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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 1,387 records · Page 77
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Background norepinephrine primes astrocytic calcium responses to subsequent norepinephrine stimuli in the cerebral cortex

Norepinephrine (NE) levels in the cerebral cortex are regulated in two modes; the brain state is correlated with slow changes in background NE concentration, while salient stimuli induce transient NE spikes. Previous studies have revealed their diverse neuromodulatory actions; however, the modulatory role of NE on astrocytic activity has been poorly characterized thus far. In this study, we evaluated the modulatory action of background NE on astrocytic responses to subsequent stimuli, using two-photon calcium imaging of acute murine cortical brain slices. We find that subthreshold background NE significantly augments calcium responses to subsequent pulsed NE stimulation in astrocytes. This priming effect is independent of neuronal activity and is mediated by the activation of β-adrenoceptors and the downstream cAMP pathway. These results indicate that background NE primes astrocytes for subsequent calcium responses to NE stimulation and suggest a novel gliomodulatory role for brain state-dependent background NE in the cerebral cortex. - Highlights: • Background NE augments the responsiveness of astrocytes to subsequent NE stimulation. • The priming effect is independent of neuronal activity and mediated by βadrenoceptor. • Background subthreshold NE may play gliomodulatory roles in the cerebral cortex.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

WNT/β-catenin pathway modulates the TNF-α-induced inflammatory response in bronchial epithelial cells

In this study, TNF-α was found to activate the WNT/β-catenin pathway in BEAS-2B human bronchial epithelial cells. Levels of phospho-LRP6, Dvl-2, and phospho-GSK-3β were elevated, while that of Axin was reduced by TNF-α treatment. Nuclear translocation of β-catenin and the reporter activity of a β-catenin-responsive promoter were increased by TNF-α treatment. Under the same experimental conditions, TNF-α activated the NF-κB signaling, which includes the phosphorylation and degradation of IκB and nuclear translocation and target DNA binding of NF-κB, and it was found that an inhibitor of NF-κB activation, JSH-23, inhibited TNF-α-induced Wnt signaling as well as NF-κB signaling. It was also found that recombinant Wnt proteins induced NF-κB nuclear translocations and its target DNA binding, suggesting that Wnt signaling and NF-κB signaling were inter-connected. TNF-α-induced modulations of IκB and NF-κB as well as pro-inflammatory cytokine expression were significantly suppressed by the transfection of β-catenin siRNA compared to that of control siRNA. Transfection of a β-catenin expression plasmid augmented the TNF-α-induced modulations of IκB and NF-κB as well as pro-inflammatory cytokine expression. These results clearly demonstrated that the WNT/β-catenin pathway modulates the inflammatory response induced by TNF-α, suggesting that this pathway may be a useful target for the effective treatment of bronchial inflammation. - Highlights: • TNF-α activated the WNT/β-catenin pathway in bronchial epithelial cells. • TNF-α-induced WNT/β-catenin pathway was inhibited by NF-κB inhibitor. • Wnt proteins induced nuclear translocation and target DNA binding of NF-κB. • TNF-α-induced NF-κB signaling was suppressed by β-catenin knock-down. • TNF-α-induced NF-κB signaling was augmented by ectopic β-catenin expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

GPR120 in adipocytes has differential roles in the production of pro-inflammatory adipocytokines

How nutritional excess leads to inflammatory responses in metabolic syndrome is not well characterized. Here, we evaluated the effects of ω-3 polyunsaturated fatty acid specific G-protein coupled receptor 120 (GPR120) activation on inflammatory pathways in adipocytes, and the influence of this process on macrophage migration. Using 3T3-L1 adipocytes, we found that agonizing GPR120 using its synthetic ligand, GSK137647, attenuated both basal and lipopolysaccharide-induced production of interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2). Moreover, the intervention reduced the phosphorylation of nuclear factor kappa B inhibitor alpha (IκBα) and nuclear translocation of nuclear factor kappa-B p65 subunit (p65). Furthermore, the silencing of GPR120 itself reduced IL-6 and CCL2 mRNA expression. Inhibition of protein kinase C (PKC) augmented the down-regulatory effect of GSK137647 on IL-6 and CCL2 mRNA. Using a luciferase assay to measure promoter activity of the IL-6 gene in mouse embryonic fibroblasts, we demonstrated that exogenous transfection of GPR120 alone reduced the promoter activity, which was augmented by GSK137647. Inhibition of PKC further reduced the promoter activity. Nevertheless, RAW 264.7 macrophages grown in conditioned medium collected from GSK137647-treated adipocytes attenuated the expressions of matrix metalloproteinases-9 and -3, and tissue inhibitor of metalloproteinase-1. Conditioned medium also inhibited the lipopolysaccharide-induced migration of these macrophages. Taken together, these findings provide critical evidence that although GPR120 is associated with a PKC-mediated pro-inflammatory pathway, the direct inhibitory effects of GPR120 on the nuclear factor kappa B pathway are anti-inflammatory. Moreover, GPR120 activity can attenuate the adipocyte-mediated enhanced production of extracellular matrix-modulating factors in macrophages and can reduce their migration by a paracrine mechanism. - Highlights: • Agonizing GPR120 differentially regulates the pro-inflammatory adipocytokines. • Agonizing GPR120 in adipocytes attenuates NF-κB mediated IL-6 and CCL2 production. • Agonizing GPR120 concomitantly triggers a PKC mediated pro-inflammatory pathway. • However, the resulted effect in adipocytes remains anti-inflammatory. • Agonizing GPR120 in adipocytes reduces macrophage migration in a paracrine manner.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Modelling the deployment of CO₂ storage in U.S. gas-bearing shales

The proliferation of commercial development in U.S. gas-bearing shales helped to drive a twelve-fold increase in domestic gas production between 2000 and 2010, and the nation's gas production rates continue to grow. While shales have long been regarded as a desirable caprock for CCS operations because of their low permeability and porosity, there is increasing interest in the feasibility of injecting CO₂ into shales to enhance methane recovery and augment CO₂ storage. Laboratory work published in recent years observes that shales with adsorbed methane appear to exhibit a stronger affinity for CO₂ adsorption, offering the potential to drive additional CH₄ recovery beyond primary production and perhaps the potential to store a larger volume of CO₂ than the volume of methane displaced. Recent research by the authors on the revenues associated with CO₂-enhanced gas recovery (CO₂-EGR) in gas-bearing shales estimates that, based on a range of EGR response rates, the average revenue per ton of CO₂ for projects managed over both EGR and subsequent storage-only phases could range from $0.50 to $18/tCO₂. While perhaps not as profitable as EOR, for regions where lower-cost storage options may be limited, shales could represent another “early opportunity” storage option if proven feasible for reliable EGR and CO₂ storage. Significant storage potential exists in gas shales, with theoretical CO₂ storage resources estimated at approximately 30-50 GtCO₂. However, an analysis of the comprehensive cost competitiveness of these various options is necessary to understand the degree to which they might meaningfully impact U.S. CCS deployment or costs. This preliminary analysis shows that the degree to which EGR-based CO₂ storage could play a role in commercial-scale deployment is heavily dependent upon the offsetting revenues associated with incremental recovery; modeling the low revenue case resulted in only five shale-based projects, while under the high revenue case, shales accounted for as much as 20 percent of total U.S. storage in the first 20 years of deployment. Interestingly, even in this highest revenue case, there appear to be no negative-cost projects that would be profitable in a no-policy environment as modeled under the assumptions employed. While this reflects a very first look at the potential for shales, it is clear that more laboratory and experimental work are needed to reduce uncertainty in key variables and begin to differentiate and identify high-potential shales for early pilot study.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Optimizing Cornell’s future geothermal district heating performance through systems engineering and simulation

Cornell University’s intention to lower its carbon footprint has motivated this engineering evaluation of using low-temperature geothermal energy to supply heat to the campus district energy system. Optimal selection and operation of heat pumps can significantly improve system performance. To support this analysis, we model the quantitative relationships between heat pump configurations and source flow, supply and distribution temperatures, facility heating design options, output heat generation, and carbon abatement outcomes. A systems approach is used for analysis, troubleshooting, and improvement of the model. The result of this effort is a dynamic tool that appropriately responds to hourly thermal demand and communicates energy response for techno-economic analysis. Simulations indicate that a single well-pair in the local Basement Contact Zone reservoir can satisfy almost 68% of annual thermal demand at nearly 20 MWth average capacity while remaining financially competitive compared to conventional heating with levelized cost of heating (LCOH) as low as $4.55/MMBTU ($15.53/MWh th ). A direct-use scheme with heat pump augmentation provided more carbon abatement and 50 to 150% more annual heat supply than one without augmentation. Exploration of three and four well-pair scenarios prove the capability to achieve 50 MW th baseload heating capacity with competitive LCOH and significant carbon reductions.

15 GEOTHERMAL ENERGY↗
DOE OSTI2024

The Effect of Air Separations on Fast Pyrolysis Products for Forest Residue Feedstocks

This study investigates the intricate relationship between biomass preprocessing and pyrolysis product yields, employing the air classification technique for the treatment of loblolly pine residues with varying moisture content. A comprehensive exploration of the physicochemical properties of air-classified loblolly pine informs a sophisticated pyrolysis simulation model. Given the complex and multifaceted nature of biomass pyrolysis, operating across diverse temporal and spatial scales, a pyrolysis kinetics-based CFD–DEM simulation method is employed to predict product yields. Results showed that the elevated moisture content amplifies particle adhesiveness, necessitating augmented air velocities for effective separation, thereby influencing the efficiency of the separation process. While carbon and hydrogen contents exhibit relative stability across diverse moisture contents and blower frequencies, the oxygen content undergoes noticeable changes. For example, the oxygen contents were measured as 29.2 and 38.6 wt% in the light fraction of 30% moisture content sample at blower frequencies of 10 and 20 Hz, respectively. An intriguing finding emerges from pyrolysis simulation, indicating that a lower blower frequency in air classification moderately enhances bio-oil yield and significantly improves its quality, particularly in terms of water content. For instance, the water content in the bio-oil was about 1.5% and 10% in the heavy and light fractions, respectively from 10% moisture sample under 15 Hz blower frequency. In summary, a detailed understanding and strategic manipulation of critical material attributes in biomass through efficient fractionation techniques are imperative for advancing fast pyrolysis as a sustainable avenue for renewable energy and chemical production.

09 BIOMASS FUELS↗
DOE OSTI2022

Enabling machine learning-ready HPC ensembles with Merlin

With the growing complexity of computational and experimental facilities, many scientific researchers are turning to machine learning (ML) techniques to analyze large scale ensemble data. With complexities such as multi-component workflows, heterogeneous machine architectures, parallel file systems, and batch scheduling, care must be taken to facilitate this analysis in a high performance computing (HPC) environment. Here, we present Merlin, a workflow framework to enable large ML-friendly ensembles of scientific HPC simulations. By augmenting traditional HPC with distributed compute technologies, Merlin aims to lower the barrier for scientific subject matter experts to incorporate ML into their analysis. As a producer–consumer workflow model, Merlin enables multi-machine, cross-batch job, dynamically allocated yet persistent workflows capable of utilizing surge-compute resources. Key features of Merlin are a flexible HPC-centric interface, low per-task overhead, multi-tiered fault recovery, and a hierarchical sampling algorithm that allows for $\mathscr{O}$(N) task execution and $\mathscr{O}$(N ln N) task queuing to ensembles of millions of tasks. In addition to Merlin’s design, we test the algorithm’s performance in an HPC center and demonstrate the ability to enqueue 40 million simulations in 100 s, with a 30 millisecond per-task overhead that is independent of ensemble size. Finally, we describe some example applications that Merlin has enabled on leadership-class HPC resources, such as the ML-augmented optimization of nuclear fusion experiments and the calibration of infectious disease models to study the progression of and possible mitigation strategies for COVID-19.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2021

Caloric Restriction Impairs Regulatory T cells Within the Tumor Microenvironment After Radiation and Primes Effector T cells

Outcomes for triple negative breast cancer (TNBC) are poor and may be improved by increasing CD8{sup +} tumor infiltrating lymphocytes (TIL) to augment antitumor immunity. Radiation (RT) can promote immunogenic cell death with increased antitumor T cell activity but also stimulates suppressive regulatory T cells (Tregs). Because metabolic alterations affect immune homeostasis and prior studies show caloric restriction (CR) combined with RT improves preclinical TNBC outcomes, we hypothesized that CR augments RT, in part, by altering intratumoral immunity. Using an in vivo model of TNBC, we treated mice with ad libitum (AL) diet, radiation, a CR diet, or CR + RT, and demonstrated an immune suppressive environment with a significant increase in CD4{sup +} CD25{sup +}Foxp3{sup +} Tregs after RT but not in CR-fed mice. CD8:Treg ratio in CR + RT TIL increased 4-fold compared with AL + RT mice. In vivo CD8 depletion was performed to assess the role of effector T cells in mitigating the effects of CR, and it was found that in mice undergoing CR, depletion of CD8 T cells resulted in increased tumor progression and decreased median survival compared with isotype control–treated mice. In addition, PD-1 expression on CD3{sup +}CD8{sup +} T cells within the tumor microenvironment was significantly increased in CR + RT versus AL + RT treated mice as per immunofluorescence. Serum from breast cancer patients undergoing RT alone or CR and RT was collected pre- and postintervention, and a cytokine array demonstrated that patients treated with CR + RT had notable decreases in immunosuppressive cytokines such as IL-2Rγ, IL-10Rβ, and TGF-β2 and 3 compared with patients receiving RT alone. In conclusion, combining CR with RT decreases intratumoral Tregs, increases CD8:Treg, and increases PD-1 expression via a process dependent on CD8 T cells in a TNBC model. Breast cancer patients undergoing CR concurrently with RT also had significant reduction in immunosuppressive cytokine levels compared with those receiving RT alone.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2014

High order curvilinear finite elements for elastic–plastic Lagrangian dynamics

This paper presents a high-order finite element method for calculating elastic–plastic flow on moving curvilinear meshes and is an extension of our general high-order curvilinear finite element approach for solving the Euler equations of gas dynamics in a Lagrangian frame [1,2]. In order to handle transition to plastic flow, we formulate the stress–strain relation in rate (or incremental) form and augment our semi-discrete equations for Lagrangian hydrodynamics with an additional evolution equation for the deviatoric stress which is valid for arbitrary order spatial discretizations of the kinematic and thermodynamic variables. The semi-discrete equation for the deviatoric stress rate is developed for 2D planar, 2D axisymmetric and full 3D geometries. For each case, the strain rate is approximated via a collocation method at zone quadrature points while the deviatoric stress is approximated using an L{sub 2} projection onto the thermodynamic basis. We apply high order, energy conserving, explicit time stepping methods to the semi-discrete equations to develop the fully discrete method. We conclude with numerical results from an extensive series of verification tests that demonstrate several practical advantages of using high-order finite elements for elastic–plastic flow.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2017

A practical globalization of one-shot optimization for optimal design of tokamak divertors

In past studies, nested optimization methods were successfully applied to design of the magnetic divertor configuration in nuclear fusion reactors. In this paper, so-called one-shot optimization methods are pursued. Due to convergence issues, a globalization strategy for the one-shot solver is sought. Whereas Griewank introduced a globalization strategy using a doubly augmented Lagrangian function that includes primal and adjoint residuals, its practical usability is limited by the necessity of second order derivatives and expensive line search iterations. In this paper, a practical alternative is offered that avoids these drawbacks by using a regular augmented Lagrangian merit function that penalizes only state residuals. Additionally, robust rank-two Hessian estimation is achieved by adaptation of Powell's damped BFGS update rule. The application of the novel one-shot approach to magnetic divertor design is considered in detail. For this purpose, the approach is adapted to be complementary with practical in parts adjoint sensitivities. Using the globalization strategy, stable convergence of the one-shot approach is achieved.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2017

Evolutionary optimization of PAW data-sets for accurate high pressure simulations

We examine the challenge of performing accurate electronic structure calculations at high pressures by comparing the results of all-electron full potential linearized augmented-plane-wave calculations, as implemented in the WIEN2k code, with those of the projector augmented wave (PAW) method, as implemented in Quantum ESPRESSO or Abinit code. In particular, we focus on developing an automated and consistent way of generating transferable PAW data-sets that can closely produce the all electron equation of state defined from zero to arbitrary high pressures. The technique we propose is an evolutionary search procedure that exploits the ATOMPAW code to generate atomic data-sets and the Quantum ESPRESSO software suite for total energy calculations. We demonstrate different aspects of its workability by optimizing PAW basis functions of some elements relatively abundant in planetary interiors. In addition, we introduce a new measure of atomic data-set goodness by considering their performance uniformity over an extended pressure range. - Highlights: • An attempt made to achieve the AE-FLAPW accuracy, at the favorable computational efficiency of the PAW approach for an outspread pressure range. • Provided an automatic and consistent route for developing efficient and transferable PAW data-sets. • Explicated an improved measure for the goodness of data-sets by including uniformity of the data-set performance over an extended pressure range.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2018

Boosting visible light photocatalytic performance of g-C3N4 nanosheets by combining with LaFeO3 nanoparticles

Highlights: • A Z-scheme LaFeO{sub 3}/g-C{sub 3}N{sub 4} hybrid was constructed by in-situ growth strategy. • LaFeO{sub 3}/g-C{sub 3}N{sub 4} exhibited greatly boosted visible light photocatalytic activity. • Holes and superoxide radicals were responsible for methyl orange degradation. • A reasonable Z-scheme was responsible for the augmented photocatalytic activity. - Abstract: A binary direct Z-scheme LaFeO{sub 3}/g-C{sub 3}N{sub 4} nanohybrid photocatalyst composed of LaFeO{sub 3} nanoparticles and g-C{sub 3}N{sub 4} nanosheets was facilely obtained by in-situ growth strategy and employed for the photocatalytic degradation of methyl orange (MO) in aqueous solution under visible light irradiation (λ > 420 nm). As expected, in comparison with pure g-C{sub 3}N{sub 4}, all of the LaFeO{sub 3}/g-C{sub 3}N{sub 4} hybrids exhibited the enhanced photocatalytic performance. Noticeably, the LaFeO{sub 3}(2.0 wt%)/g-C{sub 3}N{sub 4} composite illustrated the highest apparent photodegradation rate constant, which was nearly 17.4 and 4.1 times larger than those of pure LaFeO{sub 3} and g-C{sub 3}N{sub 4}, respectively. Such a greatly augmented catalytic activity was mainly ascribed to the efficient separation of the photogenerated charge carriers through a Z-scheme system composed of g-C{sub 3}N{sub 4} and LaFeO{sub 3}, leading to suppressing the photogenerated electrons and holes recombination in both g-C{sub 3}N{sub 4} and LaFeO{sub 3} and boosting the photocatalytic efficiency. Furthermore, a probable degradation mechanism was also proposed based on active species trapping experiments, photoluminescence spectroscopy and energy band structures.

77 NANOSCIENCE AND NANOTECHNOLOGY↗
DOE OSTI2018

Integrating quantitative defense-in-depth metrics into new reactor designs

Risk-informed, performance-based (RIPB) methods have progressed to the point where high-level guidance can be used to augment traditional, deterministic, nuclear safety design practices in areas important to nuclear reactor safety. This paper describes an approach for augmenting the traditional defense-in-depth (DID) qualitative approach with quantitative risk information from a plant-specific probabilistic risk assessment (PRA) in a way that is structured, can be applied on a consistent basis, and allows for clear acceptance criteria. Adding performance-based targets that should be achieved is expected to result in safer and more economical plant designs. Evaluations of DID can be conducted throughout the design process as well as in support of design certification and operating license applications to identify where defense protections could be enhanced or relaxed. Consistent with the United States Nuclear Regulatory Commission's policy statement encouraging greater use of PRA to improve safety decision making and regulatory efficiency, this scenario-based DID method can be used to evaluate changes and overall plant design as part of the normal design control process. Although the RIPB method presented in this paper was developed for application to advanced passive light water reactor designs, the metrics could be tailored to other reactor designs. This risk-informed approach to DID helps to ensure that public and worker risk insights are integrated into the design process holistically.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2014

On Parallel Push-Relabel based Algorithms for Bipartite Maximum Matching

We study multithreaded push-relabel based algorithms for computing maximum cardinality matching in bipartite graphs. Matching is a fundamental combinatorial (graph) problem with applications in a wide variety of problems in science and engineering. We are motivated by its use in the context of sparse linear solvers for computing maximum transversal of a matrix. We implement and test our algorithms on several multi-socket multicore systems and compare their performance to state-of-the-art augmenting path-based serial and parallel algorithms using a testset comprised of a wide range of real-world instances. Building on several heuristics for enhancing performance, we demonstrate good scaling for the parallel push-relabel algorithm. We show that it is comparable to the best augmenting path-based algorithms for bipartite matching. To the best of our knowledge, this is the first extensive study of multithreaded push-relabel based algorithms. In addition to a direct impact on the applications using matching, the proposed algorithmic techniques can be extended to preflow-push based algorithms for computing maximum flow in graphs.

Push-relabel, matching, bipartite↗
DOE OSTI2018

ElectroCat: DOE's approach to PGM-free catalyst and electrode R&D

The successful development of high-performance, durable platinum group metal-free (PGM-free) electrocatalysts and electrodes for polymer electrolyte membrane fuel cells (PEMFCs) will ultimately improve the cost-competiveness of fuel cells in a wide range of applications. This is considered to be a critical development especially for automotive fuel cell applications in order to bring the system cost of an automotive fuel cell system down to the $30/kW cost target set by the U.S. Department of Energy (DOE). The platinum group metal (PGM) electrocatalysts are a major contributor to the system cost. Addressing the technical challenges to PGM-free electrocatalyst and electrode development, therefore, represents one of DOE's most pressing research and development (R&D) priorities. ElectroCat was formed by the DOE as part of the Energy Materials Network (EMN) in early 2016, and shares with other EMN consortia the goal of decreasing the time to market for advanced materials related to clean energy technologies, in the context of increasing U.S. fuel cell electric vehicle (FCEV) manufacturing competitiveness. To accomplish this, the consortium performs core research and development and provides universities and companies streamlined access to the unique, world-class set of tools and expertise relevant to early-stage applied PGM-free catalyst R&D of the member national laboratories. Moreover, ElectroCat fosters a systematic methodology by which prospective catalysts and electrodes are prepared and analyzed rapidly and comprehensively using high-throughput, combinatorial methods. Catalyst discovery is augmented by theory as well as foundational electrocatalysis and materials knowledge at the participating national laboratories. Furthermore, ElectroCat has developed a data sharing framework, requisite of all EMN consortia, for disseminating its findings to the public via a searchable database, to further expedite incorporation of PGM-free electrocatalysts into next-generation fuel cells by advancing the general understanding of the PGM-free electrocatalyst field.

Thompson, Simon T.↗
DOE OSTI2012

Exposure to particulate hexavalent chromium exacerbates allergic asthma pathology

Airborne hexavalent chromate, Cr(VI), has been identified by the Environmental Protection Agency as a possible health threat in urban areas, due to the carcinogenic potential of some of its forms. Particulate chromates are produced in many different industrial settings, with high levels of aerosolized forms historically documented. Along with an increased risk of lung cancer, a high incidence of allergic asthma has been reported in workers exposed to certain inhaled particulate Cr(VI) compounds. However, a direct causal association between Cr(VI) and allergic asthma has not been established. We recently showed that inhaled particulate Cr(VI) induces an innate neutrophilic inflammatory response in BALB/c mice. In the current studies we investigated how the inflammation induced by inhaled particulate Cr(VI) might alter the pathology of an allergic asthmatic response. We used a well-established mouse model of allergic asthma. Groups of ovalbumin protein (OVA)-primed mice were challenged either with OVA alone, or with a combination of OVA and particulate zinc chromate, and various parameters associated with asthmatic responses were measured. Co-exposure to particulate Cr(VI) and OVA mediated a mixed form of asthma in which both eosinophils and neutrophils are present in airways, tissue pathology is markedly exacerbated, and airway hyperresponsiveness is significantly increased. Taken together these findings suggest that inhalation of particulate forms of Cr(VI) may augment the severity of ongoing allergic asthma, as well as alter its phenotype. Such findings may have implications for asthmatics in settings in which airborne particulate Cr(VI) compounds are present at high levels. -- Highlights: ► Allergic asthma correlated with exposure to certain inhaled particulate chromates. ► Direct causal association between Cr(VI) and allergic asthma not established. ► Cr exacerbated pathology and airway hyperresponsiveness in an OVA-challenged mouse. ► Particulate Cr(VI) may augment severity and alter phenotype of ongoing allergic asthma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP{sup +/+} and TIRAP{sup −/−} mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP{sup +/+} mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP{sup −/−} mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies provide novel mechanistic insights into idiosyncratic hepatotoxicity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2013

Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity

Today's developed world faces a major public health challenge in the rise in the obese population and the increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation, protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-α levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver. - Highlights: ► BDCM acute exposure sensitizes liver to increased free radical stress in obesity. ► BDCM-induced higher leptin contributes to early steatohepatitic lesions. ► Increased leptin mediates protein radical and 3-nitrotyrosine formation. ► BDCM exposure in obesity activates Kupffer cells and NADPH oxidase. ► BDCM/leptin synergy promotes necrotic cell-death and augments steatohepatitis.

60 APPLIED LIFE SCIENCES↗