particle gating. It is shown that by carefully designing the geometry of the junctions, it becomes possible to deliver multiple protein-functionalized carriers in high resolution, as well as MCF-7 and THP-1 cells from the mixture, with high fidelity and trap them in individual apartments. Integration of such junctions with magnetophoretic circuitry elements could lead to novel platforms without retrieving for the synchronous digital manipulation of particles/biomolecules in microfluidic multiplex arrays for next-generation biochips.

36 MATERIALS SCIENCE↗
DOE OSTI2023

Use of Longitudinal Serum Analysis and Machine Learning to Develop a Classifier for Cancer Early Detection

Early detection of solid tumors through a simple screening process, such as the proteomic analysis of biofluids, has the potential to significantly alter the management and outcomes of cancers. The application of advanced targeted proteomics measurements and data analysis strategies to uniformly collected serum or plasma samples would enable longitudinal studies of cancer risk, progression, and response to therapy that have the potential to significantly reduce cancer burden in general. In this article, we describe a generalizable workflow combining robust, multiplexed targeted proteomics measurements applied to longitudinal samples from the Department of Defense Serum Repository with a Random Forest machine learning method for developing and initially evaluating the performance of candidate biomarker panels for early detection of cancers. The effectiveness of this approach was demonstrated in a cohort of 175 head and neck squamous cell carcinoma patients. The outlined protocols include methods for sample preparation, instrument analysis, and data analysis and interpretation using this workflow.

Longitudinal analysis, machine learning, cancer, e↗
DOE OSTI2016

Large-Scale and Deep Quantitative Proteome Profiling Using Isobaric Labeling Coupled with Two-Dimensional LC-MS/MS

Comprehensive, quantitative information on abundances of proteins and their post-translational modifications (PTMs) can potentially provide novel biological insights into diseases pathogenesis and therapeutic intervention. Herein, we introduce a quantitative strategy utilizing isobaric stable isotope-labelling techniques combined with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS) for large-scale, deep quantitative proteome profiling of biological samples or clinical specimens such as tumor tissues. The workflow includes isobaric labeling of tryptic peptides for multiplexed and accurate quantitative analysis, basic reversed-phase LC fractionation and concatenation for reduced sample complexity, and nano-LC coupled to high resolution and high mass accuracy MS analysis for high confidence identification and quantification of proteins. This proteomic analysis strategy has been successfully applied for in-depth quantitative proteomic analysis of tumor samples, and can also be used for integrated proteome and PTM characterization, as well as comprehensive quantitative proteomic analysis across samples from large clinical cohorts.

Environmental Molecular Sciences Laboratory↗
DOE OSTI2025

Cohort-based pan-cancer analysis and experimental studies reveal ISG15 gene as a novel biomarker for prognosis and immunotherapy efficacy prediction

Abstract ISG15, an interferon-stimulated ubiquitin-like protein, plays a multifaceted role in tumorigenesis and immune regulation. This study comprehensively evaluates ISG15 as a prognostic biomarker and predictor of immunotherapy response through pan-cancer bioinformatics analysis and experimental validation. By integrating multiomics data from TCGA, GEO, and clinical cohorts, we found that ISG15 is significantly overexpressed in multiple cancers and generally correlates with poor prognosis. Elevated ISG15 expression is associated with increased immune checkpoint gene expression, particularly PD-L1, and immune infiltration, notably M2-like tumor-associated macrophages. Immunohistochemistry and multiplexed immunofluorescence confirmed a strong positive correlation between ISG15, PD-L1, and M2-TAM infiltration in lung and gastric cancer samples. Functional analysis at the single-cell level revealed significant associations between ISG15 and tumor proliferation, angiogenesis, and immune suppression. Immunotherapy cohort analysis demonstrated that tumors with high ISG15 expression responded favorably to PD-L1 inhibitors but exhibited resistance to CTLA-4 blockade, findings further validated in lung cancer patients receiving anti-PD-1 therapy. These results suggest that ISG15 is a promising biomarker for prognosis and immunotherapy response prediction across cancers. Its integration into clinical decision-making may enhance personalized treatment strategies, improve immunotherapy outcomes, and provide new insights into the tumor immune microenvironment, cancer progression, and potential therapeutic targets for future drug development.

Immunology↗