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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 973 records · Page 54
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

One-loop matching for spin-dependent quasi-TMDs

Transverse momentum dependent parton distribution functions (TMDPDFs) provide a unique probe of the three-dimensional spin structure of hadrons. We construct spin-dependent quasi-TMDPDFs that are amenable to lattice QCD calculations and that can be used to determine spin-dependent TMDPDFs. We calculate the short-distance coefficients connecting spin-dependent TMDPDFs and quasi-TMDPDFs at one-loop order. We find that the helicity and transversity distributions have the same coefficient as the unpolarized TMDPDF. We also argue that the same is true for pretzelosity and that this spin universality of the matching will hold to all orders in αs. Thus, it is possible to calculate ratios of these distributions as a function of longitudinal momentum and transverse position utilizing simpler Wilson line paths than have previously been considered.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2020

Constraining the Chiral Magnetic Effect with charge-dependent azimuthal correlations in Pb-Pb collisions at $ \sqrt{s_{\mathrm{NN}}} $ = 2.76 and 5.02 TeV

Systematic studies of charge-dependent two- and three-particle correlations in Pb-Pb collisions at $ \sqrt{s_{\mathrm{NN}}} $ = 2.76 and 5.02 TeV used to probe the Chiral Magnetic Effect (CME) are presented. These measurements are performed for charged particles in the pseudorapidity ( η ) and transverse momentum ( p T ) ranges | η | < 0 . 8 and 0 . 2 < p T < 5 GeV/ c . A significant charge-dependent signal that becomes more pronounced for peripheral collisions is reported for the CME-sensitive correlators γ 1, 1 =$\langle4cos( φ α + φ β - 2Ψ 2 )$\rangle$ and γ 1, - 3 = $\langle$cos( φ α - 3 φ β + 2Ψ 2 )$\rangle$. The results are used to estimate the contribution of background effects, associated with local charge conservation coupled to anisotropic flow modulations, to measurements of the CME. A blast-wave parametrisation that incorporates local charge conservation tuned to reproduce the centrality dependent background effects is not able to fully describe the measured γ 1 , 1 . Finally, the charge and centrality dependence of mixed-harmonics three-particle correlations, of the form γ 1, 2 = $\langle$cos( φ α + 2 φ β - 3Ψ 3 )$\rangle$, which are insensitive to the CME signal, verify again that background contributions dominate the measurement of γ 1 , 1 .

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2024

Submicron immunoglobulin particles exhibit FcγRII-dependent toxicity linked to autophagy in TNFα-stimulated endothelial cells

In intravenous immunoglobulins (IVIG), and some other immunoglobulin products, protein particles have been implicated in adverse events. Role and mechanisms of immunoglobulin particles in vascular adverse effects of blood components and manufactured biologics have not been elucidated. We have developed a model of spherical silica microparticles (SiMPs) of distinct sizes 200–2000 nm coated with different IVIG- or albumin (HSA)-coronas and investigated their effects on cultured human umbilical vein endothelial cells (HUVEC). IVIG products (1–20 mg/mL), bare SiMPs or SiMPs with IVIG-corona, did not display significant toxicity to unstimulated HUVEC. In contrast, in TNFα-stimulated HUVEC, IVIG-SiMPs induced decrease of HUVEC viability compared to HSA-SiMPs, while no toxicity of soluble IVIG was observed. 200 nm IVIG-SiMPs after 24 h treatment further increased ICAM1 (intercellular adhesion molecule 1) and tissue factor surface expression, apoptosis, mammalian target of rapamacin (mTOR)-dependent activation of autophagy, and release of extracellular vesicles, positive for mitophagy markers. Toxic effects of IVIG-SiMPs were most prominent for 200 nm SiMPs and decreased with larger SiMP size. Using blocking antibodies, toxicity of IVIG-SiMPs was found dependent on FcγRII receptor expression on HUVEC, which increased after TNFα-stimulation. Similar results were observed with different IVIG products and research grade IgG preparations. In conclusion, submicron particles with immunoglobulin corona induced size-dependent toxicity in TNFα-stimulated HUVEC via FcγRII receptors, associated with apoptosis and mTOR-dependent activation of autophagy. Testing of IVIG toxicity in endothelial cells prestimulated with proinflammatory cytokines is relevant to clinical conditions. Our results warrant further studies on endothelial toxicity of sub-visible immunoglobulin particles.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Thickness-Dependent Thermal Oxidation of Ni into NiO Thin Films

We report thickness-dependent thermal oxidation in Ni (t = 10–300 nm) thin films exposed to air annealing and the resulting vibrational, magnetic and electrical properties of Ni films deposited directly on thermally oxidized Si substrate using magnetron sputtering technique at ambient temperature. As-deposited Ni films exhibit face-centred cubic structure with fine crystals and large lattice constant (a{sub Ni}) at lower t (< 50 nm). With increasing t, a{sub Ni} decreases and approaches to bulk value. With increasing T{sub A}, a{sub Ni} not only decreases to bulk Ni due to improved crystallization but also reduces below bulk Ni for t > 50 due to formation of NiO. The relative fraction of Ni and NiO in annealed films up to 400 {sup ∘}C strongly depends on t. Annealing Ni films at 500 {sup ∘}C results into complete oxidation of Ni into granular-type NiO. X-ray reflectivity studies reveal that oxidation process occurs from surface of the films converting Ni into NiO possibly through layer by layer process, which is subtle to t. Raman spectra show that intensity ratio between one-phonon longitudinal optical (LO) and two-phonon LO bands decreases and intensity of two-magnon band increases with increasing t for films annealed at particular T{sub A}. This confirms the growth of NiO not only with increasing T{sub A}, but also with t. As-deposited films exhibit ferromagnetism at room temperature. The presence of Ni and NiO in annealed films implies coexistence of ferromagnetic and antiferromagnetic interactions, leading to tunable exchange bias (H{sub E}), whose magnitude strongly depends on the ratio between Ni and NiO. Electrical resistance (R) of the as-deposited Ni films decreases with increasing t and follows the Namba’s model. Upon annealing, R increases largely due to oxidation of Ni. The observed results are explained on the basis of thickness dependent thermal oxidation process with increasing T{sub A}.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2016

Temperature-Dependent Friction and Wear Behavior of PTFE and MoS 2

We present an investigation of the temperature-dependent friction behavior of PTFE, MoS 2 , and PTFE-on- MoS 2 . Friction behavior was measured while continuously varying contact temperature in the range -150 to 175°C while sliding in dry nitrogen, as well as for self-mated PTFE immersed in liquid nitrogen. These results contrast with previous reports of monotonic inverse temperature dependent friction behavior, as well as reported high-friction transitions and plateaus at temperatures below about -20°C that were not observed, providing new insights about the molecular mechanisms of macro-scale friction. The temperature-dependent friction behavior characteristic of self-mated PTFE was found also on the PTFE-on-MoS 2 sliding contact, suggesting that PTFE friction was defined by sub-surface deformation mechanisms and internal friction even when sliding against a lamellar lubricant with extremely low friction coefficient (μ ~ 0.02). The various relaxation temperatures of PTFE were found in the temperature-dependent friction behavior, showing excellent agreement with reported values acquired using torsional techniques measuring internal friction. Additionally, hysteresis in friction behavior suggests an increase in near-surface crystallinity at upon exceeding the high temperature relaxation, T α ~ 116°C.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Strain Rate Dependency of Simulated Welding Residual Stresses

In the present work, the influence of taking into consideration the strain rate-dependent nature of steel S355 during a calculation of the welding residual stresses through a finite element simulation is investigated. The Perzyna material model is calibrated using experimental values found in the literature and is introduced to a validated weld simulation model, where the strain rate dependency had not been taken into consideration before this study. The calculated profiles of the welding residual stresses, for strain rate-dependent and independent behavior, are then compared with experimentally measured profiles. The results of this first-step analysis show that taking into consideration strain rate dependency during a welding simulation of the investigated S355 has non-negligible influence on the calculated welding residual stresses.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Orientation dependent spall strength of tantalum single crystals

We report that it is generally recognized that single crystals exhibit orientation-dependent elastic and plastic responses. However, it is less known how the dynamic tensile, or spall, strength depends on crystalline orientation, especially for BCC materials. It has been previously shown that the dynamic tensile strength of FCC materials is highly dependent on their plastic response under compression, with a direct correlation between plastic deformation and spall strength. In BCC materials like Ta, where the primary deformation mechanism at high strain rates is a combination of slip and twinning, the quantitative dependence of spall strength on these deformation mechanisms is less understood. To fill this gap in our knowledge, a series of non-equilibrium molecular dynamics simulations are completed for six tantalum single crystal orientations: <001>, <011>, <111>, <013>, <112>, <149>, to explore the role of directional anisotropy on ductile spallation. Our results show that due to the role of non-Schmid and release effects in BCC Ta, the evolution of plasticity follows a complex trajectory through shock compression, release, and tension. Orientations that contain residual twinning deformation have a reduced spall strength proportional to the amount of twinning present. Lastly, twins and their intersections function as regions of increased stress localization within the system due to compatibility requirements and their interactions with dislocations.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Grain size dependencies of intergranular solute segregation in nanocrystalline materials

Grain boundary segregation is of increasing importance for stabilizing nanocrystalline alloys, and while segregation is typically modeled as a scale-independent phenomenon, at the finest nanocrystalline grain sizes there are several sources of grain size dependence. Here we provide quantitative detail on two grain size dependencies not previously elaborated, both of which arise from the spectrality of intergranular segregation sites. The first of these arises because a change in grain size affects which portions of the segregation spectrum are occupied by the solutes, with no change in the shape or nature of the spectrum itself. The second of these arises from the presence of higher-order grain junctions, which have unique segregation behaviors and an increasing relative presence at finer grain sizes. This paper uses molecular statics to quantify these size dependencies in detail for the case of an Al(Mg) binary alloy. Together, these two effects combined have a significant effect on the effective McLean segregation energy of more than 6 kJ/mol (from approximately -18.5 kJ/mol at 5 nm to -12.5 kJ/mol at more than 40 nm), with the majority of grain size dependence arising from the spectrality of segregation sites.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Benford’s law and continuous dependent random variables

Many mathematical, man-made and natural systems exhibit a leading-digit bias, where a first digit (base 10) of 1 occurs not 11% of the time, as one would expect if all digits were equally likely, but rather 30%. This phenomenon is known as Benford’s Law. Analyzing which datasets adhere to Benford’s Law and how quickly Benford behavior sets in are the two most important problems in the field. Most previous work studied systems of independent random variables, and relied on the independence in their analyses. Inspired by natural processes such as particle decay, we study the dependent random variables that emerge from models of decomposition of conserved quantities. We prove that in many instances the distribution of lengths of the resulting pieces converges to Benford behavior as the number of divisions grow, and give several conjectures for other fragmentation processes. The main difficulty is that the resulting random variables are dependent. We handle this by using tools from Fourier analysis and irrationality exponents to obtain quantified convergence rates as well as introducing and developing techniques to measure and control the dependencies. The construction of these tools is one of the major motivations of this work, as our approach can be applied to many other dependent systems. As an example, we show that the n! entries in the determinant expansions of n×n matrices with entries independently drawn from nice random variables converges to Benford’s Law.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2010

Caspase-dependent inhibition of store-operated Ca{sup 2+} entry into apoptosis-committed Jurkat cells

Activation of T-cells triggers store-operated Ca{sup 2+} entry, which begins a signaling cascade leading to induction of appropriate gene expression and eventually lymphocyte proliferation and differentiation. The simultaneous enhancement of Fas ligand gene expression in activated cells allows the immune response to be limited by committing the activated cells to apoptosis. In apoptotic cells the store-operated calcium entry is significantly inhibited. It has been documented that moderate activation of Fas receptor may cause reversible inhibition of store-operated channels by ceramide released from hydrolyzed sphingomyelin. Here we show that activation of Fas receptor in T-cells results in caspase-dependent decrease of cellular STIM1 and Orai1 protein content. This effect may be responsible for the substantial inhibition of Ca{sup 2+} entry into Jurkat cells undergoing apoptosis. In turn, this inhibition might prevent overloading of cells with calcium and protect them against necrosis. -- Research highlights: {yields} Fas activation reduces STIM1 and Orai1 protein content in caspase dependent manner. {yields} Fas activation partially reduces mitochondrial potential in caspase dependent manner. {yields} Fas stimulation inhibits of store-operated Ca{sup 2+} entry in caspase dependent manner. {yields} Inhibition of Ca{sup 2+} entry in apoptotic cells may protect them from secondary necrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2010

The E3 ubiquitin ligase WWP1 regulates {Delta}Np63-dependent transcription through Lys63 linkages

Research highlights: {yields} WWP1 ubiquitylates {Delta}Np63 through conjugation of Lys63-linked poly-ubiquitin chains. {yields} WWP1 does not control {Delta}Np63 protein stability. {yields} WWP1 regulates {Delta}Np63-dependent transcription. -- Abstract: The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and tumorigenesis through the regulation of epithelial progenitor cell proliferation, differentiation and apoptosis. Similarly to p53, p63 activity is regulated by post-translational modifications, including ubiquitylation. Here, we report that the WWP1 E3 ubiquitin ligase binds specifically to {Delta}Np63 isoform but it does not trigger {Delta}Np63 proteasome-dependent degradation. Accordingly, we found that WWP1-dependent ubiquitylation of {Delta}Np63 occurs through the formation of Lys63-linked poly-ubiquitin chains. Importantly, we found that WWP1 is able to increase {Delta}Np63-dependent transcription and depletion of WWP1 in human primary keratinocytes induces cell cycle arrest. All together these results indicate that WWP1 regulates {Delta}Np63 transcriptional activity, acting thus as a potential regulator of the proliferation and survival of epithelial-derived cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Antagonistic effect of disulfide-rich peptide aptamers selected by cDNA display on interleukin-6-dependent cell proliferation

Highlights: Black-Right-Pointing-Pointer Disulfide-rich peptide aptamer inhibits IL-6-dependent cell proliferation. Black-Right-Pointing-Pointer Disulfide bond of peptide aptamer is essential for its affinity to IL-6R. Black-Right-Pointing-Pointer Inhibitory effect of peptide depends on number and pattern of its disulfide bonds. -- Abstract: Several engineered protein scaffolds have been developed recently to circumvent particular disadvantages of antibodies such as their large size and complex composition, low stability, and high production costs. We previously identified peptide aptamers containing one or two disulfide-bonds as an alternative ligand to the interleukin-6 receptor (IL-6R). Peptide aptamers (32 amino acids in length) were screened from a random peptide library by in vitro peptide selection using the evolutionary molecular engineering method 'cDNA display'. In this report, the antagonistic activity of the peptide aptamers were examined by an in vitro competition enzyme-linked immunosorbent assay (ELISA) and an IL-6-dependent cell proliferation assay. The results revealed that a disulfide-rich peptide aptamer inhibited IL-6-dependent cell proliferation with similar efficacy to an anti-IL-6R monoclonal antibody.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Acetylation of cyclin-dependent kinase 5 is mediated by GCN5

Highlights: • Cyclin-dependent kinase 5 (CDK5) is present as an acetylated form. • CDK5 is acetylated by GCN5. • CDK5’s acetylation site is mapped at Lys33. • Its acetylation may affect CDK5’s kinase activity. - Abstract: Cyclin-dependent kinase 5 (CDK5), a member of atypical serine/threonine cyclin-dependent kinase family, plays a crucial role in pathophysiology of neurodegenerative disorders. Its kinase activity and substrate specificity are regulated by several independent pathways including binding with its activator, phosphorylation and S-nitrosylation. In the present study, we report that acetylation of CDK5 comprises an additional posttranslational modification within the cells. Among many candidates, we confirmed that its acetylation is enhanced by GCN5, a member of the GCN5-related N-acetyl-transferase family of histone acetyltransferase. Co-immunoprecipitation assay and fluorescent localization study indicated that GCN5 physically interacts with CDK5 and they are co-localized at the specific nuclear foci. Furthermore, liquid chromatography in conjunction with a mass spectrometry indicated that CDK5 is acetylated at Lys33 residue of ATP binding domain. Considering this lysine site is conserved among a wide range of species and other related cyclin-dependent kinases, therefore, we speculate that acetylation may alter the kinase activity of CDK5 via affecting efficacy of ATP coordination.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

AS-2, a novel inhibitor of p53-dependent apoptosis, prevents apoptotic mitochondrial dysfunction in a transcription-independent manner and protects mice from a lethal dose of ionizing radiation

Highlights: • A bidentate HQ derivative, AS-2, suppresses p53-dependent apoptosis by DNA damage. • AS-2 does not significantly affect nuclear p53 response. • UV-excited blue emission of AS-2 clearly showed its extranuclear localization. • AS-2 prevents mitochondrial dysfunction despite the increase of mitochondrial p53. • AS-2 protects mice from a radiation dose that causes lethal hematopoietic syndrome. - Abstract: In a previous study, we reported that some tetradentate zinc(II) chelators inhibit p53 through the denaturation of its zinc-requiring structure but a chelator, Bispicen, a potent inhibitor of in vitro apoptosis, failed to show any efficient radioprotective effect against irradiated mice because the toxicity of the chelator to mice. The unsuitability of using tetradentate chelators as radioprotectors prompted us to undertake a more extensive search for p53-inhibiting agents that are weaker zinc(II) chelators and therefore less toxic. Here, we show that an 8-hydroxyquinoline (8HQ) derivative, AS-2, suppresses p53-dependent apoptosis through a transcription-independent mechanism. A mechanistic study using cells with different p53 characteristics revealed that the suppressive effect of AS-2 on apoptosis is specifically mediated through p53. In addition, AS-2 was less effective in preventing p53-mediated transcription-dependent events than pifithrin-μ (PFTμ), an inhibitor of transcription-independent apoptosis by p53. Fluorescence visualization of the extranuclear distribution of AS-2 also supports that it is ineffective on the transcription-dependent pathway. Further investigations revealed that AS-2 suppressed mitochondrial apoptotic events, such as the mitochondrial release of intermembrane proteins and the loss of mitochondrial membrane potential, although AS-2 resulted in an increase in the mitochondrial translocation of p53 as opposed to the decrease of cytosolic p53, and did not affect the apoptotic interaction of p53 with Bcl-2. AS-2 also protected mice that had been exposed to a lethal dose of ionizing radiation. Our findings indicate that some types of bidentate 8HQ chelators could serve as radioprotectors with no substantial toxicity in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

PF-4708671, a specific inhibitor of p70 ribosomal S6 kinase 1, activates Nrf2 by promoting p62-dependent autophagic degradation of Keap1

p70 ribosomal S6 kinase 1 (S6K1) is an important serine/threonine kinase and downstream target of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. PF-4708671 is a specific inhibitor of S6K1, and prevents S6K1-mediated phosphorylation of the S6 protein. PF-4708671 treatment often leads to apoptotic cell death. However, the protective mechanism against PF-4708671-induced cell death has not been elucidated. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is essential for protecting cells against oxidative stress. p62, an adaptor protein in the autophagic process, enhances Nrf2 activation through the impairment of Keap1 activity. In this study, we showed that PF-4708671 induces autophagic Keap1 degradation-mediated Nrf2 activation in p62-dependent manner. Furthermore, p62-dependent Nrf2 activation plays a crucial role in protecting cells from PF-4708671-mediated apoptosis. - Highlights: • PF-4708671, a S6K1-specific inhibitor, prevents S6K1-mediated S6 phosphorylation. • However, PF-4708671 treatment often leads to apoptotic cell death. • Protective mechanism against PF-4708671-induced cell death remains to be elucidated. • PF-4708671 induced p62-dependent, autophagic Keap1 degradation-mediated Nrf2 activation. • p62-dependent Nrf2 activation protects cells from PF-4708671-mediated apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6

The proliferation of colon cancer cells is mediated in part by epidermal growth factor receptor (EGFR) signaling and requires sustained levels of cellular energy to meet its high metabolic needs. Intracellular lipid droplets (LDs) are a source of energy used for various cellular functions and they are elevated in density in human cancer, yet their regulation and function are not well understood. Here, in human colon cancer cells, EGF stimulates increases in LD density, which depends on EGFR expression and activation as well as the individual cellular capacity for lipid synthesis. Increases in LDs are blockaded by inhibition of PI3K/mTOR and PGE2 synthesis, supporting their dependency on select upstream pathways. In colon cancer cells, silencing of the FOXO3 transcription factor leads to down regulation of SIRT6, a negative regulator of lipid synthesis, and consequent increases in the LD coat protein PLIN2, revealing that increases in LDs depend on loss of FOXO3/SIRT6. Moreover, EGF stimulates loss of FOXO3/SIRT6, which is blockaded by the inhibition of upstream pathways as well as lipid synthesis, revealing existence of a negative regulatory loop between LDs and FOXO3/SIRT6. Elevated LDs are utilized by EGF treatment and their depletion through the inhibition of lipid synthesis or silencing of PLIN2 significantly attenuates proliferation. This novel mechanism of proliferative EGFR signaling leading to elevated LD density in colon cancer cells could potentially be therapeutically targeted for the treatment of tumor progression. - Highlights: • In colon cancer cells, EGFR activation leads to increases in LD density. • EGFR signaling includes PI3K/mTOR and PGE2 leading to lipid synthesis. • Increases in LDs are controlled by a negative regulatory loop with FOXO3/SIRT6. • EGFR mediated colon cancer cell proliferation depends on increased LD density.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Protective effects of estrogen against vascular calcification via estrogen receptor α-dependent growth arrest-specific gene 6 transactivation

Vascular calcification is one of the major complications of cardiovascular disease and is an independent risk factor for myocardial infarction and cardiac death. Postmenopausal women have a higher prevalence of vascular calcification compared with premenopausal women, suggesting protective effects of estrogen (E2). However, the underlying mechanisms of its beneficial effects remain unclear. In the present study, we examined the inhibitory effects of E2 on vascular smooth muscle cell (VSMC) calcification, and found that growth arrest-specific gene 6 (Gas6), a crucial molecule in vascular calcification, is transactivated by estrogen receptor α (ERα) in response to E2. In human aortic smooth muscle cells, physiological levels of E2 inhibited inorganic phosphate (Pi)-induced calcification in a concentration-dependent manner. This inhibitory effect was significantly abolished by MPP, an ERα-selective antagonist, and ERα siRNA, but not by PHTPP, an ERβ-selective antagonist, and ERβ siRNA, implicating an ERα-dependent action. Apoptosis, an essential process for Pi-induced VSMC calcification, was inhibited by E2 in a concentration-dependent manner and further, MPP abolished this inhibition. Mechanistically, E2 restored the inhibited expression of Gas6 and phospho-Akt in Pi-induced apoptosis through ERα. Furthermore, E2 significantly activated Gas6 transcription, and MPP abrogated this E2-dependent Gas6 transactivation. E2-BSA failed to activate Gas6 transcription and to inhibit Ca deposition in VSMC, suggesting beneficial actions of genomic signaling by E2/nuclear ERα. Taken together, these results indicate that E2 exerts inhibitory effects on VSMC apoptosis and calcification through ERα-mediated Gas6 transactivation. These findings indicate a potential therapeutic strategy for the prevention of vascular calcification, especially in postmenopausal women. - Highlights: • E2 inhibits Pi-induced calcification in vascular smooth muscles cells. • E2 inhibits Pi-induced apoptosis by restoration of Gas6-mediated survival pathway. • Gas6 transactivation by E2 is mediated by ERα.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Inhibition of pancreatic cancer Panc1 cell migration by omeprazole is dependent on aryl hydrocarbon receptor activation of JNK

Highlights: • Omeprazole inhibition of Panc1 cell invasion is JNK- and AhR-dependent. • The non-genomic pathway is not due to AhR mutations. • Omeprazole-AhR-JNK modulates expression of invasion genes. Several aryl hydrocarbon receptor (AhR)-active pharmaceuticals were screened as inhibitors of pancreatic cancer cell invasion and identified two compounds, omeprazole, that inhibited invasion. Inhibition of highly invasive Panc1 cell invasion by omeprazole involves an AhR-dependent non-genomic pathway, and omeprazole-mediated inhibition of Panc1 cell invasion was dependent on Jun-N-terminal kinase (JNK) and mitogen-activated kinase kinase 7 (MKK7). The failure of omeprazole to induce nuclear translocation of the AhR was not due to overexpression of cytosolic AhR partner proteins Hsp90 or XAP2, and results of DNA sequencing show that the AhR expressed in Panc1 cells was not mutated. Results of RNAseq studies indicate that omeprazole induced an AhR-dependent downregulation of several pro-invasion factors including activated leukocyte cell adhesion molecule (ALCAM), long chain fatty acid CoA-synthase (CSL4), stathmin 3 (STMN3) and neuropillin 2 (NRP2), and the specific functions of these genes are currently being investigated.

60 APPLIED LIFE SCIENCES↗