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At least 289 records · Page 16
All sourcesNASA NTRSDOE OSTI
NASA NTRS1990

Postlanding optimum designs for the assured crew return vehicle

The optimized preliminary engineering design concepts for postlanding operations of a water-landing Assured Crew Return Vehicle (ACRV) during a medical rescue mission are presented. Two ACRVs will be permanently docked to Space Station Freedom, fulfilling NASA's commitment to Assured Crew Return Capability in the event of an accident or illness. The optimized configuration of the ACRV is based on an Apollo command module (ACM) derivative. The scenario assumes landing a sick or injured crewmember on water with the possibility of a delayed rescue. Design emphasis is placed on four major areas. First is the design of a mechanism that provides a safe and time-critical means of removing the sick or injured crewmember from the ACRV. Support to the assisting rescue personnel is also provided. Second is the design of a system that orients and stabilizes the craft after landing so as to cause no further injury or discomfort to the already ill or injured crewmember. Third is the design of a system that provides full medical support to a sick or injured crewmember aboard the ACRV from the time of separation from the space station to rescue by recovery forces. Last is the design of a system that provides for the comfort and safety of the entire crew after splashdown up to the point of rescue. The four systems are conceptually integrated into the ACRV.

Hosterman, Kenneth C.↗
NASA NTRS1994

Attitude stability of a spinning spacecraft during appendage deployment/retraction

The work presented is motivated by the need for a national satellite rescue policy, not the ad hoc policy now in place. In studying different approaches for a national policy, the issue of capture and stabilization of a tumbling spacecraft must be addressed. For a rescue mission involving a tumbling spacecraft, it may be advantageous to have a rescue vehicle which is compact and 'rigid' during the rendezvous/capture phase. After capture, passive stabilization techniques could be utilized as an efficient means of detumbling the resulting system (i.e., both the rescue vehicle and captures spacecraft). Since the rescue vehicle is initially compact and 'rigid,' significant passive stabilization through energy dissipation can only be achieved through the deployment of flexible appendages. Once stabilization is accomplished, retraction of the appendages before maneuvering the system to its final destination may also prove advantageous. It is therefore of paramount interest that we study the effect of appendage deployment/retraction on the attitude stability of a spacecraft. Particular interest should be paid to appendage retraction, since if this process is destabilizing, passive stabilization as proposed may not be useful. Over the past three decades, it has been an 'on-again-off-again affair' with the problem of spacecraft appendage deployment. In most instances, these studies have been numerical simulations of specific spacecraft configurations for which there were specific concerns. The primary focus of these studies was the behavior of the appendage during deployment; the effects of appendage retraction was considered only in one of these studies. What is missing in the literature is a thorough study of the effects of appendage deployment/retraction on the attitude stability of a spacecraft. This paper presents a rigorous analysis of the stability of a spinning spacecraft during the deployment or the retraction of an appendage. The analysis is simplified such that meaningful insights into the problem can be inferred; it is not overly simplified such that critical dynamical behavior is neglected. The system is analyzed assuming that the spacecraft hub is rigid. The appendage deployment mechanism is modeled as a point mass on a massless rod whose length undergoes prescribed changes. Simplified flexibility effects of the appendage are included. The system is examined for stability by linearizing the equations in terms of small deviations from steady, noninterfering coning motion. Routh's procedure for analyzing small deviations from steady motion in dynamical systems is utilized in the analysis. The system of equations are nondimensionalized to facilitate parametric studies. The results are presented in terms of a reduced number of nondimensional parameters so that some general conclusions may be drawn. Verification of the linear analysis is presented through numerical simulations of the complete nonlinear, nonautonomous, coupled equations.

Fitz-Coy, Norman↗
NASA NTRS1992

Heat stress and a countermeasure in the Shuttle rescueman's suit

Rescue of the astronaut flight crew from a contingency landing may risk exposure of the rescue crew to toxic propellants spilling from potentially ruptured tanks in the crew module area. An Aquala dry diver's suit has been in service by the rescue team to preclude exposure, especially in the water rescue scenario. Heat stress has become a factor of concern in recent years when older and less physically-fit team members work in this suit. Methods: Field testing was initiated using fully instrumented rescue men in a simulated scenario to determine the extent of heat stress. Two tests were accomplished, one in the normal (N) configuration and one with a proposed cooling countermeasure, the Steele vest (S). Results: Heat stress was high as indicated by average rectal temperatures (Tre) of 38.28 degrees C(100.9 degrees F) after the 45 minute protocol. Slopes of the regression equations describing the increase in Tre with time were greater (P less than 0.05) with N (0.073 plus or minus .008) compared to S (0.060 plus or minus .007). Projection of time to the 38.89 degree C (102 degree F) limit was increased by 15.3 percent with the vest. Mean skin temperature (Tsk) was higher (P less than 0.05) in N (38.33 plus or minus .11 degrees C) compared to S (34.33 plus or minus .39 degrees C). Average heart rate was higher (P less than 0.05 in N than S. Sweat loss, as measured by weight loss, was more (P less than 0.05) for N (1.09 plus or minus .09 kg versus 0.77 plus or minus .06 kg). Air usage, while slightly less for S, was not statistically different. Conclusion: The use of the cool vest provided significant relief from thermal stress in spite of the addition of 3.4 kg (7.5 pounds) weight and some loss in mobility.

Doerr, D. F.↗
DOE OSTI2022

Spectroscopic characterization of Mn 2+ and Cd 2+ coordination to phosphorothioates in the conserved A9 metal site of the hammerhead ribozyme

Phosphorothioate modifications have widespread use in the field of nucleic acids. As substitution of sulfur for oxygen can alter metal coordination preferences, the phosphorothioate metal-rescue experiment is a powerful method for identifying metal coordination sites that influence specific properties in a large RNAs. The A9/G10.1 metal binding site of the hammerhead ribozyme (HHRz) has previously been shown to be functionally important through phosphorothioate rescue experiments. While an A9-S Rp substitution is inhibitory in Mg 2+ , thiophilic Cd 2+ rescues HHRz activity. Mn 2+ is also often used in phosphorothioate metal-rescue studies but does not support activity for the A9-S Rp HHRz. Here, we use EPR, electron spin-echo envelope modulation (ESEEM), and X-ray absorption spectroscopic methods to directly probe the structural consequences of Mn 2+ and Cd 2+ coordination to R p and S p phosphorothioate modifications at the A9/G10.1 site in the truncated hammerhead ribozyme (tHHRz). The results demonstrate that while Cd 2+ does indeed bind to S in the thio-substituted ligand, Mn 2+ coordinates to the non–sulfur oxo group of this phosphorothioate, regardless of isomer. Computational models demonstrate the energetic preference of Mn—O over Mn—S coordination in metal-dimethylthiophosphate models. In the case of the tHHRz, the resulting Mn 2+ coordination preference of oxygen in either R p or S p A9 phosphorothioates differentially tunes catalytic activity, with Mn—O coordination in the A9-S Rp phosphorothioate enzyme being inhibitory.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

Beneficial effects of vitamin C treatment on pregnant rats exposed to formaldehyde: Reversal of immunosuppression in the offspring

Inhalation of formaldehyde (FA) during the pregnancy induces oxidative stress in the uterus, and here we hypothesized that this mechanism may be responsible for the impaired immune response detected in the offspring. In order to investigate the protective effects of Vitamin C on the oxidative stress induced by FA in the uterine microenvironment, pregnant Wistar rats were treated with vitamin C (150 mg/kg, gavage) or vehicle (distilled water, gavage) 1 h before FA exposure (0.92 mg/m{sup 3}, 1 h/day, 5 days/week), for 21 days, and the 30 days old offspring were submitted to LPS injection (Salmonella abortus equi, 5 mg/kg, i.p.). The enhanced gene expression of iNOS, COX-1 and COX-2 and decreased gene expression of SOD-2 in the uterus of FA exposed mothers was rescued by Vit C treatment. Moreover, vitamin C rescued the impaired immune response elicited by LPS in the offspring from FA exposed mothers, by increasing the number of blood and bone marrow leukocytes, and augmenting gene expression of IL-6 and reducing mRNA levels of IL-10 and IFN in the lungs. Vitamin C treatment did not rescue the impaired TLR4-NF-kB pathway in the lung of the offspring, suggesting that FA-induced uterine oxidative stress affects other inflammatory pathways activated by LPS in the offspring. Together, data obtained here confirm our hypothesis that FA-induced oxidative stress in the uterine microenvironment modifies the programming mechanisms of the immune defenses of offspring, leading to an impaired host defense. - Highlights: • FA exposure during pregnancy induces oxidative stress in the uterus. • Vitamin C treatment blunted the oxidative stress in uterus induced by FA exposure. • Oxidative stress in uterus after FA exposure impairs the immune response of offspring. • Vitamin C in pregnant rats rescued the impaired immune response in the offspring.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

A Moist Physics Parameterization Based on Deep Learning

Abstract Current moist physics parameterization schemes in general circulation models (GCMs) are the main source of biases in simulated precipitation and atmospheric circulation. Recent advances in machine learning make it possible to explore data‐driven approaches to developing parameterization for moist physics processes such as convection and clouds. This study aims to develop a new moist physics parameterization scheme based on deep learning. We use a residual convolutional neural network (ResNet) for this purpose. It is trained with 1‐year simulation from a superparameterized GCM, SPCAM. An independent year of SPCAM simulation is used for evaluation. In the design of the neural network, referred to as ResCu, the moist static energy conservation during moist processes is considered. In addition, the past history of the atmospheric states, convection, and clouds is also considered. The predicted variables from the neural network are GCM grid‐scale heating and drying rates by convection and clouds, and cloud liquid and ice water contents. Precipitation is derived from predicted moisture tendency. In the independent data test, ResCu can accurately reproduce the SPCAM simulation in both time mean and temporal variance. Comparison with other neural networks demonstrates the superior performance of ResNet architecture. ResCu is further tested in a single‐column model for both continental midlatitude warm season convection and tropical monsoonal convection. In both cases, it simulates the timing and intensity of convective events well. In the prognostic test of tropical convection case, the simulated temperature and moisture biases with ResCu are smaller than those using conventional convection and cloud parameterizations.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2013

Signaling Specificity Provided by the Arabidopsis thaliana Heterotrimeric G-Protein γ Subunits AGG1 and AGG2 Is Partially but Not Exclusively Provided through Transcriptional Regulation

The heterotrimeric G-protein complex in Arabidopsis thaliana consists of one α, one ß and three γ subunits. While two of the γ subunits, AGG1 and AGG2 have been shown to provide functional selectivity to the Gßγ dimer in Arabidopsis, it is unclear if such selectivity is embedded in their molecular structures or conferred by the different expression patterns observed in both subunits. In order to study the molecular basis for such selectivity we tested genetic complementation of AGG1- and AGG2 driven by the respectively swapped gene promoters. When expressed in the same tissues as AGG1, AGG2 rescues some agg1 mutant phenotypes such as the hypersensitivity to Fusarium oxysporum and D-mannitol as well as the altered levels of lateral roots, but does not rescue the early flowering phenotype. Similarly, AGG1 when expressed in the same tissues as AGG2 rescues the osmotic stress and lateral-root phenotypes observed in agg2 mutants but failed to rescue the heat-stress induction of flowering. The fact that AGG1 and AGG2 are functionally interchangeable in some pathways implies that, at least for those pathways, signaling specificity resides in the distinctive spatiotemporal expression patterns exhibited by each γ subunit. On the other hand, the lack of complementation for some phenotypes indicates that there are pathways in which signaling specificity is provided by differences in the primary AGG1 and AGG2 amino acid sequences.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1989

Assured Crew Return Capability Architecture

The fundamental elements of the spacecraft Assured Crew Return Capability (ACRC) are discussed. These elements are access, response time, crew transfer, and the availability of landing sites. The use of an embedded operations concept identified as an essential element of the ACRC architecture. Several rescue assets are identified and evaluated as primary elements of an overall ACRC architecture. The investigation results lead to the following conclusions: optimum on-orbit rescue capability is provided by a rescue system integral to the operational vehicle; ground based rescue provides the most practical coverage for stranded transportation vehicles; and due to infrequent and unexpected use of ACRC, crew operations must be kept simple.

J W Craig↗
NASA NTRS1991

KSC off-runway contingency operation - Mode 7

The possibility of a mishap during a space shuttle landing at Kennedy Space Center (KSC) dictates the need for plans to rescue astronauts from areas other than the Shuttle Landing Facility (SLF). All shuttle landings are unpowered, gliding flight maneuvers, and a deviation from the planned flight profile could result in a shuttle landing or crashing somewhere other than the SLF runway. The geography of the Kennedy Space Center makes helicopter airlifting the only universal means of transportation for the rescue crew. This rescue crew is composed of KSC contractor fire-rescuemen who would ride to the crash scene on USAF HH-3 helicopters. These crews are provided with personal protective suits and training in shallow water, swamp, and dry land rescues. They aid the egress of the crew to a safe area for helicopter pickup and subsequent triage and medevac.

Maples, Arthur↗
NASA NTRS2007

Haughton-Mars Project/NASA 2006 Lunar Medical Contingency Simulation: Equipment and Methods for Medical Evacuation of an Injured Crewmember

Introduction: Achieving NASA's Space Exploration Vision scientific objectives will require human access into cratered and uneven terrain for the purpose of sample acquisition to assess geological, and perhaps even biological features and experiments. Operational risk management is critical to safely conduct the anticipated tasks. This strategy, along with associated contingency plans, will be a driver of EVA system requirements. Therefore, a medical contingency EVA scenario was performed with the Haughton-Mars Project/NASA to develop belay and medical evacuation techniques for exploration and rescue respectively. Methods: A rescue system to allow two rescuer astronauts to evacuate one in incapacitated astronaut was evaluated. The systems main components were a hard-bottomed rescue litter, hand-operated winch, rope, ground picket anchors, and a rover-winch attachment adapter. Evaluation was performed on 15-25deg slopes of dirt with embedded rock. The winch was anchored either by adapter to the rover or by pickets hammered into the ground. The litter was pulled over the surface by rope attached to the winch. Results: The rescue system was utilized effectively to extract the injured astronaut up a slope and to a waiting rover for transport to a simulated habitat for advanced medical care, although several challenges to implementation were identified and overcome. Rotational stabilization of the winch was found to be important to get maximize mechanical advantage from the extraction system. Discussion: Further research and testing needs to be performed to be able to fully consider synergies with the other Exploration surface systems, in conducting contingency operations. Structural attachment points on the surface EVA suits may be critical to assist in incapacitated evacuation. Such attach points could be helpful in microgravity incapacitated crewmember transport as well. Wheeled utility carts or wheels that may be attachable to a litter may also aid in extraction and transport. Utilizing parts of the rover (e.g. seats) to deploy as a litter may be considered. Testing in simulated 1/6-g to determine feasibility of winch operation and anchor establishment will further reduce implementation uncertainties.

Chappell, S. P.↗
NASA NTRS2010

NASA Contingency Shuttle Crew Support (CSCS) Medical Operations

The genesis of the space shuttle began in the 1930's when Eugene Sanger came up with the idea of a recyclable rocket plane that could carry a crew of people. The very first Shuttle to enter space was the Shuttle "Columbia" which launched on April 12 of 1981. Not only was "Columbia" the first Shuttle to be launched, but was also the first to utilize solid fuel rockets for U.S. manned flight. The primary objectives given to "Columbia" were to check out the overall Shuttle system, accomplish a safe ascent into orbit, and to return back to earth for a safe landing. Subsequent to its first flight Columbia flew 27 more missions but on February 1st, 2003 after a highly successful 16 day mission, the Columbia, STS-107 mission, ended in tragedy. With all Shuttle flight successes come failures such as the fatal in-flight accident of STS 107. As a result of the STS 107 accident, and other close-calls, the NASA Space Shuttle Program developed contingency procedures for a rescue mission by another Shuttle if an on-orbit repair was not possible. A rescue mission would be considered for a situation where a Shuttle and the crew were not in immediate danger, but, was unable to return to Earth or land safely. For Shuttle missions to the International Space Station (ISS), plans were developed so the Shuttle crew would remain on board ISS for an extended period of time until rescued by a "rescue" Shuttle. The damaged Shuttle would subsequently be de-orbited unmanned. During the period when the ISS Crew and Shuttle crew are on board simultaneously multiple issues would need to be worked including, but not limited to: crew diet, exercise, psychological support, workload, and ground contingency support

Adams, Adrien↗
DOE OSTI2021

Phenotypic effects of changes in the FTVTxK region of an Arabidopsis secondary wall cellulose synthase compared with results from analogous mutations in other isoforms

Abstract Understanding protein structure and function relationships in cellulose synthase (CesA), including divergent isomers, is an important goal. Here, we report results from mutant complementation assays that tested the ability of sequence variants of AtCesA7, a secondary wall CesA of Arabidopsis thaliana , to rescue the collapsed vessels, short stems, and low cellulose content of the irx3‐1 AtCesA7 null mutant. We tested a catalytic null mutation and seven missense or small domain changes in and near the AtCesA7 FTVTSK motif, which lies near the catalytic domain and may, analogously to bacterial CesA, exist within a substrate “gating loop.” A low‐to‐high gradient of rescue occurred, and even inactive AtCesA7 had a small positive effect on stem cellulose content but not stem elongation. Overall, secondary wall cellulose content and stem length were moderately correlated, but the results were consistent with threshold amounts of cellulose supporting particular developmental processes. Vibrational sum frequency generation microscopy allowed tissue‐specific analysis of cellulose content in stem xylem and interfascicular fibers, revealing subtle differences between selected genotypes that correlated with the extent of rescue of the collapsing xylem phenotype. Similar tests on PpCesA5 from the moss Physcomitrium (formerly Physcomitrella ) patens helped us to synergize the AtCesA7 results with prior results on AtCesA1 and PpCesA5. The cumulative results show that the FTVTxK region is important for the function of an angiosperm secondary wall CesA as well as widely divergent primary wall CesAs, while differences in complementation results between isomers may reflect functional differences that can be explored in further work.

Burris, Jason N.↗
DOE OSTI2024

Five amino acid mismatches in the zinc-finger domains of Cellulose Synthase 5 and Cellulose Synthase 6 cooperatively modulate their functional properties by controlling homodimerization in Arabidopsis

Cellulose synthase 5 (CESA5) and CESA6 are known to share substantial functional overlap. In the zinc-finger domain (ZN) of CESA5, there are five amino acid (AA) mismatches when compared to CESA6. These mismatches in CESA5 were replaced with their CESA6 counterparts one by one until all were replaced, generating nine engineered CESA5s. Each N-terminal enhanced yellow fluorescent protein-tagged engineered CESA5 was introduced to prc1-1, a cesa6 null mutant, and resulting mutants were subjected to phenotypic analyses. For this work, we found that five single AA-replaced CESA5 proteins partially rescue the prc1-1 mutant phenotypes to different extents. Multi-AA replaced CESA5s further rescued the mutant phenotypes in an additive manner, culminating in full recovery by CESA5 G43R + S49T+S54P+S80A+Y88F . Investigations in cellulose content, cellulose synthase complex (CSC) motility, and cellulose microfibril organization in the same mutants support the results of the phenotypic analyses. Bimolecular fluorescence complementation assays demonstrated that the level of homodimerization in every engineered CESA5 is substantially higher than CESA5. The mean fluorescence intensity of CSCs carrying each engineered CESA5 fluctuates with the degree to which the prc1-1 mutant phenotypes are rescued by introducing a corresponding engineered CESA5. Taken together, these five AA mismatches in the ZNs of CESA5 and CESA6 cooperatively modulate the functional properties of these CESAs by controlling their homodimerization capacity, which in turn imposes proportional changes on the incorporation of these CESAs into CSCs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Bcl6 promotes osteoblastogenesis through Stat1 inhibition

Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in significant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-deficient mice in vivo. Altered osteoblastogenesis in Bcl6-deficient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition. - Highlights: • Bcl6 is required for osteoblast differentiation. • Bcl6{sup −/−} mice exhibited altered osteoblastogenesis and reduced bone mass in vivo and in vitro. • We identified Stat1 as a direct target of Bcl6 in osteoblasts. • Bcl6 and Stat1 doubly deficient mice exhibited rescued bone phenotypes compared with Bcl6{sup −/−} mice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12

Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effects of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors. - Highlights: • Carnitine protects from glucose-induced reduction of stress-resistance. • Carnitine acts via the PPAR homolog DAF-12 on glucose toxicity. • Carnitine protects from glucose toxicity independent of protein degradation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Deltamethrin induced RIPK3-mediated caspase-independent non-apoptotic cell death in rat primary hepatocytes

Deltamethrin (DLM), a synthetic pyrethroid insecticide, is used all over the world for indoor and field pest management. In the present study, we investigated the elicited pathogenesis of DLM-induced hepatotoxicity in rat primary hepatocytes. DLM-induced cell death was accompanied with increased ROS generation, decreased mitochondrial membrane potential and G2/M arrest. Pre-treatment with N-acetyl cysteine/butylated hydroxyanisole/IM54 could partly rescue hepatocytes suggesting that ROS might play a role in DLM-induced toxicity. Interestingly, DLM treatment resulted in a caspase-independent but non-apoptotic cell death. Pre-treatment with pan-caspase inhibitor (ZVAD-FMK) could not rescue hepatocytes. Unaltered caspase-3 activity and absence of cleaved caspase-3 also corroborated our findings. Further, LDH release and Transmission electron microscopy (TEM) analysis demonstrated that DLM incites membrane disintegrity and necrotic damage. Immunochemical staining revealed an increased expression of inflammatory markers (TNFα, NFκB, iNOS, COX-2) following DLM treatment. Moreover, the enhanced RIPK3 expression in DLM treated groups and prominent rescue from cell death by GSK-872 indicated that DLM exposure could induce programmed necrosis in hepatocytes. The present study demonstrates that DLM could induce hepatotoxicity via non-apoptotic mode of cell death. - Highlights: • Deltamethrin (DLM) induces caspase-independent death in rat primary hepatocytes. • RIPK3 played a central role in DLM-mediated programmed necrosis in liver cells. • Reactive oxygen species played a role in DLM mediated hepatotoxity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Resveratrol prolongs lifespan and improves 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced oxidative damage and behavioural deficits in Drosophila melanogaster

Highlights: • D. melanogaster was exposed to resveratrol (RES) and 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). • RES increased longevity and ameliorated MPTP-mediated oxidative stress and inflammation in flies. • RES protected against MPTP-induced behavioural deficits and brain lesions in flies. • Thus, protective role of RES is via antioxidative and anti-inflammatory mechanisms. 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) is a neurotoxin that causes Parkinson's disease in animals via mechanisms linked with oxidative stress and inflammation. Resveratrol is a natural polyphenol and a phytoalexin with antioxidative and antiinflammatory properties. Here, we investigated the rescue role of resveratrol on MPTP-triggered toxicity in Drosophila melanogaster for the first time. D. melanogaster (Harwich strain, 1-to 3- days old) were first orally exposed to resveratrol (0, 7.5, 15, 30, 60 and 120 mg/kg diet) and MPTP (0, 250, 500, 1000, 2000, and 3000 μM) for longevity and 7 days survival assays respectively. Consequently, we selected resveratrol (30 and 60 mg/kg diet) to evaluate its rescue role on MPTP (250 and 500 μM)-induced toxicity in D. melanogaster after 3 days of oral treatment. Specifically, we evaluated markers of neurotoxicity (acetylcholinesterase and negative geotaxis), inflammation (nitric oxide), oxidative stress-antioxidant status (hydrogen peroxide, total thiol, catalase and glutathione-S-transferase), cell viability and fecundity. The data showed that resveratrol increased lifespan of D. melanogaster in a dose-dependent manner up to 60 mg/kg diet. Further, resveratrol restored MPTP-induced inhibition of catalase, glutathione-S-transferase and acetylcholinesterase activities in D. melanogaster. Moreover, resveratrol ameliorated MPTP-triggered cell death, histological alterations, behavioural deficits and accumulation of nitric oxide and hydrogen peroxide levels in flies (p < 0.05). Conclusively, the lifespan extension effects of resveratrol and its rescue role on MPTP- mediated toxicity in the flies may be due to its antioxidant and anti-inflammatory properties.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Loss of Leucyl-tRNA synthetase b leads to ILFS1-like symptoms in zebrafish

Highlights: • Loss of larsb mimics infantile liver failure syndrome type 1 in zebrafish. • mTORC1 hyperactivation is responsible for the phenotype of larsb{sup cq68} mutant. • Rapamycin treatment can partially rescue the liver defect of larsb{sup cq68} mutant. Leucyl-tRNA synthetase (LARS) is a kind of aminoacyl-tRNA synthetases (aaRSs), which is important for protein synthesis. Following the discovery of three clinical cases which carry LARS mutations, it has been designated as the infantile liver failure syndrome type 1 (ILFS1) gene. ILFS1 is a kind of infantile hepatopathy, which is difficult to diagnose and manage. As the mechanism underlying this disease is poorly understood and LARS is conserved among vertebrates, we obtained zebrafish larsb{sup cq68} mutant via CRISPR/Cas9 technology to investigate the role of larsb in vivo. In mutant, the proliferation ability of liver was drastically decreased at later stages accompanied with severe DNA damage. Further studies demonstrated that the mTORC1 signaling was hyperactivated in larsb{sup cq68} mutant. Inhibition of mTORC1 signaling pathway by Rapamycin or mTORC1 morpholino can partially rescue the liver failure of the mutants. These data revealed that larsb mutation caused ILFS1-like phenotype in zebrafish, and indicated this mutant may serve as a potential model for ILFS1. Furthermore, we demonstrated that rapamycin treatment can partially rescue the liver defect in mutants, thus providing a practicable therapeutic plan for ILFS1.

60 APPLIED LIFE SCIENCES↗