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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 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

Protein structure prediction guided by crosslinking restraints – A systematic evaluation of the impact of the crosslinking spacer length

Recent development of high-resolution mass spectrometry (MS) instruments enables chemical crosslinking (XL) to become a high-throughput method for obtaining structural information about proteins. Restraints derived from XL-MS experiments have been used successfully for structure refinement and protein–protein docking. However, one formidable question is under which circumstances XL-MS data might be sufficient to determine a protein’s tertiary structure de novo? Answering this question will not only include understanding the impact of XL-MS data on sampling and scoring within a de novo protein structure prediction algorithm, it must also determine an optimal crosslinker type and length for protein structure determination. While a longer crosslinker will yield more restraints, the value of each restraint for protein structure prediction decreases as the restraint is consistent with a larger conformational space. In this study, the number of crosslinks and their discriminative power was systematically analyzed in silico on a set of 2055 non-redundant protein folds considering Lys–Lys, Lys–Asp, Lys–Glu, Cys–Cys, and Arg–Arg reactive crosslinkers between 1 and 60 Å. Depending on the protein size a heuristic was developed that determines the optimal crosslinker length. Next, simulated restraints of variable length were used to de novo predict the tertiary structure of fifteen proteins using the BCL::Fold algorithm. The results demonstrate that a distinct crosslinker length exists for which information content for de novo protein structure prediction is maximized. The sampling accuracy improves on average by 1.0 Å and up to 2.2 Å in the most prominent example. XL-MS restraints enable consistently an improved selection of native-like models with an average enrichment of 2.1.

Biochemistry & Molecular Biology↗
DOE OSTI2025

Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1)Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model

Abstract The B cell lymphoma 2 (Bcl-2) family of proteins are key regulators of intrinsic apoptosis. The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1), which is associated with high tumor grade, poor survival, and resistance to treatment, has emerged as a promising candidate for treating hematological and solid cancers. Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the (R)-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed. The macrocyclic inhibitors bind Mcl-1 with subnanomolar affinity and offer improved potency in cell culture growth inhibition assays. Inhibitor 13 achieved tumor regression in a lung cancer-derived tumor xenograft model in mice as a monotherapy. The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor 25 displayed a >10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors.

Pharmacology & Pharmacy↗
DOE OSTI2018

Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Furthermore, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption

Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac 239 -infected rhesus macaques (RMs) were treated with anti-IL-10, anti-IL-10 plus anti-PD-1 (combo) or vehicle. ART was interrupted 12 weeks after introduction of immunotherapy. Durable control of viral rebound was observed in nine out of ten combo-treated RMs for >24 weeks post-ATI. Induction of inflammatory cytokines, proliferation of effector CD8 + T cells in lymph nodes and reduced expression of BCL-2 in CD4 + T cells pre-ATI predicted control of viral rebound. Twenty-four weeks post-ATI, lower viral load was associated with higher frequencies of memory T cells expressing TCF-1 and of SIV-specific CD4 + and CD8 + T cells in blood and lymph nodes of combo-treated RMs. These results map a path to achieve long-lasting control of HIV and/or SIV following discontinuation of ART.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

miR-98 and its host gene Huwe1 target Caspase-3 in Silica nanoparticles-treated male germ cells

Silica nanoparticles (NP) is one of the most commonly used nanomaterials with potential health hazards. However, the effects of Silica NP on germ cells and the underlying mechanisms are still unclear. In this study, GC-2 and TM-4, which are two different types of male germ cells were exposed to Silica NP for 24h and then general cytotoxicity and multi-parameter cytotoxicity were evaluated. Our results showed that Silica NP could induce apoptosis in GC-2 cells. Transmission electron microscopy (TEM) results showed that Silica NP was localized in the lysosomes of GC-2 cells. High content screening (HCS) showed that Silica NP exposure could increased cell permeabilization and decreased mitochondrial membrane potential in GC-2 cells. The mRNA and protein levels of apoptosis markers (Bax, Caspase-3, Caspase-9) in GC-2 cells were significantly increased, while Bcl-2 was decreased. Accordingly, the expression level of miR-98, which can regulate Caspase-3, was significantly decreased. Huwe1, the host gene of miR-98, was positively associated with miR-98 expression after Silica NP exposure. Dual luciferase reporter assay suggested that miR-98 directly targets Caspase-3. These results suggest that Silica NP induces apoptosis via loss of mitochondrial membrane potential and Caspase-3 activation, while miR-98 plays key role in modulating this effect.

Science & Technology - Other Topics↗
DOE OSTI2015

An experimental and theoretical study of the electronic spectrum of the HBCl free radical

Following our previous discovery of the spectra of the HBX (X = F, Cl, and Br) free radicals [S.-G. He, F. X. Sunahori, and D. J. Clouthier, J. Am. Chem. Soc. 127, 10814 (2005)], the A{sup ~2}A{sup ″}Π−X{sup ~2}A{sup ′} band systems of the HBCl and DBCl free radicals have been studied in detail. The radicals have been prepared in a pulsed electric discharge jet using a precursor mixture of BCl{sub 3} and H{sub 2} or D{sub 2} in high pressure argon. Laser-induced fluorescence (LIF) and single vibronic level emission spectra have been recorded to map out the ground and excited state vibrational energy levels. The band system involves a linear-bent transition between the two Renner-Teller components of what would be a {sup 2}Π electronic state at linearity. We have used high level ab initio theory to calculate the ground and excited state potential energy surfaces and have determined the vibronic energy levels variationally. The theory results were used to assign the LIF spectra which involve transitions from the ground state zero-point level to high vibrational levels of the excited state. The correspondence between theory and experiment, including the transition frequencies, upper state band symmetries, and H, B, and Cl isotope shifts, was used to validate the assignments.

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

Applied quantum chemistry: Spectroscopic detection and characterization of the F{sub 2}BS and Cl{sub 2}BS free radicals in the gas phase

In this and previous work [D. J. Clouthier, J. Chem. Phys. 141, 244309 (2014)], the spectroscopic signatures of the X{sub 2}BY (X = H, halogen, Y = O, S) free radicals have been predicted using high level ab initio theory. The theoretical results have been used to calculate the electronic absorption and single vibronic level (SVL) emission spectra of the radicals under typical jet-cooled conditions. Using these diagnostic predictions, the previously unknown F{sub 2}BS and Cl{sub 2}BS free radicals have been identified and characterized. The radicals were prepared in a free jet expansion by subjecting precursor mixtures of BF{sub 3} or BCl{sub 3} and CS{sub 2} vapor to an electric discharge at the exit of a pulsed molecular beam valve. The B{sup ~2}A{sub 1}–X{sup ~} {sup 2}B{sub 2} laser-induced fluorescence spectra were found within 150 cm{sup −1} of their theoretically predicted positions with vibronic structure consistent with our Franck-Condon simulations. The B{sup ~2}A{sub 1} state emits down to the ground state and to the low-lying A{sup ~2}B{sub 1} excited state and the correspondence between the observed and theoretically derived SVL emission Franck-Condon profiles was used to positively identify the radicals and make assignments. Excited state Coriolis coupling effects complicate the emission spectra of both radicals. In addition, a forbidden component of the electronically allowed B{sup ~}–X{sup ~} band system of Cl{sub 2}BS is evident, as signaled by the activity in the b{sub 2} modes in the spectrum. Symmetry arguments indicate that this component gains intensity due to a vibronic interaction of the B{sup ~2}A{sub 1} state with a nearby electronic state of {sup 2}B{sub 2} symmetry.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2022

β -Ga 2 O 3 Schottky barrier diodes with 4.1 MV/cm field strength by deep plasma etching field-termination Available

In this work, we demonstrate a deep mesa etch design for efficient edge field termination in β-Ga 2 O 3 Schottky barrier diodes (SBDs). The proposed design enabled parallel plate fields higher than 4.1 MV/cm with negligible change to the device ON characteristics. The effect of BCl 3 /Cl 2 -based dry etch on (100) and (010) etched vertical sidewalls is also analyzed. A remarkable anisotropy in depletion was observed for etch along (100) and (010) sidewalls. In conclusion, this work provides insight into the impact of etching on n-type Ga 2 O 3 and shows a promising method to realize efficient field termination for high breakdown field strength SBDs.

42 ENGINEERING↗
DOE OSTI2024

Altered post-fracture systemic bone loss in a mouse model of osteocyte dysfunction

Femur fracture leads to loss of bone at uninjured skeletal sites, which may increase risk of subsequent fracture. Osteocytes, the most abundant bone cells, can directly resorb bone matrix and regulate osteoclast and osteoblast activity, but their role in systemic bone loss after fracture remains poorly understood. In this study we used a transgenic (TG+) mouse model that overexpresses human B-cell lymphoma 2 (BCL-2) in osteoblasts and osteocytes. This causes enhanced osteoblast proliferation, followed by disruption in lacunar-canalicular connectivity and massive osteocyte death by 10 wk of age. We hypothesized that reduced viable osteocyte density would decrease the magnitude of systemic bone loss after femur fracture, reduce perilacunar remodeling, and alter callus formation. Bone remodeling was assessed using serum biomarkers of bone formation and resorption at 5 d post-fracture. We used micro-computed tomography, high resolution x-ray microscopy, mechanical testing, and Raman spectroscopy to quantify the magnitude of systemic bone loss, as well as changes in osteocyte lacunar volume, bone strength, and bone composition 2 wk post-fracture. Fracture was associated with a reduction in circulating markers of bone resorption in non-transgenic (TG-) animals. TG+ mice exhibited high bone mass in the limbs, greater cortical elastic modulus and reduced post-yield displacement. After fracture, TG+ mice lost less trabecular bone than TG- mice, but conversely TG+ mice exhibited trends toward a lower yield point and reduced femoral cortical thickness after fracture, though these were not statistically significant. Lacunar density was greater in TG+ mice, but fracture did not alter lacunar volume in TG+ or TG- mice. These findings suggest that osteocytes potentially play a significant role in the post-traumatic systemic response to fracture, though the effects differ between trabecular and cortical bone.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Evolution of titanium residue on the walls of a plasma-etching reactor and its effect on the polysilicon etching rate

The variation in polysilicon plasma etching rates caused by Ti residue on the reactor walls was investigated. The amount of Ti residue was measured using attenuated total reflection Fourier transform infrared spectroscopy with the HgCdTe (MCT) detector installed on the side of the reactor. As the amount of Ti residue increased, the number of fluorine radicals and the polysilicon etching rate increased. However, a maximum limit in the etching rate was observed. A mechanism of rate variation was proposed, whereby F radical consumption on the quartz reactor wall is suppressed by the Ti residue. The authors also investigated a plasma-cleaning method for the removal of Ti residue without using a BCl{sub 3} gas, because the reaction products (e.g., boron oxide) on the reactor walls frequently cause contamination of the product wafers during etching. CH-assisted chlorine cleaning, which is a combination of CHF{sub 3} and Cl{sub 2} plasma treatment, was found to effectively remove Ti residue from the reactor walls. This result shows that CH radicals play an important role in deoxidizing and/or defluorinating Ti residue on the reactor walls.

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

In-situ etch rate study of Hf{sub x}La{sub y}O{sub z} in Cl{sub 2}/BCl{sub 3} plasmas using the quartz crystal microbalance

The etch rate of Hf{sub x}La{sub y}O{sub z} films in Cl{sub 2}/BCl{sub 3} plasmas was measured in-situ in an inductively coupled plasma reactor using a quartz crystal microbalance and corroborated by cross-sectional SEM measurements. The etch rate depended on the ion energy as well as the plasma chemistry. In contrast to other Hf-based ternary oxides, the etch rate of Hf{sub x}La{sub y}O{sub z} films was higher in Cl{sub 2} than in BCl{sub 3}. In the etching of Hf{sub 0.25}La{sub 0.12}O{sub 0.63}, Hf appeared to be preferentially removed in Cl{sub 2} plasmas, per surface compositional analysis by x-ray photoelectron spectroscopy and the detection of HfCl{sub 3} generation in mass spectroscopy. These findings were consistent with the higher etch rate of Hf{sub 0.25}La{sub 0.12}O{sub 0.63} than that of La{sub 2}O{sub 3}.

36 MATERIALS SCIENCE↗
DOE OSTI2016

Comparison of B{sub 2}O{sub 3} and BN deposited by atomic layer deposition for forming ultrashallow dopant regions by solid state diffusion

In this study, the authors investigated atomic layer deposition (ALD) of B{sub 2}O{sub 3} and BN for conformal, ultrashallow B doping applications and compared the effect of dopant-containing overlayers on sheet resistance (R{sub s}) and B profiles for both types of films subjected to a drive-in thermal anneal. For the deposition of B{sub 2}O{sub 3}, tris(dimethylamido)borane and O{sub 3} were used as coreactants and for the deposition of BN, BCl{sub 3} and NH{sub 3} were used as coreactants. Due to the extreme air instability of B{sub 2}O{sub 3} films, physical analysis was performed on B{sub 2}O{sub 3} films, which were capped in-situ with ∼30 Å ALD grown Al{sub 2}O{sub 3} layers. For the BN films, in-situ ALD grown Si{sub 3}N{sub 4} capping layers (∼30 Å) were used for comparison. From spectroscopic ellipsometry, a thickness decrease was observed after 1000 °C, 30 s anneal for the B{sub 2}O{sub 3} containing stack with 60 ALD cycles of B{sub 2}O{sub 3}, whereas the BN containing stacks showed negligible thickness decrease after the annealing step, regardless of the number of BN cycles tested. The postanneal reduction in film thickness as well as decrease in R{sub s} for the B{sub 2}O{sub 3} containing stack suggests that the solid state diffusion dopant mechanism is effective, whereas for the BN containing stacks this phenomenon seems to be suppressed. Further clarification of the effectiveness of the B{sub 2}O{sub 3} containing layer compared to the film stacks with BN was evidenced in backside secondary ion mass spectrometry profiling of B atoms. Thus, B{sub 2}O{sub 3} formed by an ALD process and subsequently capped in-situ followed by a drive-in anneal offers promise as a dopant source for ultrashallow doping, whereas the same method using BN seems ineffective. An integrated approach for B{sub 2}O{sub 3} deposition and annealing on a clustered tool also demonstrated controllable R{sub s} reduction without the use of a capping layer.

36 MATERIALS SCIENCE↗
DOE OSTI2022

Hole in one: Pathways to deterministic single-acceptor incorporation in Si(100)-2 x 1

We report that stochastic incorporation kinetics can be a limiting factor in the scalability of semiconductor fabrication technologies using atomic-precision techniques. While these technologies have recently been extended from donors to acceptors, the extent to which kinetics will impact single-acceptor incorporation has yet to be assessed. To identify the precursor molecule and dosing conditions that are promising for deterministic incorporation, we develop and apply an atomistic model for the single-acceptor incorporation rates of several recently demonstrated molecules: diborane (B 2 H 6 ), boron trichloride (BCl 3 ), and aluminum trichloride in both monomer (AlCl 3 ) and dimer forms (Al 2 Cl 6 ). While all three precursors can realize single-acceptor incorporation, we predict that diborane is unlikely to realize deterministic incorporation, boron trichloride can realize deterministic incorporation with modest heating (50 °C), and aluminum trichloride can realize deterministic incorporation at room temperature. We conclude that both boron and aluminum trichloride are promising precursors for atomic-precision single-acceptor applications, with the potential to enable the reliable production of large arrays of single-atom quantum devices.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2016

Fabrication of a terahertz quantum-cascade laser with a double metal waveguide based on multilayer GaAs/AlGaAs heterostructures

The Postgrowth processing of GaAs/AlGaAs multilayer heterostructures for terahertz quantumcascade lasers (QCLs) are studied. This procedure includes the thermocompression bonding of In–Au multilayer heterostructures with a doped n{sup +}-GaAs substrate, mechanical grinding, and selective wet etching of the substrate, and dry etching of QCL ridge mesastripes through a Ti/Au metallization mask 50 and 100 μm wide. Reactive-ion-etching modes with an inductively coupled plasma source in a BCl{sub 3}/Ar gas mixture are selected to obtain vertical walls of the QCL ridge mesastripes with minimum Ti/Au mask sputtering.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Low-Energy Defectless Dry Etching of the AlGaN/AlN/GaN HEMT Barrier Layer

A method of defectless dry etching of an AlGaN barrier layer is proposed, which consists in repeated plasmachemical oxidation of AlGaN and removal of the oxide layer by means of reactive ion etching in inductively coupled BCl{sub 3} plasma. Using the proposed etching technology, AlGaN/AlN/GaN high-electron-mobility transistors (HEMTs) with a buried gate have been successfully fabricated for the first time. It is shown that the currents of obtained HEMTs are independent of the number of etching cycles, while the gate operating point shifts toward positive voltages up to obtaining transistors operating in the enhancement mode.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2022

Protective Effect of Phloretin against Hydrogen Peroxide-Induced Oxidative Damage by Enhancing Autophagic Flux in DF-1 Cells

Phloretin (PHL) is a dihydrochalcone flavonoid isolated from the peel and root bark of apples, strawberries, and other plants with antioxidative characteristic. In this study, we aimed to investigate the protective effect and the potential mechanism of PHL on hydrogen peroxide (H2O2)-induced oxidative damage in DF-1 cells. The results showed that PHL exhibited no cytotoxic effect on DF-1 cells at concentration below 20 μM. PHL markedly increased H2O2-reduced cell viability, decreased H2O2-induced apoptosis, as evidenced by reduced apoptosis rate, the upregulation of gene and protein level of Bcl-2, and the downregulation of gene and protein level of Bax and Cleaved caspase3. In addition, PHL reduced H2O2-induced reactive oxygen species (ROS) production and restored antioxidant enzymes activities as well as mitochondrial membrane potential in a dose-dependent manner. Moreover, PHL prior to H2O2 further increased LC3-II level, promoted p62 turnover and improved lysosomal function. Importantly, autophagy inhibitor chloroquine (CQ) reversed the protective effect of PHL, and increased H2O2-induced apoptosis. Furthermore, PHL inhibited the phosphorylation levels of ERK, p38, and JNK. Collectively, these results indicate that PHL could attenuate H2O2-induced oxidative injury and apoptosis by maintaining lysosomal function and promoting autophagic flux, and MAPKs pathway may be involved in this process. Our study provides evidence that PHL could as a new strategy to against oxidative damage in poultry industry.

Song, Dan↗
DOE OSTI2020

Materials Data on LiB6S4(Cl3O4)2 by Materials Project

Li(SO2)4(BCl)6 crystallizes in the triclinic P-1 space group. The structure is zero-dimensional and consists of twelve chloroborane molecules and one Li(SO2)4 cluster. In the Li(SO2)4 cluster, Li1+ is bonded in a trigonal bipyramidal geometry to five O2- atoms. There are a spread of Li–O bond distances ranging from 2.03–2.28 Å. There are four inequivalent S+0.75+ sites. In the first S+0.75+ site, S+0.75+ is bonded in a bent 120 degrees geometry to two O2- atoms. Both S–O bond lengths are 1.45 Å. In the second S+0.75+ site, S+0.75+ is bonded in a bent 120 degrees geometry to two O2- atoms. There is one shorter (1.45 Å) and one longer (1.46 Å) S–O bond length. In the third S+0.75+ site, S+0.75+ is bonded in a bent 120 degrees geometry to two O2- atoms. Both S–O bond lengths are 1.45 Å. In the fourth S+0.75+ site, S+0.75+ is bonded in a bent 120 degrees geometry to two O2- atoms. Both S–O bond lengths are 1.45 Å. There are eight inequivalent O2- sites. In the first O2- site, O2- is bonded in a linear geometry to one Li1+ and one S+0.75+ atom. In the second O2- site, O2- is bonded in a bent 150 degrees geometry to one Li1+ and one S+0.75+ atom. In the third O2- site, O2- is bonded in a bent 150 degrees geometry to one Li1+ and one S+0.75+ atom. In the fourth O2- site, O2- is bonded in a single-bond geometry to one S+0.75+ atom. In the fifth O2- site, O2- is bonded in a bent 150 degrees geometry to one Li1+ and one S+0.75+ atom. In the sixth O2- site, O2- is bonded in a single-bond geometry to one S+0.75+ atom. In the seventh O2- site, O2- is bonded in a bent 150 degrees geometry to one Li1+ and one S+0.75+ atom. In the eighth O2- site, O2- is bonded in a single-bond geometry to one S+0.75+ atom.

36 MATERIALS SCIENCE↗