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At least 19 records

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NASA NTRS2000

Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K(+) channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional CaR

The existence in osteoblasts of the G-protein-coupled extracellular calcium (Ca(o)(2+))-sensing receptor (CaR) that was originally cloned from parathyroid and kidney remains controversial. In our recent studies, we utilized multiple detection methods to demonstrate the expression of CaR transcripts and protein in several osteoblastic cell lines, including murine MC3T3-E1 cells. Although we and others have shown that high Ca(o)(2+) and other polycationic CaR agonists modulate the function of MC3T3-E1 cells, none of these actions has been unequivocally shown to be mediated by the CaR. Previous investigations using neurons and lens epithelial cells have shown that activation of the CaR stimulates Ca(2+)-activated K(+) channels. Because osteoblastic cells express a similar type of channel, we have examined the effects of specific "calcimimetic" CaR activators on the activity of a Ca(2+)-activated K(+) channel in MC3T3-E1 cells as a way of showing that the CaR is not only expressed in those cells but is functionally active. Patch-clamp analysis in the cell-attached mode showed that raising Ca(o)(2+) from 0.75 to 2.75 mmol/L elicited about a fourfold increase in the open state probability (P(o)) of an outward K(+) channel with a conductance of approximately 92 pS. The selective calcimimetic CaR activator, NPS R-467 (0.5 micromol/L), evoked a similar activation of the channel, while its less active stereoisomer, NPSS-467 (0.5 micromol/L), did not. Thus, the CaR is not only expressed in MC3T3-E1 cells, but is also functionally coupled to the activity of a Ca(2+)-activated K(+) channel. This receptor, therefore, could transduce local or systemic changes in Ca(o)(2+) into changes in the activity of this ion channel and related physiological processes in these and perhaps other osteoblastic cells.

NASA Discipline Musculoskeletal↗

DOE OSTI2024

Implications of stop-and-go traffic on training learning-based car-following control

Learning-based car-following control (LCC) of connected and autonomous vehicles (CAVs) is gaining significant attention with the advancement of computing power and data accessibility. While the flexibility and large model capacity of model-free architecture enable LCC to potentially outperform the model-based car-following (CF) model in improving traffic efficiency and mitigating congestion, the generalizability of LCC for traffic conditions different from the training environment/dataset is not well-understood. Herein, this study seeks to explore the impact of stop-and-go traffic in the training dataset on the generalizability of LCC. It uses the characteristics of lead vehicle trajectories to describe stop-and-go traffic, and links the theory of identifiability (i.e., obtaining a unique parameter estimation result using sensor measurements) to the generalizability of behavior cloning (BC) and policy-based deep reinforcement learning (DRL). Correspondingly, the study shows theoretically that: (i) stop-and-go traffic can enable the property of identifiability and enhance the control performance of BC-based LCC in different traffic conditions; (ii) stop-and-go traffic is not necessary for DRL-based LCC to generalize to different traffic conditions; (iii) DRL-based LCC trained with only constant-speed lead vehicle trajectories (not sufficient to ensure identifiability) can be generalized to different traffic conditions; and (iv) stop-and-go traffic increases variance in the training dataset, which improves the convergence of parameter estimation while negatively impacting the convergence of DRL to the optimal control policy. Numerical experiments validate the above findings, illustrating that BC-based LCC entails comprehensive training datasets for generalizing to different traffic conditions, while DRL-based LCC can achieve generalization with simple free-flow traffic training environments. This further suggests DRL as a more promising and cost-effective LCC approach to reduce operational costs, mitigate traffic congestion, and enhance safety and mobility, which can accelerate the deployment and acceptance of CAVs.

33 ADVANCED PROPULSION SYSTEMS↗

NASA NTRS1976

Results of baseline tests of the EVA Metro sedan, Citi-car, Jet Industries Electra-van, CDA town car, and Otis P-500 van

Five electric vehicles were tested at vehicle test tracks using the SAE. The tests provide range data at steady speeds and for several driving cycles. Most tests were conducted with lead-acid traction batteries. The Otis Van and the Copper Electric Town Car were also tested with lead-acid and nickel-zinc batteries. The tests showed a range increase of from 82 to 101 percent depending on vehicle, speed, and test cycle.

Stenger, F. J.↗

NASA NTRS2004

Advanced Infant Car Seat Would Increase Highway Safety

An advanced infant car seat has been proposed to increase highway safety by reducing the incidence of crying, fussy behavior, and other child-related distractions that divert an adult driver s attention from driving. In addition to a conventional infant car seat with safety restraints, the proposed advanced infant car seat would include a number of components and subsystems that would function together as a comprehensive infant-care system that would keep its occupant safe, comfortable, and entertained, and would enable the driver to monitor the baby without having to either stop the car or turn around to face the infant during driving. The system would include a vibrator with bulb switch to operate; the switch would double as a squeeze toy that would make its own specific sound. A music subsystem would include loudspeakers built into the seat plus digital and analog circuitry that would utilize plug-in memory modules to synthesize music or a variety of other sounds. The music subsystem would include a built-in sound generator that could synthesize white noise or a human heartbeat to calm the baby to sleep. A second bulb switch could be used to control the music subsystem and would double as a squeeze toy that would make a distinct sound. An anti-noise sound-suppression system would isolate the baby from potentially disturbing ambient external noises. This subsystem would include small microphones, placed near the baby s ears, to detect ambient noise. The outputs of the microphone would be amplified and fed to the loudspeakers at appropriate amplitude and in a phase opposite that of the detected ambient noise, such that the net ambient sound arriving at the baby s ears would be almost completely cancelled. A video-camera subsystem would enable the driver to monitor the baby visually while continuing to face forward. One or more portable miniature video cameras could be embedded in the side of the infant car seat (see figure) or in a flip-down handle. The outputs of the video cameras would be transmitted by radio or infrared to a portable, miniature receiver/video monitor unit that would be attached to the dashboard of the car. The video-camera subsystem can also be used within transmission/reception range when the seat was removed from the car. The system would include a biotelemetric and tracking subsystem, which would include a Global Positioning System receiver for measuring its location. This subsystem would transmit the location of the infant car seat (even if the seat were not in a car) along with such biometric data as the baby s heart rate, perspiration rate, urinary status, temperature, and rate of breathing. Upon detecting any anomalies in the biometric data, this subsystem would send a warning to a paging device installed in the car or carried by the driver, so that the driver could pull the car off the road to attend to the baby. A motion detector in this subsystem would send a warning if the infant car seat were to be moved or otherwise disturbed unexpectedly while the infant was seated in it: this warning function, in combination with the position- tracking function, could help in finding a baby who had been kidnapped with the seat. Removable rechargeable batteries would enable uninterrupted functioning of all parts of the system while transporting the baby to and from the car. The batteries could be recharged via the cigarette-lighter outlet in the car or by use of an external AC-powered charger.

Dabney, Richard↗

DOE OSTI2021

Disruption of adenosine 2A receptor improves the anti-tumor function of anti-mesothelin CAR T cells both in vitro and in vivo

Chimeric antigen receptor (CAR) T cells have been successfully used for the treatment of hematological malignancies including acute and chronic lymphoblastic leukemia. However, results of CAR T cell projects in solid tumors have been less impressive to date, partly because of immunosuppressive tumor microenvironment (TME). It is widely known that high adenosine production is an important factor causing tumor-induced immunosuppression in TME, and adenosine mediates the suppression of anti-tumor T cell responses via binding and signaling through adenosine 2a receptor (A2aR). Previous studies have shown that adenosine generated by cancer cells significantly inhibits T cell anti-tumor activity through binding and then activating adenosine 2A receptors (A2aRs) of T cells. Based on the previous work, in our study, we evaluated whether A2aR disruption by shRNA could enhance the anti-tumor function of anti-mesothelin (MSLN) CAR T cells both in vitro and in vivo. For this goal above, we used MSLN-positive human ovarian serous carcinoma cells (SKOV3) and human colon cancer cells (HCT116) as target cancer cells while MSLN-negative human ovarian cancer cells (ES2) as non-target cancer cells. We observed that targeting cell-intrinsic A2aR through shRNA overexpression caused significant A2aR disruption in CAR T cells and profoundly increased CAR T cell efficacy in both CAR T cell cytokine production and cytotoxicity towards MSLN-positive cancer cells in vitro. More importantly, in SKOV3 xenograft mouse models, anti-MSLN CAR-T cells significantly reduced the tumor burden compared with non-transduced T cells, and the anti-tumor activity of A2aR-disrupted anti-MSLN CAR-T cells was stronger than that of wild-type anti-MSLN CAR-T cells. Altogether, our study showed enhanced anti-tumor efficacy caused by shRNA-mediated A2aR disruption in anti-MSLN CAR T cells both in vitro and in vivo, which proved that shRNA-mediated modification of gene expression might be an excellent strategy for improving CAR T cell function in immunosuppressive tumor microenvironment (TME) and could potentially improve the outcome of treatment in clinical trials.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1996

Flying Cars

Flying cars have nearly mythical appeal to nonpilots, a group that includes almost the whole human race. The appeal resides in the perceived utility of flying cars, vehicles that offer portal-to-portal transportation, yet break the bonds of road and traffic and travel freely through the sky at the drivers will. Part of the appeal is an assumption that flying cars can be as easy to fly as to drive. Flying cars have been part of the dream of aviation since the dawn of powered flight. Glenn Curtiss built, displayed, and maybe even flew a flying car in 1917, the Curtiss Autoplane. Many roadable airplanes were built in the 1930's, like the Waterman Arrowbile and the Fulton Airphibian. Two flying cars came close to production in the early 1950's. Ted Hall built a series of flying cars culminating in the Convaircar, sponsored by Consolidated Vultee, General Motors, and Hertz. Molt Taylor built and certified his Aerocar, and Ford came close to producing them. Three Aerocars are still flyable, two in museums in Seattle and Oshkosh, and the third owned and flown by Ed Sweeny. Flying cars do have problems, which so far have prevented commercial success. An obvious problem is complexity of the vehicle, the infrastructure, or both. Another is the difficulty of matching low power for normal driving with high power in flight. An automobile uses only about 20 hp at traffic speeds, while a personal airplane needs about 160 hp at speeds typical of flight. Many automobile engines can deliver 160 hp, but not for very long. A more subtle issue involves the drag of automobiles and airplanes. A good personal airplane can fly 30 miles per gallon of fuel at 200 mph. A good sports car would need 660 hp at the same speed and would travel only 3 miles per gallon. The difference is drag area, about 4.5 sq ft for the automobile and 1.4 sq ft for the airplane. A flying car better have the drag area of the airplane, not the car!

Crow, Steven↗

NASA NTRS2017

Assessment of Satellite-Derived Surface Reflectances by NASA's CAR Airborne Radiometer over Railroad Valley, Nevada

CAR (Cloud Absorption Radiometer) is a multi-angular and multi-spectral airborne radiometer instrument, whose radiometric and geometric characteristics are well calibrated and adjusted before and after each flight campaign. CAR was built by NASA (National Aeronautics and Space Administration) in 1984. On 16 May 2008, a CAR flight campaign took place over the well-known calibration and validation site of Railroad Valley in Nevada (38.504 deg N, 115.692 deg W).The campaign coincided with the overpasses of several key EO (Earth Observation) satellites such as Landsat-7, Envisat and Terra. Thus, there are nearly simultaneous measurements from these satellites and the CAR airborne sensor over the same calibration site. The CAR spectral bands are close to those of most EO satellites. CAR has the ability to cover the whole range of azimuth view angles and a variety of zenith angles depending on altitude and, as a consequence, the biases seen between satellite and CAR measurements due to both unmatched spectral bands and unmatched angles can be significantly reduced. A comparison is presented here between CARs land surface reflectance (BRF or Bidirectional Reflectance Factor) with those derived from Terra/MODIS (MOD09 and MAIAC), Terra/MISR, Envisat/MERIS and Landsat-7. In this study, we utilized CAR data from low altitude flights (approx. 180 m above the surface) in order to minimize the effects of the atmosphere on these measurements and then obtain a valuable ground-truth data set of surface reflectance. Furthermore, this study shows that differences between measurements caused by surface heterogeneity can be tolerated, thanks to the high homogeneity of the study site on the one hand, and on the other hand, to the spatial sampling and the large number of CAR samples. These results demonstrate that satellite BRF measurements over this site are in good agreement with CAR with variable biases across different spectral bands. This is most likely due to residual aerosol effects in the EO derived reflectances.

calibration↗

DOE OSTI2022

How do perceptions of safety and car ownership importance affect autonomous vehicle adoption?

In this study, we explicitly modeled how individuals' perceptions of automated vehicle (AV) safety and the importance they place on car ownership affect mode choices involving conventional and automated vehicles in the context of privately owned cars and ridehailing services. We adopted psychometric questions to capture these two latent variables and designed a stated preference survey based on the participants' actual travel patterns. Then, we quantified the impact of these latent variables on mode choices using an integrated choice and latent variable (ICLV) model. We found that both latent variables have a statistically significant effect on mode choices. The results show that car ownership importance has the most potent effect on privately owned cars (conventional car and self-driving car), followed by driverless ridehailing and conventional ridehailing. We also found that changes in safety perception are equivalent to sizable changes in price. In addition, we further investigated the impact of improvements in safety perception through four scenarios. The scenario testing results show that as the distribution of perceived safety is compressed toward positive safety perception, the market share of AVs spikes and dominates regular cars. Our results demonstrate that based on our respondents' current understanding of AVs, even if AV prices were comparable to regular cars, we cannot expect widespread use of AVs. However, improvements in AVs' safety and, consequently, consumer safety perception can considerably expand AVs' market share, and may offset the high cost of using the technology.

33 ADVANCED PROPULSION SYSTEMS↗

DOE OSTI2022

Gas detection sensitivity of hybrid fs/ps and fs/ns CARS

Coherent anti-Stokes Raman scattering (CARS) is commonly used for thermometry and concentration measurement of major species. The quadratic scaling of CARS signal with number density has limited the use of CARS for detection of minor species, where more sensitive approaches may be more attractive. However, significant advancements in ultrafast CARS approaches have been made over the past two decades, including the development of hybrid CARS demonstrated to yield greatly increased excitation efficiencies. Yet, detailed detection limits of hybrid CARS have not been well established. In this Letter, detection limits for N 2 , H 2 , CO, and C 2 H 4 by point-wise hybrid femtosecond (fs)/picosecond (ps) CARS are determined to be of the order of 10 15 molecules/cm 3 . Here, the possible benefit of fs/nanosecond (ns) hybrid CARS is also discussed.

74 ATOMIC AND MOLECULAR PHYSICS↗

NASA NTRS2001

The New Cloud Absorption Radiometer (CAR) Software: One Model for NASA Remote Sensing Virtual Instruments

The Cloud Absorption Radiometer (CAR) instrument has been the most frequently used airborne instrument built in-house at NASA Goddard Space Flight Center, having flown scientific research missions on-board various aircraft to many locations in the United States, Azores, Brazil, and Kuwait since 1983. The CAR instrument is capable of measuring scattered light by clouds in fourteen spectral bands in UV, visible and near-infrared region. This document describes the control, data acquisition, display, and file storage software for the new version of CAR. This software completely replaces the prior CAR Data System and Control Panel with a compact and robust virtual instrument computer interface. Additionally, the instrument is now usable for the first time for taking data in an off-aircraft mode. The new instrument is controlled via a LabVIEW v5. 1.1-developed software interface that utilizes, (1) serial port writes to write commands to the controller module of the instrument, and (2) serial port reads to acquire data from the controller module of the instrument. Step-by-step operational procedures are provided in this document. A suite of other software programs has been developed to complement the actual CAR virtual instrument. These programs include: (1) a simulator mode that allows pretesting of new features that might be added in the future, as well as demonstrations to CAR customers, and development at times when the instrument/hardware is off-location, and (2) a post-experiment data viewer that can be used to view all segments of individual data cycles and to locate positions where 'start' and stop' byte sequences were incorrectly formulated by the instrument controller. The CAR software described here is expected to be the basis for CAR operation for many missions and many years to come.

Roth, Don J.↗

NASA NTRS2001

Development and Validation of the Controller Acceptance Rating Scale (CARS): Results of Empirical Research

The measurement of operational acceptability is important for the development, implementation, and evolution of air traffic management decision support tools. The Controller Acceptance Rating Scale was developed at NASA Ames Research Center for the development and evaluation of the Passive Final Approach Spacing Tool. CARS was modeled after a well-known pilot evaluation rating instrument, the Cooper-Harper Scale, and has since been used in the evaluation of the User Request Evaluation Tool, developed by MITRE's Center for Advanced Aviation System Development. In this paper, we provide a discussion of the development of CARS and an analysis of the empirical data collected with CARS to examine construct validity. Results of intraclass correlations indicated statistically significant reliability for the CARS. From the subjective workload data that were collected in conjunction with the CARS, it appears that the expected set of workload attributes was correlated with the CARS. As expected, the analysis also showed that CARS was a sensitive indicator of the impact of decision support tools on controller operations. Suggestions for future CARS development and its improvement are also provided.

Lee, Katharine K.↗

NASA NTRS2008

Eta Car: The Good, the Bad and the Ugly of Nebular and Stellar Confusion

Observations in the far-UV provide a unique opportunity to investigate the very massive star Eta Car and its hot binary companion, Eta Car B. Eta Car was observed with FUSE over a large portion of the 5.54 year spectroscopic period before and after the 2003.5 minimum. The observed spectrum is defined by strong stellar wind signatures, primarily from Eta Car A, complicated by the strong absorptions of the ejecta surrounding Eta Car plus interstellar absorption. The Homunculus and Little Homunculus are massive bipolar ejecta historically associable with LBV outbursts in the 1840s and the 1890s and are linked to absorptions at -513 and -146 km/s, respectively. The FUSE spectra are confused by the extended nebulosity and thermal drifting of the FUSE co-pointed instruments. Interpretation is further complicated by two B-stars sufficiently close to h Car to be included most of the time in the large FUSE aperture. Followup observations partially succeeded in obtaining spectra of at least one of these B-stars through the smaller apertures, allowing potential separation of the B-star contributions and h Car. A complete analysis of all available spectra is currently underway. Our ultimate goals are to directly detect the hot secondary star if possible with FUSE and to identify the absorption contributions to the overall spectrum especially of the stellar members and the massive ejecta.

Gull, T.R.↗

NASA NTRS2010

Advancements in Dual-Pump Broadband CARS for Supersonic Combustion Measurements

Space- and time-resolved measurements of temperature and species mole fractions of nitrogen, oxygen, and hydrogen were obtained with a dual-pump coherent anti-Stokes Raman spectroscopy (CARS) system in hydrogen-fueled supersonic combustion free jet flows. These measurements were taken to provide time-resolved fluid properties of turbulent supersonic combustion for use in the creation and verification of computational fluid dynamic (CFD) models. CFD models of turbulent supersonic combustion flow currently facilitate the design of air-breathing supersonic combustion ramjet (scramjet) engines. Measurements were made in supersonic axi-symmetric free jets of two scales. First, the measurement system was tested in a laboratory environment using a laboratory-scale burner (approx.10 mm at nozzle exit). The flow structures of the laboratory-burner were too small to be resolved with the CARS measurements volume, but the composition and temperature of the jet allowed the performance of the system to be evaluated. Subsequently, the system was tested in a burner that was approximately 6 times larger, whose length scales are better resolved by the CARS measurement volume. During both these measurements, weaknesses of the CARS system, such as sensitivity to vibrations and beam steering and inability to measure temperature or species concentrations in hydrogen fuel injection regions were indentified. Solutions were then implemented in improved CARS systems. One of these improved systems is a dual-pump broadband CARS technique called, Width Increased Dual-pump Enhanced CARS (WIDECARS). The two lowest rotational energy levels of hydrogen detectable by WIDECARS are H2 S(3) and H2 S(4). The detection of these lines gives the system the capability to measure temperature and species concentrations in regions of the flow containing pure hydrogen fuel at room temperature. WIDECARS is also designed for measurements of all the major species (except water) in supersonic combustion flows fueled with hydrogen and hydrogen/ethylene mixtures (N2, O2, H2, C2H4, CO, and CO2). This instrument can characterize supersonic combustion fueled with surrogate fuel mixtures of hydrogen and ethylene. This information can lead to a better understanding of the chemistry and performance of supersonic combustion fueled with cracked jet propulsion (JP)-type fuel.

Tedder, Sarah Augusta Umberger↗

DOE OSTI2023

How Time Inefficient and Uncertain are Paratransit Trips Compared to Car Trips

The Americans with Disabilities Act (ADA) stipulates that paratransit mobility be comparable to public transit. However, with just under 5% of the population relying on public transportation, transit is not a representative benchmark. To highlight this inequality, we compare trip times by paratransit to counterfactual car-based travel. Using 2.5 years of demand data from the Denver Regional Transportation District's Access-a-Ride service, we compare paratransit trip times to counterfactual car-based trips for the same origin-destination pairs, controlling for various trip characteristics. Compared to car travel, the findings indicate high variability and uncertainty associated with paratransit trip times. For the same origin-destination pairs, the mean paratransit trip time is almost twice that of the mean car travel time, with a standard deviation for paratransit trip time fourfold that of the standard deviation for car trip time. For perspective, traveling an average of 10 mi during the 7-8 a.m. morning peak can take about 16 min by car with almost no variability, while that same trip can take an average of 25 min by paratransit, with 5% of trips being outside the 95% confidence interval and thus unpredictable. Paratransit trip time inefficiency tends to be particularly worse for females; older adults; those making trips between 9 and 11 a.m.; cash-paying customers; those making shorter trips; and those traveling during inclement weather, including cold temperatures. These findings suggest a need to re-assess using public transit as a benchmark for paratransit supply as regulated by the ADA.

accessible transportation and mobility↗

NASA NTRS1971

Dynamic responses of railroad car models to vertical and lateral rail inputs

Simplified dynamic models were applied in a study of vibration in a high-speed railroad car. The mathematical models used were a four-degree-of-freedom model for vertical responses to vertical rail inputs and a ten-degree-of-freedom model for lateral response to lateral or rolling (cross-level) inputs from the rails. Elastic properties of the passenger car body were represented by bending and torsion of a uniform beam. Rail-to-car (truck) suspensions were modeled as spring-mass-dashpot oscillators. Lateral spring nonlinearities approximating certain complicated truck mechanisms were introduced. The models were excited by displacement and, in some cases, velocity inputs from the rails by both deterministic (including sinusoidal) and random input functions. Results were obtained both in the frequency and time domains. Solutions in the time domain for the lateral model were obtained for a wide variety of transient and random inputs generated on-line by an analog computer. Variations in one of the damping properties of the lateral car suspension gave large fluctuations in response over a range of car speeds for a given input. This damping coefficient was significant in reducing lateral car responses that were higher for nonlinear springs for three different inputs.

Sewall, J. L.↗

NASA NTRS2008

Fuel Savings and Aerodynamic Drag Reduction from Rail Car Covers

The potential for energy savings by reducing the aerodynamic drag of rail cars is significant. A previous study of aerodynamic drag of coal cars suggests that a 25% reduction in drag of empty cars would correspond to a 5% fuel savings for a round trip [1]. Rail statistics for the United States [2] report that approximately 5.7 billion liters of diesel fuel were consumed for coal transportation in 2002, so a 5% fuel savings would total 284 million liters. This corresponds to 2% of Class I railroad fuel consumption nationwide. As part of a DOE-sponsored study, the aerodynamic drag of scale rail cars was measured in a wind tunnel. The goal of the study was to measure the drag reduction of various rail-car cover designs. The cover designs tested yielded an average drag reduction of 43% relative to empty cars corresponding to an estimated round-trip fuel savings of 9%.

Storms, Bruce↗

DOE OSTI2021

Activation of the CaR-CSE/H2S pathway confers cardioprotection against ischemia-reperfusion injury

Ischemia-reperfusion (I/R) injury is a multifactorial process triggered when an organ is subjected to transiently reduced blood supply. The result is a cascade of pathological complications and organ damage due to the production of reactive oxygen species following reperfusion. The present study aims to evaluate the role of activated calcium-sensing receptor (CaR)-cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway in I/R injury. Firstly, an I/R rat model with CSE knockout was constructed. Transthoracic echocardiography, TTC and HE staining were performed to determine the cardiac function of rats following I/R Injury, followed by TUNEL staining observation on apoptosis. Besides, with the attempt to better elucidate how CaR-CSE/H2S affects I/R, in-vitro culture of human coronary artery endothelial cells (HCAECs) was conducted with gadolinium chloride (GdCl3, a CaR agonist), H{sub 2}O{sub 2}, siRNA against CSE (siCSE), or W7 (a CaM inhibitor). The interaction between CSE and CaM was subsequently detected. Plasma oxidative stress indexes, H2S and CSE, and apoptosis-related proteins were all analyzed following cell apoptosis. We found that H2S elevation led to the improvement whereas CSE knockdown decreased cardiac function in rats with I/R injury. Moreover, oxidative stress injury in I/R rats with CSE knockout was aggravated, while the increased expression of H2S and CSE in the aortic tissues resulted in alleviated the oxidative stress injury. Moreover, increased H2S and CSE levels were found to inhibit cell apoptotic ability in the aortic tissues after I/R injury, thus attenuating oxidative stress injury, accompanied by inhibited expression of apoptosis-related proteins. In HCAECs following oxidative stress treatment, siCSE and CaM inhibitor were observed to reverse the protection of CaR agonist. Coimmunoprecipitation assay revealed the interaction between CSE and CaM. Taken together, all above-mentioned data provides evidence that activation of the CaR-CSE/H2S pathway may confer a potent protective effect in cardiac I/R injury.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Molecular basis of crosstalk in nuclear receptors: heterodimerization between PXR and CAR and the implication in gene regulation

The 48 human nuclear receptors (NRs) form a superfamily of transcription factors that regulate major physiological and pathological processes. Emerging evidence suggests that NR crosstalk can fundamentally change our understanding of NR biology, but detailed molecular mechanisms of crosstalk are lacking. Here, we report the molecular basis of crosstalk between the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), where they form a novel heterodimer, resulting in their mutual inhibition. PXR and CAR regulate drug metabolism and energy metabolism. Although they have been broadly perceived as functionally redundant, a growing number of reports suggests a mutual inhibitory relation, but their precise mode of coordinated action remains unknown. Using methods including RNA sequencing, small-angle X-ray scattering and crosslinking mass spectrometry we demonstrate that the mutual inhibition altered gene expression globally and is attributed to the novel PXR–CAR heterodimerization via the same interface used by each receptor to heterodimerize with its functional partner, retinoid X receptor (RXR). These findings establish an unexpected functional relation between PXR, CAR and RXR, change the perceived functional relation between PXR and CAR, open new perspectives on elucidating their role and designing approaches to regulate them, and highlight the importance to comprehensively investigate nuclear receptor crosstalk.

59 BASIC BIOLOGICAL SCIENCES↗