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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 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

β1,6 GlcNAc branches-modified protein tyrosine phosphatase Mu attenuates its tyrosine phosphatase activity and promotes glioma cell migration through PLCγ-PKC pathways

The metastatic potential of malignant tumor has been shown to be correlated with the increased expression of tri- and tetra-antennary β1,6-N-acetylglucosamine (β1,6-GlcNAc) N-glycans. In this study, We found that GnT-V expression was negatively correlated with receptor protein tyrosine phosphatase type μ(RPTPμ) in human glioma tissues. To study whether RPTPμ is a novel substance of GnT-V which further affect RPTPμ′s downstream dephosphorylation function, we preform lentiviral infection with GnT-V gene to construct stably transfected GnT-V glial cell lines. We found RPTPμ undergone severer cleavage in GnT-V transfected glioma cells compare to Mock cells. RPTPμ intracellular domain fragments increased while β1,6-GlcNAc-branched N-glycans increased, in consistent with the decrease of RPTPμ′s catalytic activity. The results showed that abnormal glycosylation could decrease the phosphorylation activity of PTP μ, and affect PLCγ-PKC pathways. Both protease inhibitor Furin and N-glycan biosynthesis inhibitor swainsonine could decrease cell mobility in GnT-V-U87 transfectants and other glioma cell lines. All results above suggest increased post-translational modification of RPTPμ N-glycans by GnT-V attenuates its tyrosine phosphatase activity and promotes glioma cell migration through PLCγ-PKC pathways, and that the β1,6-GlcNAc-branched N-glycans of RPTPμ play a crucial role in glioma invasivity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Cross-slip and easy-glide CRSS in titanium: Theoretical predictions and in-situ TEM measurements

This study investigates the mechanics of prismatic and first-order pyramidal $\langle$a$\rangle$ slip in titanium (Ti), elucidating the physics of easy-glide and cross-slip through a combination of theory and experiments. Screw-character prismatic (Pr) dislocations in Ti are of particular interest because their complex cores can be stable or unstable, leading to activation by either cross-slip or planar glide. To investigate these mechanisms, site-specific micro tensile samples were prepared using focused ion beam (FIB) milling and mounted on a push-to-pull (PTP) device for in-situ transmission electron microscopy (TEM) tensile testing. The in-situ experiments provide direct observations of the onset of dislocation motion and the precise determination of the critical resolved shear stress (CRSS) for the activated mechanisms, and its evolution with load cycling. A comprehensive theory has been developed to predict the CRSS values for easy glide, cross-slip, and multiplication of dislocations. Predicted critical stresses for pyramidal (π)-to-Pr and reverse cross-slip agree closely with the experimental measurements. The latter cross-slip stress is a factor of two higher than that of unobstructed planar slip. The model accounts for overlapping dislocation cores and employs a Wigner-Seitz based cell to evaluate misfit energies. By combining ab initio density functional theory (DFT) with anisotropic elasticity, the framework identifies minimum energy pathways for dislocation glide, which can be intermittent and zig-zag. A simplified expression utilizing (π) and Pr Schmid factor ratios is proposed for critical stress corresponding to (π)-to-Pr cross-slip transition. The results are strongly dependent on crystal orientation, underscoring non-Schmid behavior. Overall, this study explores key critical stress parameters essential for informing higher-scale simulations of plasticity in Ti.

Critical stress↗
DOE OSTI2020

Direct processing of PbZr 0.53 Ti 0.47 O 3 films on glass and polymeric substrates

This work reports on direct crystallization of PbZr 0.53 Ti 0.47 O 3 (PZT) thin films on glass and polymeric substrates, using pulsed thermal processing (PTP). Specifically, xenon flash lamps deliver pulses of high intensity, short duration, broadband light to the surface of a chemical solution deposited thin film, resulting in the crystallization of the film. Structural analysis by X-ray diffraction (XRD) and transmission electron microscopy show the existence of perovskite structure in nano-sized grains (≤5 nm). Local functional analysis by band excitation piezoelectric spectroscopy and electrostatic force microscopy confirm the presence of a ferroelectric phase and retention of voltage-written polarization for multiple days. Based on structural and functional analyses, strategies are discussed for optimization of pulse voltage and duration for the realization of crystalline ferroelectric thin films. For ~200 nm-thick PZT films on glass substrates, 500 μs-long pulses were required for crystallization, starting with 100 pulses at 350 V, 10 or 25 pulses at 400 V and in general lower number of pulses at higher voltages (resulting in higher radiant energy). Overall power densities of >6.4 kW/cm 2 were needed for appearance of peaks corresponding to the perovskite phase in the XRD. Films on glass processed at 350–400 V had a higher degree of 111-oriented perovskite grains. Higher applied radiant energy (through increased pulse voltage or count) resulted in more random and/or partially 001-oriented films. For ~1 μm-thick PZT films on polymeric substrates, 10 to 25 250 μs-long pulses at voltages ranging between 200 to 250 V, corresponding to power densities of ~2.8 kW/cm 2 , were optimal for maximized perovskite phase crystallization, while avoiding substrate damage.

36 MATERIALS SCIENCE↗
DOE OSTI2016

Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein–ligand interactions were characterized. Furthermore, these studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2018

Dual Allosteric Inhibition of SHP2 Phosphatase

SHP2 is a cytoplasmic protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell proliferation, differentiation, and survival. Recently, we reported an allosteric mechanism of inhibition that stabilizes the auto-inhibited conformation of SHP2. SHP099 (1) was identified and characterized as a moderately potent, orally bioavailable, allosteric small molecule inhibitor, which binds to a tunnel-like pocket formed by the confluence of three domains of SHP2. In this report, we describe further screening strategies that enabled the identification of a second, distinct small molecule allosteric site. SHP244 (2) was identified as a weak inhibitor of SHP2 with modest thermal stabilization of the enzyme. X-ray crystallography revealed that 2 binds and stabilizes the inactive, closed conformation of SHP2, at a distinct, previously unexplored binding site—a cleft formed at the interface of the N-terminal SH2 and PTP domains. Derivatization of 2 using structure-based design resulted in an increase in SHP2 thermal stabilization, biochemical inhibition, and subsequent MAPK pathway modulation. Downregulation of DUSP6 mRNA, a downstream MAPK pathway marker, was observed in KYSE-520 cancer cells. Remarkably, simultaneous occupation of both allosteric sites by 1 and 2 was possible, as characterized by cooperative biochemical inhibition experiments and X-ray crystallography. Combining an allosteric site 1 inhibitor with an allosteric site 2 inhibitor led to enhanced pharmacological pathway inhibition in cells. This work illustrates a rare example of dual allosteric targeted protein inhibition, demonstrates screening methodology and tactics to identify allosteric inhibitors, and enables further interrogation of SHP2 in cancer and related pathologies.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Conformational Dynamics and Catalytic Backups in a Hyper-thermostable Engineered Archaeal Protein Tyrosine Phosphatase

Protein tyrosine phosphatases (PTPs) are a family of enzymes that play important roles in regulating cellular signaling pathways. The activity of these enzymes is regulated by the motion of a catalytic loop that places a critical conserved aspartic acid side chain into the active site for acid–base catalysis upon loop closure. These enzymes also have a conserved phosphate-binding loop that is typically highly rigid and forms a well-defined anion-binding nest. The intimate links between loop dynamics and chemistry in these enzymes make PTPs an excellent model system for understanding the role of loop dynamics in protein function and evolution. In this context, archaeal PTPs, which have often evolved in extremophilic organisms, are highly understudied, despite their unusual biophysical properties. We present here an engineered chimeric PTP (ShufPTP) generated by shuffling the amino acid sequence of five extant hyperthermophilic archaeal PTPs. Despite ShufPTP’s high sequence similarity to its natural counterparts, it presents a suite of unique properties, including high flexibility of the phosphate binding P-loop, facile oxidation of the active-site cysteine, mechanistic promiscuity, and, most notably, hyperthermostability, with a denaturation temperature likely >130 °C (>8 °C higher than the highest recorded growth temperature of any archaeal strain). Our combined structural, biochemical, biophysical, and computational analysis provides insight both into how small steps in evolutionary space can radically modulate the biophysical properties of an enzyme and showcases the tremendous potential of archaeal enzymes for biotechnology, to generate novel enzymes capable of operating under extreme conditions.

archaea↗
DOE OSTI2020

Scalable neutral H 2 O 2 electrosynthesis by platinum diphosphide nanocrystals by regulating oxygen reduction reaction pathways

Despite progress in small scale electrocatalytic production of hydrogen peroxide (H 2 O 2 ) using a rotating ring-disk electrode, further work is needed to develop a non-toxic, selective, and stable O 2 -to-H 2 O 2 electrocatalyst for realizing continuous on-site production of neutral hydrogen peroxide. We report ultrasmall and monodisperse colloidal PtP 2 nanocrystals that achieve H 2 O 2 production at near zero-overpotential with near unity H 2 O 2 selectivity at 0.27 V vs. RHE. Density functional theory calculations indicate that P promotes hydrogenation of OOH* to H 2 O 2 by weakening the Pt-OOH* bond and suppressing the dissociative OOH* to O* pathway. Atomic layer deposition of Al 2 O 3 prevents NC aggregation and enables application in a polymer electrolyte membrane fuel cell (PEMFC) with a maximum r(H 2 O 2 ) of 2.26 mmol h -1 cm -2 and a current efficiency of 78.8% even at a high current density of 150 mA cm -2 . Catalyst stability enables an accumulated neutral H 2 O 2 concentration in 600 mL of 3.0 wt% (pH = 6.6).

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

Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4 CRBN , and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Dissecting protein tyrosine phosphatase signaling by engineered chemogenetic control of its activity

Protein tyrosine phosphatases (PTPases) are critical mediators of dynamic cell signaling. A tool capable of identifying transient signaling events downstream of PTPases is essential to understand phosphatase function on a physiological time scale. We report a broadly applicable protein engineering method for allosteric regulation of PTPases. This method enables dissection of transient events and reconstruction of individual signaling pathways. Implementation of this approach for Shp2 phosphatase revealed parallel MAPK and ROCK II dependent pathways downstream of Shp2, mediating transient cell spreading and migration. Furthermore, we show that the N-SH2 domain of Shp2 regulates MAPK-independent, ROCK II-dependent cell migration. Engineered targeting of Shp2 activity to different protein complexes revealed that Shp2-FAK signaling induces cell spreading whereas Shp2-Gab1 or Shp2-Gab2 mediates cell migration. We identified specific transient morphodynamic processes induced by Shp2 and determined the role of individual signaling pathways downstream of Shp2 in regulating these events. Broad application of this approach is demonstrated by regulating PTP1B and PTP-PEST phosphatases.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

TH-AB-201-08: Ion Chamber Dose Measurements - Problems with the Temperature-Pressure Correction Factor

Purpose: To investigate the behavior of ionization chambers over a wide pressure range. Methods: Three cylindrical and two parallel-plate designs of ion chamber were investigated. The ion chambers were placed in vessel where the pressure was varied from atmospheric (101 kPa) down to 5 kPa. Measurements were made using 60Co and high-energy electron beams. The pressure was measured to better than 0.1% and multiple data sets were obtained for each chamber at both polarities to investigate pressure cycling and dependency on the sign of the charge collected. Results: For all types of chamber, the ionization current, corrected using the standard PTP, showed a similar behaviour. Deviations from the standard theory were generally small for Co-60 but very significant for electron beams, up to 20 % below P = 10 kPa. The effect was found to be always larger when collecting negative charge, suggesting a dependence on free-electron collection. The most likely source of such electrons is low-energy electrons emitted from the electrodes. This signal would be independent of air pressure within the chamber cavity. The data was analyzed to extract this signal and it was found to be a non-negligible component of the ionization current at atmospheric pressure. In the case of the parallel plate chambers, the effect was approximately 0.25 %. For the cylindrical chambers the effect was larger - up to 1.2 % - and dependent on the chamber type, which would be consistent with electron emission from different wall materials. For the electron beams, the correction factor was dependent on the electron energy and approximately double that observed in 60Co. Conclusion: Measurements have indicated significant deviations of the standard pressure correction that are consistent with electron emission from chamber electrodes. This has implications for both primary standard and reference ion chamber-based dosimetry.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2022

Conserved conformational dynamics determine enzyme activity

Homologous enzymes often exhibit different catalytic rates despite a fully conserved active site. The canonical view is that an enzyme sequence defines its structure and function and, more recently, that intrinsic protein dynamics at different time scales enable and/or promote catalytic activity. Here, we show that, using the protein tyrosine phosphatase PTP1B, residues surrounding the PTP1B active site promote dynamically coordinated chemistry necessary for PTP1B function. However, residues distant to the active site also undergo distinct intermediate time scale dynamics and these dynamics are correlated with its catalytic activity and thus allow for different catalytic rates in this enzyme family. We identify these previously undetected motions using coevolutionary coupling analysis and nuclear magnetic resonance spectroscopy. Our findings strongly indicate that conserved dynamics drives the enzymatic activity of the PTP family. Characterization of these conserved dynamics allows for the identification of novel regulatory elements (therapeutic binding pockets) that can be leveraged for the control of enzymes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Targeting prostate tumor low–molecular weight tyrosine phosphatase for oxidation-sensitizing therapy

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low–molecular weight PTP (LMPTP)—encoded by the ACP1 gene—is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9–generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr 270 . PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor 2–mediated stress response, and enhanced reactive oxygen species after exposure to taxane drugs. LMPTP inhibition slowed primary and bone metastatic prostate tumor growth in mice. These findings reveal a role for LMPTP as a critical promoter of PCa growth and metastasis and validate LMPTP inhibition as a therapeutic strategy for treating PCa through sensitization to oxidative stress.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Materials Data on Pr(PPt)2 by Materials Project

Pr(PtP)2 crystallizes in the tetragonal I4/mmm space group. The structure is three-dimensional. Pr3+ is bonded in a 8-coordinate geometry to eight P3- atoms. There are four shorter (3.23 Å) and four longer (3.24 Å) Pr–P bond lengths. There are two inequivalent Pt+1.50+ sites. In the first Pt+1.50+ site, Pt+1.50+ is bonded in a 5-coordinate geometry to five P3- atoms. There are one shorter (2.40 Å) and four longer (2.42 Å) Pt–P bond lengths. In the second Pt+1.50+ site, Pt+1.50+ is bonded in a distorted rectangular see-saw-like geometry to four equivalent P3- atoms. All Pt–P bond lengths are 2.54 Å. There are two inequivalent P3- sites. In the first P3- site, P3- is bonded in a 10-coordinate geometry to four equivalent Pr3+, five Pt+1.50+, and one P3- atom. The P–P bond length is 2.69 Å. In the second P3- site, P3- is bonded in a 8-coordinate geometry to four equivalent Pr3+ and four equivalent Pt+1.50+ atoms.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Materials Data on SrEu(PPt)2 by Materials Project

SrEu(PtP)2 crystallizes in the trigonal P-3m1 space group. The structure is three-dimensional. Sr2+ is bonded to six equivalent P3- atoms to form distorted SrP6 octahedra that share corners with twelve equivalent EuP6 octahedra, edges with six equivalent SrP6 octahedra, and faces with two equivalent EuP6 octahedra. The corner-sharing octahedral tilt angles are 43°. All Sr–P bond lengths are 3.34 Å. Eu2+ is bonded to six equivalent P3- atoms to form EuP6 octahedra that share corners with twelve equivalent SrP6 octahedra, edges with six equivalent EuP6 octahedra, and faces with two equivalent SrP6 octahedra. The corner-sharing octahedral tilt angles are 43°. All Eu–P bond lengths are 3.19 Å. Pt1+ is bonded in a trigonal planar geometry to three equivalent P3- atoms. All Pt–P bond lengths are 2.40 Å. P3- is bonded in a 3-coordinate geometry to three equivalent Sr2+, three equivalent Eu2+, and three equivalent Pt1+ atoms.

36 MATERIALS SCIENCE↗
DOE OSTI2019

Materials Data on PPt by Materials Project

PtP is Wurtzite structured and crystallizes in the hexagonal P6_3mc space group. The structure is three-dimensional. Pt2+ is bonded to four equivalent P2- atoms to form corner-sharing PtP4 tetrahedra. There are three shorter (2.32 Å) and one longer (2.34 Å) Pt–P bond lengths. P2- is bonded to four equivalent Pt2+ atoms to form corner-sharing PPt4 tetrahedra.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Materials Data on Nd(PPt)2 by Materials Project

Nd(PtP)2 crystallizes in the tetragonal I4/mmm space group. The structure is three-dimensional. Nd2+ is bonded in a 8-coordinate geometry to eight Pt2- atoms. There are four shorter (3.24 Å) and four longer (3.31 Å) Nd–Pt bond lengths. There are two inequivalent Pt2- sites. In the first Pt2- site, Pt2- is bonded in a 5-coordinate geometry to four equivalent Nd2+ and five P1+ atoms. There are one shorter (2.39 Å) and four longer (2.42 Å) Pt–P bond lengths. In the second Pt2- site, Pt2- is bonded in a 12-coordinate geometry to four equivalent Nd2+ and four equivalent P1+ atoms. All Pt–P bond lengths are 2.54 Å. There are two inequivalent P1+ sites. In the first P1+ site, P1+ is bonded in a 5-coordinate geometry to five Pt2- atoms. In the second P1+ site, P1+ is bonded to four equivalent Pt2- atoms to form a mixture of distorted edge and corner-sharing PPt4 tetrahedra.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Materials Data on Ce(PPt)2 by Materials Project

Ce(PtP)2 crystallizes in the tetragonal I4/mmm space group. The structure is three-dimensional. Ce3+ is bonded in a 8-coordinate geometry to eight P3- atoms. There are four shorter (3.20 Å) and four longer (3.23 Å) Ce–P bond lengths. There are two inequivalent Pt+1.50+ sites. In the first Pt+1.50+ site, Pt+1.50+ is bonded in a 5-coordinate geometry to five P3- atoms. There are one shorter (2.36 Å) and four longer (2.42 Å) Pt–P bond lengths. In the second Pt+1.50+ site, Pt+1.50+ is bonded in a distorted rectangular see-saw-like geometry to four equivalent P3- atoms. All Pt–P bond lengths are 2.54 Å. There are two inequivalent P3- sites. In the first P3- site, P3- is bonded in a 1-coordinate geometry to four equivalent Ce3+, five Pt+1.50+, and one P3- atom. The P–P bond length is 2.71 Å. In the second P3- site, P3- is bonded in a 8-coordinate geometry to four equivalent Ce3+ and four equivalent Pt+1.50+ atoms.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Seismic Models for Near-Surface Explosion Yield Estimation in Alluvium and Sedimentary Rock

Seismic ground-motion data provide valuable constraints on explosion characteristics, such as yield and height-of-burst/depth-of-burial (HOB/DOB). In this study, we investigate a range of seismic amplitude features and their efficacy in minimizing errors associated with yield estimation. Using a set of explosion recordings from experiments conducted in alluvium and sedimentary rock geologies, we investigated the effectiveness of three different seismic feature types over a range of different frequencies. Using both velocity and displacement data, we investigated the zero-to-peak (ZTP) amplitude of the first arriving P wave, the peak-to-peak (PTP) amplitude of the first arriving P wave, and the P rms amplitude over various time windows starting with the P wave. These three basic features were measured on both vertical component only data and the vertical–radial vector sum. In total, there were 56 different combinations investigated. Our seismic models combine the effects of scaled range and scaled HOB/DOB on the observed seismic features. The results show that the vertical–radial vector sum of the ZTP amplitudes measured on displacement seismograms most consistently produce models with the smallest difference between predicted amplitude values and observed amplitude values when accounting for both alluvium and sedimentary rock lithology. The improvement in fit to the data when incorporating the difference in source lithology is significant. Lastly, if an alluvium lithology is assumed for a sedimentary rock lithology, the difference in yield could be up to ~3.0 times the appropriate yield in the far field.

58 GEOSCIENCES↗