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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

The Fragility of Bedform‐Induced Hyporheic Zones: Exploring Impacts of Dynamic Groundwater Table Fluctuations

Abstract Hyporheic zones are commonly regarded as resilient and enduring interfaces between groundwater and surface water in river corridors. In particular, bedform‐induced advective pumping hyporheic exchange (bedform‐induced exchange) is often perceived as a relatively persistent mechanism in natural river systems driving water, solutes, and energy exchanges between the channel and its surrounding streambed sediments. Numerous studies have been based on this presumption. To evaluate the persistence of hyporheic zones under varying hydrologic conditions, we use a multi‐physics framework to model advective pumping bedform‐induced hyporheic exchange in response to a series of seasonal‐ and event‐scale groundwater table fluctuation scenarios, which lead to episodic river‐aquifer disconnections and reconnections. Our results suggest that hyporheic exchange is not as ubiquitous as generally assumed. Instead, the bedform‐induced hyporheic exchange is restricted to a narrow range of conditions characterized by minor river‐groundwater head differences, is intermittent, and can be easily obliterated by minor losing groundwater conditions. These findings shed light on the fragility of bedform‐induced hyporheic exchange and have important implications for biogeochemical transformations along river corridors.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Impacts of Forest Management-Induced Productivity Changes on Future Land Use and Land Cover Change

Anthropogenic land use and land cover change (LULCC) is projected to continue in the future. However, the influence of forest management on forest productivity change and subsequent LULCC projections remains under-investigated. This study explored the impacts of forest management-induced change in forest productivity on LULCC throughout the 21st century. Specifically, we developed a framework to softly couple the Global Change Analysis Model and Global Timber Model to consider forest management-induced forest productivity change and projected future LULCC across the five Shared Socioeconomic Pathways (SSPs). We found future increases in forest management intensity overall drive the increase of forest productivity. The forest management-induced forest productivity change shows diverse responses across all SSPs, with a global increase from 2015 to 2100 ranging from 3.9% (SSP3) to 8.8% (SSP1). This further leads to an overall decrease in the total area with a change of land use types, with the largest decrease under SSP1 (-7.5%) and the smallest decrease under SSP3 (-0.7%) in 2100. Among land use types, considering forest management-induced change significantly reduces the expansion of managed forest and also reduces the loss of natural land in 2100 across SSPs. This suggests that ignoring forest management-induced forest productivity change underestimates the efficiency of wood production, overestimates the managed forest expansion required to meet the future demand, and consequently, potentially introduces uncertainties into relevant analyses, for example, carbon cycle and biodiversity. Thus, we advocate to better account for the impacts of forest management in future LULCC projections.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Observed Increase in Tropical Cyclone‐Induced Sea Surface Cooling Near the U.S. Southeast Coast

Abstract Tropical cyclones (TCs) induce substantial upper‐ocean mixing and upwelling, leading to sea surface cooling. In this study, we explore changes in TC‐induced cold wakes along the United States (U.S.) Southeast and Gulf Coasts during 1982–2020. Our study shows a significant increase in TC‐induced sea surface temperature (SST) cooling of about 0.20°C near the U.S. Southeast Coast over this period. However, for the U.S. Gulf Coast, trends in TC‐induced SST cooling are insignificant. Analysis of the large‐scale oceanic environments indicate that the increasing TC‐induced cold wakes near the Southeast coast have been predominantly caused by the cooling of subsurface waters in that region. This upper‐ocean change is attributed to the enhancement of surface pressure gradient across land‐sea boundary and the associated increase in alongshore winds over there. Further analysis with climate models reveals the important role of anthropogenic forcings in driving these changes in the atmospheric circulation response along the U.S. Southeast Coast.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Multiplexed characterization of rationally designed promoter architectures deconstructs combinatorial logic for IPTG-inducible systems

Abstract A crucial step towards engineering biological systems is the ability to precisely tune the genetic response to environmental stimuli. In the case of Escherichia coli inducible promoters, our incomplete understanding of the relationship between sequence composition and gene expression hinders our ability to predictably control transcriptional responses. Here, we profile the expression dynamics of 8269 rationally designed, IPTG-inducible promoters that collectively explore the individual and combinatorial effects of RNA polymerase and LacI repressor binding site strengths. We then fit a statistical mechanics model to measured expression that accurately models gene expression and reveals properties of theoretically optimal inducible promoters. Furthermore, we characterize three alternative promoter architectures and show that repositioning binding sites within promoters influences the types of combinatorial effects observed between promoter elements. In total, this approach enables us to deconstruct relationships between inducible promoter elements and discover practical insights for engineering inducible promoters with desirable characteristics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Giant electric field-induced second harmonic generation in polar skyrmions

Electric field-induced second harmonic generation allows electrically controlling nonlinear light-matter interactions crucial for emerging integrated photonics applications. Despite its wide presence in materials, the figures-of-merit of electric field-induced second harmonic generation are yet to be elevated to enable novel device functionalities. Here, we show that the polar skyrmions, a topological phase spontaneously formed in PbTiO3/SrTiO3 ferroelectric superlattices, exhibit a high comprehensive electric field-induced second harmonic generation performance. The second-order nonlinear susceptibility and modulation depth, measured under non-resonant 800 nm excitation, reach ~54.2 pm V −1 and ~664% V −1 , respectively, and high response bandwidth (higher than 10 MHz), wide operating temperature range (up to ~400 K) and good fatigue resistance (>10 10 cycles) are also demonstrated. Through combined in-situ experiments and phase-field simulations, we establish the microscopic links between the exotic polarization configuration and field-induced transition paths of the skyrmions and their electric field-induced second harmonic generation response. Our study not only presents a highly competitive thin-film material ready for constructing on-chip devices, but opens up new avenues of utilizing topological polar structures in the fields of photonics and optoelectronics.

Nonlinear optics↗
DOE OSTI2025

Widespread underestimation of rain-induced soil carbon emissions from global drylands

Dryland carbon fluxes, particularly those driven by ecosystem respiration, are highly sensitive to water availability and rain pulses. However, the magnitude of rain-induced carbon emissions remains unclear globally. Here we quantify the impact of rain-pulse events on the carbon balance of global drylands and characterize their spatiotemporal controls. Using eddy-covariance observations of carbon, water and energy fluxes from 34 dryland sites worldwide, we produce an inventory of over 1,800 manually identified rain-induced CO2 pulse events. Based on this inventory, a machine learning algorithm is developed to automatically detect rain-induced CO2 pulse events. Our findings show that existing partitioning methods underestimate ecosystem respiration and photosynthesis by up to 30% during rain-pulse events, which annually contribute 16.9 ± 2.8% of ecosystem respiration and 9.6 ± 2.2% of net ecosystem productivity. We show that the carbon loss intensity correlates most strongly with annual productivity, aridity and soil pH. Finally, we identify a universal decay rate of rain-induced CO2 pulses and use it to bias-correct respiration estimates. Our research highlights the importance of rain-induced carbon emissions for the carbon balance of global drylands and suggests that ecosystem models may largely underrepresent the influence of rain pulses on the carbon cycle of drylands.

Nguyen, Ngoc B↗
DOE OSTI2025

Characterization of proton-induced damage in thick, p-channel skipper-CCDs

Here, in this work, we characterize the radiation-induced damage in two thick, p-channel skipper-CCDs irradiated unbiased and at room temperature with 217-MeV protons. We evaluate the overall performance of the sensors and demonstrate their single-electron/single-photon sensitivity after receiving a fluence on the order of 10 10 protons/cm 2 . Using the pocket-pumping technique, we quantify and characterize the proton-induced defects from displacement damage. We report an overall trap density of 0.134 traps/pixel for a displacement damage dose of 2.3 × 10 7 MeV/g. Three main proton-induced trap species were identified, V 2 , C i O i and V n O m , and their characteristic trap energies and cross sections were extracted. We found that while divacancies are the most common proton-induced defects, C i O i defects have a greater impact on charge integrity at typical operating temperatures because their emission-time constants are comparable or larger than typical readout times. To estimate ionization damage, we measure the characteristic output transistor curves. We found no threshold voltage shifts after irradiation. Our results highlight the potential of skipper-CCDs for applications requiring high-radiation tolerance and can be used to find the operating conditions in which effects of radiation-induced damage are mitigated.

47 OTHER INSTRUMENTATION↗
DOE OSTI2024

Predicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs—a proof-of-concept study with doxorubicin

Abstract Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anticancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for exploring the interindividual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intraindividual variability of iPSC-CM-related assays and presented a proof of concept to prospectively predict doxorubicin (DOX)-induced cardiotoxicity (DIC) using donor-specific iPSC-CMs. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intraindividual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice and largely replicated the reported mechanisms. By categorizing iPSC-CMs into resistant and sensitive cell lines based on their time- and concentration-related phenotypic responses to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we identified a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. Our results support the utilization of donor-specific iPSC-CMs in assessing interindividual differences in DIC. Further studies will encompass a large panel of donor-specific iPSC-CMs to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.

Toxicology↗
DOE OSTI2026

Electron-irradiation induced creep in amorphous alloys

Electron-irradiation induced creep rates in amorphous alloys, a-SiO2, Fe79B16Si5, Cu60Ta40, and Cu50Ti50, were measured at room temperature using a miniaturized beam-bending apparatus within a transmission electron microscope operated at 200 keV. The creep rates of these amorphous samples increased nearly linearly with both e-beam current density and applied stress, while a reference crystalline (c-)SiO2 sample failed to creep under the same conditions. The irradiation induced creep compliance of a-SiO2 was ~ 15 times larger than that of Fe79B16Si5 and over 1,000 times larger than that of the two Cu alloys. Molecular dynamics computer simulations were employed to simulate electron irradiation induced creep using interatomic potentials representing amorphous Cu75Zr25, Ni80P20, and SiO2 as model systems. The irradiation induced creep compliances calculated for Cu75Zr25 during 200 keV electron irradiation provided good quantitative agreement with the two Cu-based alloys, but that for a-SiO2 was ~ 180 times too small. These results indicate that unlike neutron or ion-beam induced creep in a-SiO2, creep under electron irradiation is dominated by the effects of ionization owing largely to the far higher ratio of electronic stopping to nuclear stopping for electrons than for ions.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Nonlinear ion transport mediated by induced charge in ultrathin nanoporous membranes

Ultrathin membranes with nanoporous conduits show promise for ionic separations and desalination applications, but the mechanisms underlying the nonlinear ionic transport observed in these systems are not well understood. Here, in this work, we demonstrate how induced charge at membrane interfaces can lead to nonlinear ionic transport and voltage-dependent conductance through such channels. The application of an electric field on a polarizable membrane leads to induced charges at the membrane interfaces. The induced charges in turn are screened by diffuse charges in the electrolyte, which are acted upon by the electric field. For extremely thin membranes, the induced charge effect can be significant even for moderate applied voltages commonly used in experiments. We apply a continuum Poisson-Nernst-Planck model to characterize the current-voltage behavior of ultrathin membranes over a wide parameter space. The predictions of the model are compared to recent experiments on graphene and MoS 2 membranes in an electric field. We expect the role of induced charge to be especially pronounced in the limit of atomically thin membranes.

36 MATERIALS SCIENCE↗
DOE OSTI2020

Influence of Tabula Rasa on Process- and Light-Induced Degradation of Solar Cells Fabricated From Czochralski Silicon

Monocrystalline Si solar cells are fabricated from Czochralski (Cz) Si, which contains 10 17 –10 18 cm -3 oxygen atoms. Cz Si undergoes degradation during high-temperature thermal processing steps, such as dopant diffusion to form the p - n junction. This degradation in the bulk minority carrier lifetime can be related to the formation of oxygen precipitates. We found that a high-temperature annealing process known as tabula rasa (TR) not only mitigates process-induced degradation via oxygen precipitate nuclei dissolution, but also modifies subsequent light-induced degradation. We report on the bulk carrier lifetime of n - and p -type Cz Si after TR, which homogenizes the interstitial oxygen in the bulk Si to its monoatomic form in either an N 2 or O 2 environment. A control sample, which was not subjected to a TR processing step, experienced severe process-induced degradation during a boron emitter thermal budget as oxygen precipitates were formed in the Si bulk. These precipitates could be imaged using photoluminescence. Additionally, samples that underwent a TR processing step prior to the boron emitter thermal budget show efficient gettering of metallic impurities compared to the control sample, which showed a decline in the implied open-circuit voltage after the gettering step. Furthermore, modification of the interstitial oxygen bonding by TR had a strong effect on the light-induced degradation kinetics. Instead of a typically observed monotonic decrease, minority carrier lifetime increases first, followed by a nonmonotonic decrease over a ~20 h period. Finally, we conclude that by modifying the interstitial oxygen bonding via TR pretreatment, p -type Cz Si wafers become substantially resistant to harsh solar cell processes and strongly modified light-induced degradation, which would open alternative ways to mitigate this degradation mechanism.

14 SOLAR ENERGY↗
DOE OSTI2022

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

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

Song, Dan↗
DOE OSTI2024

Cyclic Injection Leads to Larger and More Frequent Induced Earthquakes under Volume-Controlled Conditions

As carbon storage technologies advance globally, methods to understand and mitigate induced earthquakes become increasingly important. Although the physical processes that relate increased subsurface pore pressure changes to induced earthquakes have long been known, reliable methods to forecast and control induced seismic sequences remain elusive. Suggested reservoir engineering scenarios for mitigating induced earthquakes typically involve modulation of the injection rate. Some operators have implemented periodic shutdowns (i.e., effective cycling of injection rates) to allow reservoir pressures to equilibrate (e.g., Paradox Valley) or shut-in wells after the occurrence of an event of concern (e.g., Basel, Switzerland). Other proposed scenarios include altering injection rates, actively managing pressures through coproduction of fluids, and preinjection brine extraction. Here, in this work, we use 3D physics-based earthquake simulations to understand the effects of different injection scenarios on induced earthquake rates, maximum event magnitudes, and postinjection seismicity. For comparability, the modeled injection considers the same cumulative volume over the project’s operational life but varies the schedule and rates of fluid injected. Simulation results show that cyclic injection leads to more frequent and larger events than constant injection. Furthermore, with intermittent injection scenario, a significant number of events are shown to occur during pauses in injection, and the seismicity rate remains elevated for longer into the postinjection phase compared to the constant injection scenario.

58 GEOSCIENCES↗
DOE OSTI2024

Sulfur speciation in dacitic melts using X-ray absorption near-edge structure spectroscopy of the S K -edge (S-XANES): Consideration of radiation-induced changes and the implications for sulfur in natural arc systems

Abstract The synchrotron technique of micro X-ray absorption near-edge structure spectroscopy at the sulfur K-edge (S-XANES) provides a unique opportunity to measure the proportion of different oxidation states of sulfur (S) in silicate glasses. Although applied extensively in the analysis of basaltic silicate glasses, few S-XANES studies have investigated variations in S oxidation states with fO2 in felsic silicate glasses. In addition, no study has systematically compared the S-XANES results obtained from the same samples at different photon flux densities to quantify the relationship between exposure time and changes in S speciation in silicate glass, as has been done for Fe and V. This study evaluates observed differences in S speciation measured in experimentally produced H2O-saturated dacitic glasses over a range of reducing to oxidizing conditions (from log fO2 = ΔFMQ-0.7 to ΔFMQ+3.3; FMQ is the fayalite-magnetite-quartz mineral redox buffer) and equilibrated at 1000 °C and 300 MPa. S-XANES spectra were collected at three different photon flux densities using three microspectroscopy beamlines. As is observed in S-XANES analyses of basaltic silicate glasses, beam-induced changes to the S6+/ΣS are observed as a function of photon flux density and beam exposure time. Our results demonstrate that silicate glasses of dacitic composition undergo beam-induced photo-reduction in samples equilibrated at ΔFMQ > +1.75 and photo-oxidation if equilibrated at ΔFMQ < +1. The time required to observe beam-induced changes in the spectra varies as a function of flux density, and our study establishes an upper photon density limit at ~1.0 × 1012 photons/µm2. The S6+/ΣS calculated from spectra collected below this absorbed photon limit at intermediate flux densities (~1–4 × 109 photons/s per µm2) are affected by beam damage, as no conditions were found to be completely free of beam-induced changes. However, the S6+/ΣS ratios calculated below the limit at intermediate flux densities are consistent with thermodynamic constraints, demonstrating that S6+/ΣS ratios calculated from S-XANES spectra can be considered reliable for estimating the oxygen fugacity. Our results carry important implications for the S budget of felsic magmas and dissolution mechanisms in evolved melts. While our results from all three flux densities show the presence of S4+ dissolved in relatively oxidized (ΔFMQ > +1.75) dacitic glass, even in the spectra exposed to the lowest photon densities, we are unable to rule out the possibility that the S4+ signal is the result of instantaneous X-ray irradiation induced beam damage using S-XANES alone. When our spectra are compared to S-XANES spectra from basaltic silicate glasses, important differences exist in the solubility of S2– and S6+ between dacitic silicate melts, pointing to differences in solubility mechanisms as melt composition changes. This study highlights the need for further investigation into beam damage systematics, presence of S4+, and the solubility mechanisms of different oxidation states of S as silicate melt composition changes.

Geochemistry & Geophysics↗
DOE OSTI2023

Nanosecond Repetitively Pulsed (NRP) Plasmas: Relationship Between Induced Flow and Plasma Characteristics at Atmospheric Pressure (Final Technical Report)

The local flow fields induced by plasma discharges at atmospheric pressure can play a critical role in aerodynamic flow and combustion control and have significant implications for plasma-based technologies in medicine and environmental engineering. However, the coupling between the plasma characteristics, the geometry and the induced flow field is not well understood. The primary goal of this work is to determine the relationship between the plasma characteristics and the induced flow field for nanosecond pulsed discharges at atmospheric pressure. A comprehensive experimental investigation of plasmas produced by nanosecond high-voltage pulses in a pin-to-pin electrode configuration was conducted, employing several measurement techniques including microwave and laser Rayleigh scattering, optical emission spectroscopy, and high-speed imaging. The flow field induced by the nanosecond plasma was measured and characterized using measurements of the velocity (particle image velocimetry) and density (background oriented schlieren) with unprecedented spatiotemporal resolution. The experimental measurements were complemented by development of a one-dimensional model of the plasma discharge and a high-fidelity computational fluid dynamics (CFD) simulation of the subsequent plasma-induced flow field.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
DOE OSTI2025

Characterization and Quantification of Radiation-Induced Clusters/Precipitates in RPV Steels Using STEM-EDS and Machine Learning

Over the operational lifespan of a nuclear reactor, reactor pressure vessel (RPV) steels are subjected to significant neutron irradiation, resulting in complex microstructural changes and the consequent degradation of mechanical properties. Various physically motivated correlation models have been developed to predict neutron irradiation-induced embrittlement of RPVs under different irradiation conditions. However, the efficient and accurate characterizations and quantification of radiation-induced clusters in RPVs are still challenging, which will affect the precision of the predictive models for embrittlement of RPV components. In the DOE Visiting Faculty Program (VFP) research work at Oak Ridge National Lab (ORNL), I integrate machine learning to aid Scanning Transmission Electron Microscopy – Energy Dispersive X-ray Spectroscopy (STEM-EDS) analyses, which improve the characterization and quantification of radiation-induced clusters in RPV steels, thereby enabling more accurate predictions of material behavior under irradiation. The surveillance base- and welded- RPV steels were annealed at various temperatures of 340 °C, 450 °C and 500 °C for up to 168 hours, respectively. Afterwards, I have characterized radiation-induced clusters using advanced STEM-EDS techniques and subsequently applying machine learning algorithms to analyze and refine STEM-EDS datasets, enhancing the quantification of clusters compositions and distributions. In the end, an efficient workflow for integrating STEM-EDS data analysis with machine learning to address challenges including noise reduction has been developed. The completion of this VFP work will support bridge critical gaps in the accurate quantification of radiation-induced clusters in RPV steels using STEM-EDS and support the development of more precise models for predicting RPV embrittlement in the Light Water Reactor Sustainability program supported by Department of Energy and enhancing the collaboration between ORNL and Alred University. The outcome of the VFP project will leverage a few research papers submission to peer-reviewed journals in the relevant scientific field and a few oral presentations at national and international conferences.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2023

Phenothiazines Rapidly Induce Laccase Expression and Lignin-Degrading Properties in the White-Rot Fungus Phlebia radiata

Phlebia radiata is a widespread white-rot basidiomycete fungus with significance in diverse biotechnological applications due to its ability to degrade aromatic compounds, xenobiotics, and lignin using an assortment of oxidative enzymes including laccase. In this work, a chemical screen with 480 conditions was conducted to identify chemical inducers of laccase expression in P. radiata. Among the chemicals tested, phenothiazines were observed to induce laccase activity in P. radiata, with promethazine being the strongest laccase inducer of the phenothiazine-derived compounds examined. Secretomes produced by promethazine-treated P. radiata exhibited increased laccase protein abundance, increased enzymatic activity, and an enhanced ability to degrade phenolic model lignin compounds. Transcriptomics analyses revealed that promethazine rapidly induced the expression of genes encoding lignin-degrading enzymes, including laccase and various oxidoreductases, showing that the increased laccase activity was due to increased laccase gene expression. Finally, the generality of promethazine as an inducer of laccases in fungi was demonstrated by showing that promethazine treatment also increased laccase activity in other relevant fungal species with known lignin conversion capabilities including Trametes versicolor and Pleurotus ostreatus.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Heparan sulfate promotes TRAIL-induced tumor cell apoptosis

TRAIL (TNF-related apoptosis-inducing ligand) is a potent inducer of tumor cell apoptosis through TRAIL receptors. While it has been previously pursued as a potential anti-tumor therapy, the enthusiasm subsided due to unsuccessful clinical trials and the fact that many tumors are resistant to TRAIL. In this report, we identified heparan sulfate (HS) as an important regulator of TRAIL-induced apoptosis. TRAIL binds HS with high affinity (K D = 73 nM) and HS induces TRAIL to form higher-order oligomers. The HS-binding site of TRAIL is located at the N-terminus of soluble TRAIL, which includes three basic residues. Binding to cell surface HS plays an essential role in promoting the apoptotic activity of TRAIL in both breast cancer and myeloma cells, and this promoting effect can be blocked by heparin, which is commonly administered to cancer patients. We also quantified HS content in several lines of myeloma cells and found that the cell line showing the most resistance to TRAIL has the least expression of HS, which suggests that HS expression in tumor cells could play a role in regulating sensitivity towards TRAIL. We also discovered that death receptor 5 (DR5), TRAIL, and HS can form a ternary complex and that cell surface HS plays an active role in promoting TRAIL-induced cellular internalization of DR5. Combined, our study suggests that TRAIL-HS interactions could play multiple roles in regulating the apoptotic potency of TRAIL and might be an important point of consideration when designing future TRAIL-based anti-tumor therapy.

60 APPLIED LIFE SCIENCES↗