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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 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity

Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1R132H mutation destabilizes an IDH1 “regulatory segment,” which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity. We also report crystal structures of oncogenic IDH2 mutant isoforms, highlighting the fact that the analogous segment of IDH2 is not similarly destabilized. This intrinsic stability of IDH2 may contribute to observed inhibitor IDH1 isoform selectivity. Moreover, discrete residues in the IDH1 allosteric pocket that differ from IDH2 may also guide IDH1 isoform selectivity. These data provide a deeper understanding of how IDH1 inhibitors achieve mutant and isoform selectivity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Single-cell RNA sequencing reveals an altered gene expression pattern as a result of CRISPR/cas9-mediated deletion of Gene 33/Mig6 and chronic exposure to hexavalent chromium in human lung epithelial cells

Gene 33 (Mig6, ERRFI1) is an adaptor protein with multiple cellular functions. We recently reported that depletion of this protein promotes lung epithelial cell transformation induced by hexavalent chromium [Cr(VI)]. However, the early molecular events that mediate this process are not clear. In the present study, we used single-cell RNA sequencing to compare gene expression profiles between BEAS-2B lung epithelial cells chronically exposed to a sublethal dose of Cr(VI) with or without CRISPR/cas9-mediated deletion of Gene 33. Our data reveal 83 differentially expressed genes. The most notable changes are genes associated with cell adhesion, oxidative stresses, protein ubiquitination, epithelial-mesenchymal transition/metastasis, and WNT signaling. Up-regulation of some neuro-specific genes is also evident, particularly ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a deubiquitinase and potential biomarker for lung cancer. Gene 33 deletion and/or Cr(VI) exposure did not cause discernable changes in cell morphology. However, Gene 33 deletion led to a modest but significant reduction of cells in the G2/M phase of the cell cycle regardless of Cr(VI) exposure. Gene 33 deletion also significantly reduced cell proliferation. Interestingly, Cr(VI) exposure eliminated the difference in cell proliferation between the two genotypes. Gene 33 deletion also significantly elevated cell migration. Our data indicate that combined Gene 33 deletion and chronic Cr(VI) exposure produces a gene expression pattern and a phenotype resemble those of the transformed lung epithelial cells. Given the known association of UCHL1 with lung cancer, we propose that UCHL1 is an important player in the early stage of lung epithelial cell transformation and tumorigenesis. - Highlights: • CRISPR/cas9-mediated deletion of Gene 33 (Mig6, ERRFI1) was carried out in BEAS-2B cells. • Single cell RNA-seq revealed 83 differentially expressed genes as a result of Gene 33 depletion and chronic Cr(VI) exposure. • UCHL1 and KRBOX1 are the most differentially expressed genes. • Gene 33-depleted cells showed a phenotype and a gene expression pattern indicating cell transformation. • UCHL1 may play a key role in lung epithelial cell transformation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Atom-at-a-Time Radioactive Molecule Identification: Looking toward Studies of Superheavy Elements

The chemical behavior of superheavy elements (SHEs, Z > 103) remains poorly understood. Their chemical properties are expected to deviate from established trends, challenging the predictive power of the periodic table. To investigate these elements experimentally, they must first be synthesized through nuclear reactions and then quickly subjected to chemical studies before they decay. Given the low production rates of these reactions and the need for measurements on an atom-at-a-time basis, innovative techniques are needed. Here, to address these challenges, a novel gas-phase chemistry method has been developed at Lawrence Berkeley National Laboratory, utilizing the Berkeley Gas-filled Separator and FIONA. This technique enables the production, identification, and study of molecular species formed by SHEs. As a proof of concept, we present measurements on the formation and identification of 151,152 HoO + molecules, demonstrating the capability to study the production of radioactive molecules under controlled conditions and directly identify them via their mass-to-charge ratio. These measurements validate the effectiveness of this technique for low-statistics SHE studies, highlighting the potential of this approach to ignite the next generation of experimental SHE chemistry research, offering a path to re-evaluate SHE placement on the periodic table.

Chemistry↗
DOE OSTI2019

Efficient Thick-Film Polymer Solar Cells with Enhanced Fill Factors via Increased Fullerene Loading

Developing effective methods to make efficient bulk-heterojunction polymer solar cells at roll-to-roll relevant active layer thickness is of significant importance. We investigate the effect of fullerene content in polymer:fullerene blends on the fill factor (FF) and on the performance of thick-film solar cells for four different donor polymers PTB7-Th, PDPP-TPT, BDT-FBT-2T, and poly[5,5'-bis(2-butyloctyl)-(2,2'-bithiophene)-4,4'-dicarboxylate-alt-5,5'-2,2'-bithiophene] (PDCBT). At a few hundreds of nanometers thickness, increased FFs are observed in all cases and improved overall device performances are obtained except for PDCBT upon increasing fullerene content in blend films. This fullerene content effect was studied in more detail by electrical and morphological characterization. The results suggest enhanced electron mobility and suppressed bimolecular recombination upon increasing fullerene content in thick polymer:fullerene blend films, which are the result of larger fullerene aggregates and improved interconnectivity of the fullerene phases that provide continuous percolating pathways for electron transport in thick films. These findings are important because an effective and straightforward method that enables fabricating efficient thick-film polymer solar cells is desirable for large-scale manufacturing via roll-to-roll processing and for multijunction devices.

14 SOLAR ENERGY↗
DOE OSTI2016

Optimization of 3-Pyrimidin-4-yl-oxazolidin-2-ones as Allosteric and Mutant Specific Inhibitors of IDH1

High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1 R132H . Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure–activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood–brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.

2-HG↗
DOE OSTI2013

Atomic mass dependent electrostatic diagnostics of colliding laser plasma plumes

The behaviours of colliding laser plasma plumes (C{sub p}) compared with single plasma plumes (S{sub p}) are investigated for 14 different atomic mass targets. A Faraday cup, situated at the end of a drift tube (L = 0.99 m), is employed to record the time-of-flight (TOF) current traces for all elements and both plume configurations, for a fixed laser intensity of I{sub p} = 4.2 × 10{sup 10} W cm{sup −2} (F = 0.25 kJ cm{sup −2}). The ratio of the peak current from the C{sub p} relative to twice that from the S{sub p} is designated as the peak current ratio while the ratio of the integrated charge yield from the C{sub p} relative to twice that from the S{sub p} is designated as the charge yield ratio. Variation of the position of the Faraday cup within the drift tube (L = 0.33, 0.55, and 0.99 m) in conjunction with a lower laser fluence (F = 0.14 kJ cm{sup −2}) facilitated direct comparison of the changing TOF traces from both plasma configurations for the five lightest elements studied (C, Al, Si, Ti, and Mn). The results are discussed in the frame of laser plasma hydrodynamic modelling to approximate the critical recombination distance L{sub CR}. The dynamics of colliding laser plasma plumes and the atomic mass dependence trends observed are presented and discussed.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2014

Photon strength and the low-energy enhancement

Several measurements in medium mass nuclei have reported a low-energy enhancement in the photon strength function. Although, much effort has been invested in unraveling the mysteries of this effect, its physical origin is still not conclusively understood. Here, a completely model-independent experimental approach to investigate the existence of this enhancement is presented. The experiment was designed to study statistical feeding from the quasi-continuum (below the neutron separation energy) to individual low-lying discrete levels in {sup 95}Mo produced in the (d, p) reaction. A key aspect to successfully study gamma decay from the region of high-level density is the detection and extraction of correlated particle-gamma-gamma events which was accomplished using an array of Clover HPGe detectors and large area annular silicon detectors. The entrance channel excitation energy into the residual nucleus produced in the reaction was inferred from the detected proton energies in the silicon detectors. Gating on gamma-transitions originating from low-lying discrete levels specifies the state fed by statistical gamma-rays. Any particle-gamma-gamma event in combination with specific energy sum requirements ensures a clean and unambiguous determination of the initial and final state of the observed gamma rays. With these requirements the statistical feeding to individual discrete levels is extracted on an event-by-event basis. The results are presented and compared to {sup 95}Mo photon strength function data measured at the University of Oslo.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2014

Ion flux enhancements and oscillations in spatially confined laser produced aluminum plasmas

Ion signals from laser produced plasmas (LPPs) generated inside aluminum rectangular cavities at a fixed depth d = 2 mm and varying width, x = 1.0, 1.6, and 2.75 mm were obtained by spatially varying the position of a negatively biased Langmuir probe. Damped oscillatory features superimposed on Maxwellian distributed ion signals were observed. Depending on the distance of the probe from the target surface, three to twelve fold enhancements in peak ion density were observed via confinement of the LPP, generated within rectangular cavities of varying width which constrained the plasma plume to near one dimensional expansion in the vertical plane. The effects of lateral spatial confinement on the expansion velocity of the LPP plume front, the temperature, density and expansion velocity of ions, enhancement of ion flux, and ion energy distribution were recorded. The periodic behavior of ion signals was analyzed and found to be related to the electron plasma frequency and electron-ion collision frequency. The effects of confinement and enhancement of various ion parameters and expansion velocities of the LPP ion plume are explained on the basis of shock wave theory.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2022

A Decade of GRETINA Science

High-resolution γ-ray detector arrays have driven many scientific advances and discoveries in nuclear physics. Today, they provide a powerful and essential tool for a broad class of measurements in the study of nuclear structure and reactions, nuclear astrophysics, and applied nuclear science. In this article, we present an overview of the scientific program that has been enabled by the γ-ray tracking array GRETINA [Pas13]. This program is being carried out at both stable and radioactive ion beam facilities, employs a wide range of beam energies and reactions (from the Coulomb barrier to more than 30% the speed of light), and reflects the varied application of a γ-ray tracking array.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2016

Xenon bubble chambers for direct dark matter detection

The search for dark matter is one of today's most exciting fields. As bigger detectors are being built to increase their sensitivity, background reduction is an ever more challenging issue. To this end, a new type of dark matter detector is proposed, a xenon bubble chamber, which would combine the strengths of liquid xenon TPCs, namely event by event energy resolution, with those of a bubble chamber, namely insensitivity to electronic recoils. In addition, it would be the first time ever that a dark matter detector is active on all three detection channels, ionization and scintillation characteristic of xenon detectors, and heat through bubble formation in superheated fluids. Preliminary simulations show that, depending on threshold, a discrimination of 99.99% to 99.9999+% can be achieved, which is on par or better than many current experiments. Furthermore, a prototype is being built at the University at Albany, SUNY. The prototype is currently undergoing seals, thermal, and compression testing.

Dark Matter detectors↗