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At least 1,423 records · Page 79
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Unearthing principal strengthening factors tuning the additive manufactured 15-5 PH stainless steel

Additive manufactured (AM) materials exhibit enhanced performance, while post-processing is essential to reinforce its properties. Controlling the tunable factors and the underlying strengthening mechanisms during the post-processing are a key to answering the calls from the industry and end users. We identified the principal strengthening factors that contribute to AM stainless steel under heat-treatment and weighed their importance. The as-built sample exhibited a unique microstructure with a heterogeneous grain size distribution, a small amount of retained austenite, high dislocation density, and dispersed oxide particles. The strengthening primarily by dislocation forest and additionally by heterogeneous grain size contributed to the as-built sample. Although aging slightly decreased dislocation strengthening, superior aging enhancement was achieved by Cu-precipitates. The solid-solutionizing not only increased the effective grain size but also reduced the dislocation density by eliminating the heterogeneous microstructure, which deteriorated the precipitation hardenability. Our findings shed light on the performance optimization of AM metals.

36 MATERIALS SCIENCE↗
DOE OSTI2024

Identifying multiple synergistic factors on the susceptibility to stress relaxation cracking in variously heat-treated weldments

The 347H austenitic stainless steel has been widely used for pressure vessels and pipeline (PVP) applications due to its excellent creep and corrosion resistance, which fit ideally to the harsh conditions in petrochemical industries, fossil fuel or nuclear power plants, and modern energy storages. However, a failure mode has been commonly observed with cracks emerging at the heat affected zone (HAZ) of weldments during post-weld heat treatment (PWHT) or under intermediate to high temperature service conditions. This phenomenon is termed as Stress Relaxation Cracking (SRC) since the purpose of PWHT is to relieve the welding-induced residual stress fields, or as Stress Age Cracking (SAC) if failure happens during service. A leading literature explanation of this failure suggests that the residual stress relaxation and the precipitation dissolution and/or re-precipitation occur in the same temperature range, which can lead to locally high strains and thus to crack at the grain boundaries. Since in situ spatial measurements of residual stress fields, microstructural evolution, and failure processes are nearly infeasible, this work recourses to a micromechanical finite element framework that models the high temperature failure as the nucleation and growth of grain boundary cavities, whereas various parameters such as thermomechanical loading history and its evolution, the competition of grain-interior dislocation creep and grain-boundary diffusion in failure lifetime, and microstructural heterogeneities (such as the precipitate free zone near grain boundaries) can be quantitatively incorporated. It can be concluded from these microstructure-explicit simulations that an accurate knowledge of residual stress evolution and a carefully calibrated set of material constitutive parameters are the essential prerequisites for lifetime predictions. The understanding of individual governing factors also leads to a mechanistic interpretation of the observed SRC susceptibility C-curves. In conclusion, these results suggest that the criticality of residual stress evolution, but not the precipitation-induced local strains, be the leading factor for SRC.

347H stainless steel weldments↗
DOE OSTI2017

Hippocampal dose from stereotactic radiosurgery for 4 to 10 brain metastases: Risk factors, feasibility of dose reduction via re-optimization, and patient outcomes

This study aimed to report hippocampal dose from single-fraction stereotactic radiosurgery (SRS) for 4 to 10 brain metastases and determine feasibility of hippocampal-sparing SRS. Patients with 4 to 10 brain metastases receiving single-isocenter, multi-target single-fraction SRS were identified. Hippocampi were contoured using the Radiation Therapy Oncology Group (RTOG) 0933 atlas. RTOG 0933 dose constraints were converted to a biologically effective dose using an alpha/beta of 2 (D{sub 100} 421 cGy, D{sub max} 665 cGy). Number of metastases, total target volume, prescribed dose, and distance of nearest metastasis (dmin) were analyzed as risk factors for exceeding hippocampal constraints. If hippocampi exceeded constraints, the SRS plan was re-optimized. Key dosimetric parameters were compared between original and re-optimized plans. To determine if a single target can exceed constraints, all targets but the closest metastasis were removed from the plan, and dosimetry was compared. Forty plans were identified. Fifteen hippocampi (19%) exceeded constraints in 12 SRS plans. Hippocampal sparing was achieved in 10 of 12 replanned cases (83%). Risk factors associated with exceeding hippocampal constraints were decreasing dmin (24.0 vs 8.0 mm, p = 0.002; odds ratio [OR] 1.14, 95% confidence interval [CI] 1.04 to 1.26) and total target volume (5.46 cm{sup 3}vs 1.98 cm{sup 3}, p = 0.03; OR 1.14, 95% CI 1.00 to 1.32). There was no difference in exceeding constraints for 4 to 5 vs 6 to 10 metastases (27% vs 21%, p = 0.409) or prescribed dose (18 Gy, p = 0.58). For re-optimized plans, there were no significant differences in planning target volume (PTV) coverage (99.6% vs 99.0%, p = 0.17) or conformality index (1.47 vs 1.4, p = 0.78). Six (50%) plans exceeded constraints with a single target. A substantial minority of hippocampi receive high radiation dose from SRS for 4 to 10 brain metastases. Decreasing distance of the closest metastasis and total target volume are associated with exceeding hippocampal constraints. Re-optimizing these plans yielded hippocampal-sparing SRS plans with acceptable dosimetry. Prospective evaluation of the impact of hippocampal dose from SRS on neurocognition merits consideration.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Microstructure-based prediction of thermal aging strength reduction factors for grade 91 ferritic-martensitic steel

This study aimed to develop a microstructure-based mechanistic approach to address the long-term thermal aging effect on yield stress and ultimate tensile strength and to provide a physical basis for developing thermal aging factors for G91 for a design life of 60 years. Several heats of G91 steel were examined. Controlled aging experiments were conducted on two heats at temperatures of 550, 600, and 650 °C for times up to ~64,000 h. Specimens were also taken from archived creep-tested specimens of G91 and from a tube removed from the Kingston coal-fired power plant to obtain data that cover a wide range of temperatures and for aging times up to 155,000 h. Thermal aging caused significant subgrain recovery, coarsening of M 23 C 6 carbides at subgrain boundaries and MX carbonitrides within subgrains. The intermetallic Laves phase forms during aging and grows rapidly. The growth rate of the subgrain width and MX mean size during thermal aging were described by kinetic models. Thermal aging results in the reductions in the yield stress and the ultimate tensile strength of G91. The effects of thermal aging on the reductions in yield stress and ultimate tensile strength were well described by the microstructure-strength model that considers three superimposed strengthening mechanisms, namely, sub-boundary strengthening, MX precipitation hardening, and Mo solid solution strengthening. Furthermore, the model was independently validated by the ASME Code values and is being used by the ASME to develop the aging-induced strength reduction factors for G91 steel for a design life of 60 years.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Improved RF measurements of SRF cavity quality factors

SRF cavity quality factors can be accurately measured using RF-power based techniques only when the cavity is very close to critically coupled. This limitation is from systematic errors driven by non-ideal RF components. When the cavity is not close to critically coupled, these systematic effects limit the accuracy of the measurements. The combination of the complex base-band envelopes of the cavity RF signals in combination with a trombone in the circuit allow the relative calibration of the RF signals to be extracted from the data and systematic effects to be characterized and suppressed. The improved calibration allows accurate measurements to be made over a much wider range of couplings. Demonstration of these techniques during testing of a single-spoke resonator with a coupling factor of near 7 will be presented, along with recommendations for application of these techniques.

43 PARTICLE ACCELERATORS↗
DOE OSTI2018

Nuclear modification factor of D 0 mesons in PbPb collisions at s NN = 5.02 TeV

The transverse momentum ( p T ) spectrum of prompt D 0 mesons and their antiparticles has been measured via the hadronic decay channels D 0 → K – π + and D - 0 → K + π – in p p and PbPb collisions at a centre-of-mass energy of 5.02 TeV per nucleon pair with the CMS detector at the LHC. The measurement is performed in the D 0 meson p T range of 2–100 GeV/ c and in the rapidity range of | y | < 1 . The p p (PbPb) dataset used for this analysis corresponds to an integrated luminosity of 27.4 pb –1 (530 μb –1 ). The measured D 0 meson p T spectrum in pp collisions is well described by perturbative QCD calculations. The nuclear modification factor, comparing D 0 meson yields in PbPb and p p collisions, was extracted for both minimum-bias and the 10% most central PbPb interactions. For central events, the D 0 meson yield in the PbPb collisions is suppressed by a factor of 5–6 compared to the p p reference in the p T range of 6–10 GeV/ c . For D 0 mesons in the high- p T range of 60–100 GeV/ c , a significantly smaller suppression is observed. The results are also compared to theoretical calculations.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2022

Measurement of the nuclear modification factor for muons from charm and bottom hadrons in Pb+Pb collisions at 5.02 TeV with the ATLAS detector

Heavy-flavour hadron production provides information about the transport properties and microscopic structure of the quark–gluon plasma created in ultra-relativistic heavy-ion collisions. A measurement of the muons from semileptonic decays of charm and bottom hadrons produced in Pb+Pb and pp collisions at a nucleon–nucleon centre-of-mass energy of 5.02 TeV with the ATLAS detector at the Large Hadron Collider is presented. The Pb+Pb data were collected in 2015 and 2018 with sampled integrated luminosities of 208 μb –1 and 38 μb –1 , respectively, and pp data with a sampled integrated luminosity of 1.17 pb –1 were collected in 2017. Muons from heavy-flavour semileptonic decays are separated from the light-flavour hadronic background using the momentum imbalance between the inner detector and muon spectrometer measurements, and muons originating from charm and bottom decays are further separated via the muon track's transverse impact parameter. Differential yields in Pb+Pb collisions and differential cross sections in pp collisions for such muons are measured as a function of muon transverse momentum from 4 GeV to 30 GeV in the absolute pseudorapidity interval |n| < 2. Nuclear modification factors for charm and bottom muons are presented as a function of muon transverse momentum in intervals of Pb+Pb collision centrality. The bottom muon results are the most precise measurement of b quark nuclear modification at low transverse momentum where reconstruction of B hadrons is challenging. The measured nuclear modification factors quantify a significant suppression of the yields of muons from decays of charm and bottom hadrons, with stronger effects for muons from charm hadron decays.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗
DOE OSTI2023

Shape polarization in the tin isotopes near N = 60 from precision g-factor measurements on short-lived 11/2 - isomers

The g factors of 11/2 - isomers in semimagic 109 Sn and 111 Sn (isomeric lifetimes $\tau$ = 2.9(3) ns and $\tau$ = 14.4(7) ns, respectively) were measured by an extension of the Time Differential Perturbed Angular Distribution technique, which uses LaBr3 detectors and the hyperfine fields of a gadolinium host to achieve precise measurements in a new regime of short-lived isomers. The results, g(11/2 - ; 109 Sn) = -0.186(8) and g(11/2 - ; 111 Sn) = -0.214(4), are significantly lower in magnitude than those of the 11/2 - isomers in the heavier isotopes and depart from the value expected for a near pure neutron h 11/2 configuration. Broken-symmetry density functional theory calculations applied to the sequence of 11/2 - states reproduce the magnitude and location of this deviation. The g(11/2 - ) values are affected by shape core polarization; the odd Oh 11/2 neutron couples to J π = 2 + , 4 + , 6 + ... configurations in the weakly-deformed effective core, causing a decrease in the g-factor magnitudes.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2025

Timelike form factor for the anomalous process γ⁎π → ππ

The form factor 𝐹 3𝜋 (𝑠, 𝑡, 𝑢) for the anomalous process 𝛾∗𝜋 → 𝜋𝜋 is calculated in the isospin limit for several values of the light current-quark mass (i.e., the pion mass) using Dyson–Schwinger and Bethe–Salpeter equations. Beyond a quark interaction kernel representing gluon-mediated interactions, leading beyond-rainbow-ladder effects at low energies are incorporated by back-coupling pions as explicit degrees of freedom. Building upon an earlier calculation of the quark-photon vertex that captures the branch cut associated with the two-pion threshold and the ρ-meson resonance, the form factor 𝐹 3𝜋 (𝑠, 𝑡, 𝑢) is determined for timelike Mandelstam s. In particular, predictions are made for the kinematics relevant to the Primakoff reaction studied with COMPASS/AMBER at CERN.

Miramontes, Angel S. [Univ. of Valencia (Spain)] (↗
DOE OSTI2021

Assessment of the driving factors of CO 2 mitigation costs of household biogas systems in China: A LMDI decomposition with cost analysis model

China has been placing a substantial focus on biogas for reducing energy consumption and carbon dioxide (CO 2 ) emissions. The operation mode of biogas systems may make the CO 2 reduction target over-optimistic. There is limited research to investigate the influential factors that may be causing the gap between the actual and theoretical CO 2 reduction costs of biogas systems in China. In this research, by using field survey data of 209 biogas users and 489 non-biogas users from 19 villages in 2015, the gap between actual and theoretical unit CO 2 reduction cost is quantified at approximately 156 USD/t CO 2 . By employing the Logarithmic Mean Divisia Index I (LMDI) model, it is found that both the cost effect (48%) and the reduction effect (52%) contribute to the unit CO 2 reduction cost gap. Furthermore, four influential factors–household labor, accessibility to the energy resource, acceptance of biogas technology, and subsidy–significantly narrow the gap between actual and theoretical CO 2 reduction costs, while the levelized subsidy contributes to widening the gap. On average, biogas systems should be operated for at least four years and the substitution rate should be more than 67% in order to keep the gap between actual and theoretical CO 2 reduction costs under 50%.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗
DOE OSTI2017

Von Willebrand factor deficiency reduces liver fibrosis in mice

Liver diseases are associated with complex changes in the hemostatic system and elevated levels of the platelet-adhesive protein Von Willebrand factor (VWF) are reported in patients with acute and chronic liver damage. Although elevated levels of VWF are associated with fibrosis in the general population, the role of VWF in acute and chronic liver injury has not been examined in depth in experimental settings. We tested the hypothesis that VWF deficiency inhibits experimental liver injury and fibrosis. Wild-type (WT) and VWF-deficient mice were challenged with carbon tetrachloride (CCl{sub 4}) and the impact of VWF deficiency on acute liver injury and chronic liver fibrosis was determined. VWF deficiency did not significantly affect acute CCl{sub 4}-induced hepatocellular necrosis in mice. Chronic CCl{sub 4} challenge, twice weekly for 6 weeks, significantly increased hepatic stellate cell activation and collagen deposition in livers of WT mice. Interestingly, hepatic induction of several profibrogenic and stellate cell activation genes was attenuated in VWF-deficient mice. Moreover, birefringent sirius red staining (indicating type I and III collagens) and type I collagen immunofluorescence indicated a reduction in hepatic collagen deposition in CCl{sub 4}-exposed VWF-deficient mice compared to CCl{sub 4}-exposed WT mice. The results indicate that VWF deficiency attenuates chronic CCl{sub 4}-induced liver fibrosis without affecting acute hepatocellular necrosis. The results are the first to demonstrate that VWF deficiency reduces the progression of liver fibrosis, suggesting a mechanistic role of elevated plasma VWF levels in cirrhosis. - Highlights: • Plasma von Willebrand Factor (VWF) levels increase in experimental liver damage. • VWF contributes to liver myofibroblast activation in experimental fibrosis. • VWF deficiency reduces experimental fibrosis without affecting acute liver injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Evaluating and modeling the effects of surface sampling factors on the recovery of organic chemical attribution signatures using the accelerated diffusion sampler and solvent extraction

In this study, an experimental design matrix was created and executed in order to test the effects of various real-world factors on the ability of the (1) accelerated diffusion sampler with solid phase micro-extraction (ADS-SPME) and (2) solvent extraction to capture organic chemical attribution signatures (CAS) from dimethyl methylphosphonate (DMMP) spiked onto painted wall board (PWB) surfaces. The DMMP CAS organic impurities sampled by ADS-SPME and solvent extraction were analyzed by gas chromatography/mass spectrometry (GC/MS). The number of detected DMMP CAS impurities and their respective GC/MS peak areas were determined as a function of DMMP stock, DMMP spiked volume, exposure time, SPME sampling time, and ADS headspace pressure. Based on the statistical analysis of experimental results, several general conclusions are made: (1) ADS-SPME with vacuum (i.e., reduced pressure) increased the amount of detected CAS impurity, as measured by GC/MS peak area, by a factor of 1.7 to 1.9 for PWB under certain experimental conditions, (2) the amount of detected CAS impurity was most influenced by spiked volume, stock, and ADS headspace pressure, (3) the ADS had no measurable effect on the number of detected DMMP impurities, that is, the ADS (with and without reduced pressure) had no practical effect on the DMMP impurity profile collected from spiked PWB, and (4) solvent extraction out performed ADS-SPME in terms of consistently capturing all or most of the targeted DMMP impurities from spiked PWB.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Quantifying the relative contribution of factors to household vehicle miles of travel

Household vehicle miles of travel (VMT) has been exhibiting a steady growth in post-recession years in the United States and has reached record levels in 2017. With transportation accounting for 27 percent of greenhouse gas emissions, planning professionals are increasingly seeking ways to curb vehicular travel to advance sustainable, vibrant, and healthy communities. Although there is considerable understanding of the various factors that influence household vehicular travel, there is little knowledge of their relative contribution to explaining variance in household VMT. This paper presents a holistic analysis to identify the relative contribution of socio-economic and demographic characteristics, built environment attributes, residential self-selection effects, and social and spatial dependency effects in explaining household VMT production. The modeling framework employs a simultaneous equations model of residential location (density) choice and household VMT generation. The analysis is performed using household travel survey data from the New York metropolitan region. Model results showed insignificant spatial dependency effects, with socio-demographic variables explaining 33 percent, density (as a key measure of built environment attributes) explaining 12 percent, and self-selection effects explaining 11 percent of the total variance in the logarithm of household VMT. The remaining 44 percent remains unexplained and attributable to omitted variables and unobserved idiosyncratic factors, calling for further research in this domain to better understand the relative contribution of various drivers of household VMT.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗
DOE OSTI2017

Relative merits and limiting factors for x-ray and electron microscopy of thick, hydrated organic materials

Electron and x-ray microscopes allow one to image the entire, unlabeled structure of hydrated materials at a resolution well beyond what visible light microscopes can achieve. However, both approaches involve ionizing radiation, so that radiation damage must be considered as one of the limits to imaging. Drawing upon earlier work, we describe here a unified approach to estimating the image contrast (and thus the required exposure and corresponding radiation dose) in both x-ray and electron microscopy. This approach accounts for factors such as plural and inelastic scattering, and (in electron microscopy) the use of energy filters to obtain so-called "zero loss" images. As expected, it shows that electron microscopy offers lower dose for specimens thinner than about 1 mu m (such as for studies of macromolecules, viruses, bacteria and archaebacteria, and thin sectioned material), while x-ray microscopy offers superior characteristics for imaging thicker specimen such as whole eukaryotic cells, thick-sectioned tissues, and organs. The required radiation dose scales strongly as a function of the desired spatial resolution, allowing one to understand the limits of live and frozen hydrated specimen imaging. Lastly, we consider the factors limiting x-ray microscopy of thicker materials, suggesting that specimens as thick as a whole mouse brain can be imaged with x-ray microscopes without significant image degradation should appropriate image reconstruction methods be identified.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Inversion of dynamical Bragg intensities to complex structure factors by iterated projections. For Ultramic. 2020. ("Pico" Festschrift, May 2021)

We discuss a method for recovering complex structure factors from many simultaneously excited Bragg beam intensities is described. The method is applied to simulated transmission electron diffraction data over a wide range of crystal thickness and beam energies. The method is based on iterated projections between structure and scattering matrices, which are related by a matrix unitary transformation, exponential, which we invert. The algorithm removes multiple-scattering perturbations from diffraction data and might be extended to other fields, including X-ray and neutron diffraction and cryo-electron microscopy. Because coherent multiple scattering involves interference between Bragg beams, the method also solves the phase problem. Unlike dynamical inversion from electron microscope images or ptychography data, the method, which starts with Bragg beam intensities, provides complex structure factors unaffected by focusing errors or resolution limitations imposed by lenses. We provide inversions from simulated data with 441 simultaneously excited Bragg beams over a range of thickness and beam energy. We discuss the retrieval of chirality information from enantiomorphs, the efficient incorporation of symmetry information using the irreducible representation of the group of structure matrices, and the effect of HOLZ lines to provide three-dimensional information.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2017

Spliceosome-associated factor CTNNBL1 promotes proliferation and invasion in ovarian cancer

Ovarian cancer is the most lethal gynecologic malignancy and the molecular pathogenesis of high-grade serous ovarian carcinoma has not been completely characterized. Numerous studies have shown that altered splicing patterns and splicing factors were found to contribute to tumor development and progression. In this study, we demonstrated that spliceosome-associated factor CTNNBL1 was significantly upregulated in high-grade serous ovarian carcinoma, the elevated level of CTNNBL1 indicates poor prognosis in patients with high-grade serous ovarian carcinoma. Functional characterization revealed that CTNNBL1 promoted the proliferation and invasion of ovarian cancer cells in vitro. Furthermore, through transcriptome analysis, we found CTNNBL1 regulates multiple splicing events and gene expression in ovarian cancer cells. Importantly, we identified IFI16 and FOXM1 splicing was regulated by CTNNBL1. To our knowledge, this is the first study exploring the expression, functional roles and regulated splicing events of CTNNBL1 in ovarian cancer. - Highlights: • CTNNBL1 was upregulated in high-grade serous ovarian carcinoma and associated with poor prognosis. • CTNNBL1 promoted the proliferation and invasion of ovarian cancer cells in vitro. • Transcriptome analysis showed CTNNBL1 regulates multiple splicing events and gene expression in ovarian cancer cells. • FOXM1and IFI16 splicing were regulated by CTNNBL1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Hepatocyte nuclear factor 4A improves hepatic differentiation of immortalized adult human hepatocytes and improves liver function and survival

Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes, but insufficient differentiation and phenotypic instability restrict their clinical application. This study aimed to determine the role of hepatocyte nuclear factor 4A (HNF4A) in hepatic differentiation of IHH, and whether encapsulation of IHH overexpressing HNF4A could improve liver function and survival in rats with acute liver failure (ALF). Primary human hepatocytes were transduced with lentivirus-mediated catalytic subunit of human telomerase reverse transcriptase (hTERT) to establish IHH. Cells were analyzed for telomerase activity, proliferative capacity, hepatocyte markers, and tumorigenicity (c-myc) expression. Hepatocyte markers, hepatocellular functions, and morphology were studied in the HNF4A-overexpressing IHH. Hepatocyte markers and karyotype analysis were completed in the primary hepatocytes using shRNA knockdown of HNF4A. Nuclear translocation of β-catenin was assessed. Rat models of ALF were treated with encapsulated IHH or HNF4A-overexpressing IHH. A HNF4A-positive IHH line was established, which was non-tumorigenic and conserved properties of primary hepatocytes. HNF4A overexpression significantly enhanced mRNA levels of genes related to hepatic differentiation in IHH. Urea levels were increased by the overexpression of HNF4A, as measured 24 h after ammonium chloride addition, similar to that of primary hepatocytes. Chromosomal abnormalities were observed in primary hepatocytes transfected with HNF4A shRNA. HNF4α overexpression could significantly promote β-catenin activation. Transplantation of HNF4A overexpressing IHH resulted in better liver function and survival of rats with ALF compared with IHH. HNF4A improved hepatic differentiation of IHH. Transplantation of HNF4A-overexpressing IHH could improve the liver function and survival in a rat model of ALF. - Highlights: • Immortalized human hepatocytes (IHH) could provide an unlimited supply of hepatocytes. • Hepatocyte nuclear factor 4A (HNF4A) plays a role in hepatic differentiation. • HNF4A improved hepatic differentiation of IHH. • Transplantation of HNF4A-overexpressing IHH could improve liver function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Optimizing combination of liver-enriched transcription factors and nuclear receptors simultaneously favors ammonia and drug metabolism in liver cells

The HepG2 cell line is widely used in studying liver diseases because of its immortalization, but its clinical application is limited by its low expression of the urea synthesis key enzymes and cytochromes P450 (CYPs). On the basis of our previous work, we investigated the transcriptional regulation of arginase 1 (Arg1) and ornithine transcarbamylase (OTC) in HepG2 cells. We also screened for the optimal combination of liver enrichment transcription factors (LETFs) and xenobiotic nuclear receptors that can promote the expression of key urea synthases and five major CYPs in HepG2 cells. Thus, recombinant HepG2 cells were established. Results showed that C/EBPβ, not C/EBPα, could upregulate expression of Arg1 and PGC1α and HNF4α cooperatively regulate the expression of OTC. The two optimal combinations C/EBPβ+HNF4α+HNF6+PXR and C/EBPβ+HNF4α+HNF6+CAR were selected. Compared with the control cells, the recombinant HepG2 cells modified by the two optimal combinations exhibited enhanced ammonia metabolism and CYP enzyme activity. Moreover, the HepG2/(C/EBPβ+HNF4α+HNF6+PXR) cells more strongly reduced ammonia than any other combination tested in this study. The present work indicated that optimizing the combination of transcription factors will simultaneously promote hepatocyte ammonia metabolism and drug metabolism. The recombinant HepG2 liver cell line constructed by the optimal combination provided an improved alternative means for bioartificial liver applications and drug toxicity testing.

60 APPLIED LIFE SCIENCES↗