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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 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
NASA NTRS1991

Characterization of adaptation in phototropism of Arabidopsis thaliana

Phototropic curvature has been measured for etiolated Arabidopsis thaliana seedlings with and without a preirradiation. A bilateral preirradiation with 450-nm light at a fluence greater than about 0.1 micromole per square meter causes a rapid desensitization to a subsequent 450-nanometer unilateral irradiation at 0.5 micromole per square meter. Following a refractory period, the capacity to respond phototropically recovers to the predesensitization level, and the response is then enhanced. The length of the refractory period is between 10 and 20 minutes. Both the time needed for recovery and the extent of enhancement increase with increasing fluence of the bilateral preirradiation. Based on the relative spectral sensitivities of desensitization and enhancement, these responses can be separated. Desensitization is induced by blue light but not by red light. Enhancement, however, is induced by both blue and red light. Thus, enhancement can be induced without desensitization but not vice versa. Both desensitization and enhancement affect only the magnitude of the response and do not affect the fluence threshold.

NASA Program Space Biology↗
DOE OSTI2021

Cation and Anion Channelrhodopsins: Sequence Motifs and Taxonomic Distribution

Cation and anion channelrhodopsins (CCRs and ACRs, respectively) primarily from two algal species, Chlamydomonas reinhardtii and Guillardia theta, have become widely used as optogenetic tools to control cell membrane potential with light. We mined algal and other protist polynucleotide sequencing projects and metagenomic samples to identify 75 channelrhodopsin homologs from four channelrhodopsin families, including one revealed in dinoflagellates in this study. We carried out electrophysiological analysis of 33 natural channelrhodopsin variants from different phylogenetic lineages and 10 metagenomic homologs in search of sequence determinants of ion selectivity, photocurrent desensitization, and spectral tuning in channelrhodopsins. Our results show that association of a reduced number of glutamates near the conductance path with anion selectivity depends on a wider protein context, because prasinophyte homologs with a glutamate pattern identical to that in cryptophyte ACRs are cation selective. Desensitization is also broadly context dependent, as in one branch of stramenopile ACRs and their metagenomic homologs, its extent roughly correlates with phylogenetic relationship of their sequences. Regarding spectral tuning, we identified two prasinophyte CCRs with red-shifted spectra to 585 nm. They exhibit a third residue pattern in their retinal-binding pockets distinctly different from those of the only two types of red-shifted channelrhodopsins known (i.e., the CCR Chrimson and RubyACRs). In cryptophyte ACRs we identified three specific residue positions in the retinal-binding pocket that define the wavelength of their spectral maxima. Lastly, we found that dinoflagellate rhodopsins with a TCP motif in the third transmembrane helix and a metagenomic homolog exhibit channel activity. Channelrhodopsins are widely used in neuroscience and cardiology as research tools and are considered prospective therapeutics, but their natural diversity and mechanisms remain poorly characterized. Genomic and metagenomic sequencing projects are producing an ever-increasing wealth of data, whereas biophysical characterization of the encoded proteins lags behind. In this study, we used manual and automated patch clamp recording of representative members of four channelrhodopsin families, including a family in dinoflagellates that we report in this study. Our results contribute to a better understanding of molecular determinants of ionic selectivity, photocurrent desensitization, and spectral tuning in channelrhodopsins.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2000

Beta-adrenoceptor dysfunction after inhibition of NO synthesis

G(s) protein-coupled beta-adrenoceptors rapidly desensitize on exposure to agonists in reconstituted membrane preparations, whereas rapid tachyphylaxis to beta-adrenoceptor-mediated vasodilation does not readily occur in vivo. This study examined the possibility that endothelium-derived nitrosyl factors prevent the rapid desensitization of beta-adrenoceptors in the vascular smooth muscle of resistance arteries in pentobarbital-anesthetized rats. The fall in mean arterial blood pressure and in hindquarter vascular resistance produced by the beta-adrenoceptor agonist isoproterenol (ISO, 0.1 to 10 microg/kg IV) was slightly but significantly smaller in rats treated with the NO synthase inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/kg IV) than in saline-treated rats. The ISO-induced fall in mesenteric resistance was similar in L-NAME-treated and in saline-treated rats. The fall in hindquarter vascular resistance and in mesenteric resistance produced by ISO (8 x 10 microg/kg IV) was subject to tachyphylaxis on repeated injection in rats treated with L-NAME (100 micromol/kg IV) but not in rats treated with saline. Injections of L-S:-nitrosocysteine (1200 nmol/kg IV), a lipophobic S:-nitrosothiol, before each injection of ISO (10 microg/kg IV) prevented tachyphylaxis to ISO in L-NAME-treated rats. The vasodilator effects of ISO (0.1 to 10 microg/kg IV) in L-NAME-treated rats that received 8 injections of ISO (10 microg/kg IV) were markedly smaller than in L-NAME-treated rats that received 8 injections of saline. These results indicate that (1) the vasodilator actions of ISO in pentobarbital-anesthetized rats only minimally involve the release of endothelium-derived nitrosyl factors, (2) the effects of ISO are subject to development of tachyphylaxis in L-NAME-treated rats, and (3) tachyphylaxis to ISO is prevented by L-S:-nitrosocysteine. These findings suggest that endothelium-derived nitrosyl factors may prevent desensitization of beta-adrenoceptors in vivo.

NASA Discipline Regulatory Physiology↗
DOE OSTI2023

Structural interplay of anesthetics and paralytics on muscle nicotinic receptors

General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics. The mechanisms by which anesthetics and neuromuscular blockers inhibit nicotinic receptors are poorly understood but underlie safe and effective surgeries. Here we took a direct structural approach to define how a commonly used anesthetic and two neuromuscular blockers act on a muscle-type nicotinic receptor. We discover that the intravenous anesthetic etomidate binds at an intrasubunit site in the transmembrane domain and stabilizes a non-conducting, desensitized-like state of the channel. The depolarizing neuromuscular blocker succinylcholine also stabilizes a desensitized channel but does so through binding to the classical neurotransmitter site. Rocuronium binds in this same neurotransmitter site but locks the receptor in a resting, non-conducting state. Together, this study reveals a structural mechanism for how general anesthetics work on excitatory nicotinic receptors and further rationalizes clinical observations in how general anesthetics and neuromuscular blockers interact.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Structural dynamics at cytosolic interprotomer interfaces control gating of a mammalian TRPM5 channel

The transient receptor potential melastatin (TRPM) tetrameric cation channels are involved in a wide range of biological functions, from temperature sensing and taste transduction to regulation of cardiac function, inflammatory pain, and insulin secretion. The structurally conserved TRPM cytoplasmic domains make up >70 % of the total protein. To investigate the mechanism by which the TRPM cytoplasmic domains contribute to gating, we employed electrophysiology and cryo-EM to study TRPM5—a channel that primarily relies on activation via intracellular Ca 2+ . Here, we show that activation of mammalian TRPM5 channels is strongly altered by Ca 2+ -dependent desensitization. Structures of rat TRPM5 identify a series of conformational transitions triggered by Ca 2+ binding, whereby formation and dissolution of cytoplasmic interprotomer interfaces appear to control activation and desensitization of the channel. This study shows the importance of the cytoplasmic assembly in TRPM5 channel function and sets the stage for future investigations of other members of the TRPM family.

Science & Technology - Other Topics↗
DOE OSTI2022

Gating choreography and mechanism of the human proton-activated chloride channel $\mathrm{ASOR}$

The proton-activated chloride channel ASOR (TMEM206/PAC) permeates anions across cellular membranes in response to acidification, thereby enhancing acid-induced cell death and regulating endocytosis. The molecular mechanisms of pH-dependent control are not understood, in part because structural information for an activated conformation of ASOR is lacking. Here, we reconstitute function from purified protein and present a 3.1-Å-resolution cryo–electron microscopy structure of human ASOR at acidic pH in an activated conformation. The work contextualizes a previous acidic pH structure as a desensitized conformation. Combined with electrophysiological studies and high-resolution structures of resting and desensitized states, the work reveals mechanisms of proton sensing and ion pore gating. Clusters of extracellular acidic residues function as pH sensors and coalesce when protonated. Ensuing conformational changes induce metamorphosis of transmembrane helices to fashion an ion conduction pathway unique to the activated conformation. The studies identify a new paradigm of channel gating in this ubiquitous ion channel.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

VPS26 Moonlights as an Arrestin-like Adapter for a 7-transmembrane RGS 2 protein in Arabidopsis thaliana

Extracellular signals perceived by 7-transmembrane (7TM)-spanning receptors on the plasma membrane utilize a cytoplasmic adaptor that propagates signaling and initiates a feedback circuit for desensitization by removal of these receptors at the plasma membrane leading to desensitization to that signal. Signal (agonist) binding often evokes phosphorylation at the C-terminal tail of many 7TM G-protein-coupled receptors in animal cells which then recruits a cytoplasmic intermediate adaptor, β-arrestin, that sets in motion clathrin-mediated endocytosis (CME). Some 7TM receptors have agonist-induced phosphorylation and CME that do not involve β-arrestin, therefore it is unclear how these phosphorylated 7TM receptors are internalized. Arrestins, neither α– or β-types, are not encoded in the Arabidopsis genome, yet Arabidopsis cells have a well characterized signal-induced CME of a 7TM protein, Regulator of G Signaling 1 (AtRGS1). We show that a component of the retromer complex, VPS26, moonlights as an arrestin-like adapter. VPS26A and VPS26B form heterodimer instead of homodimer or monomer. flg22, a bacterium-derived signal that alerts plant cells of the presence of a potential pathogen, induces phosphorylation of AtRGS1 within a cluster of serines in its C-terminal tail, dimerization, and its CME. The phosphorylated C-terminal tail peptide binds to VPS26A/B heterodimer with greater affinity than the unphosphorylated peptide. We propose that VPS26 serves as an arrestin-like adaptor in the CME of AtRGS1 dimerization biased for VPS26 signaling.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Inhibition of the proton-activated chloride channel PAC by PIP 2

Proton-activated chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by PACC1 (TMEM206). PAC regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP 2 ) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP 2 at pH 4.0 and identified its putative binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain (TMD). While the overall conformation resembles the previously resolved PAC structure in the desensitized state, the TMD undergoes remodeling upon PIP 2 -binding. Structural and electrophysiological analyses suggest that PIP 2 inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. Our findings identify PIP 2 as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1983

Metallurgical studies of NITRONIC 40 with reference to its use for cryogenic wind tunnel models

The characterstics of NITRONIC 40 were investigated in connection with its use in cryogenic wind tunnel models. In particular, the effects of carbide and sigma-phase precipitation resulting from heat treatment and the presence of delta ferrite were evaluated in relation to their effects on mechanical properties and the potential consequences of such degradation. Methods were examined for desensitizing the material and for possible removal of delta ferrite as a means of restoring the material to its advertised properties. It was found that heat treatment followed by cryogenic quenching is a technique capable of desensitizing NITRONIC 40. However, it was concluded that it is extremely difficult, if not impossible, to remove the delta ferrite from the existing stock of material. Furthermore, heat treatments for removing delta ferrite have to take place at temperatures that cause very large grain growth. The implications of using the degraded NITRONIC 40 material for cryogenic model testing were reviewed, and recommendations were submitted with regard to the acceptability of the material. The experience gained from the study of NITRONIC 40 clearly identifies the need to implement a policy for purchasing top-quality materials for cryogenic wind tunnel model applications.

Wigley, D. A.↗
NASA NTRS2004

Effect of high-dose irradiation on the optically stimulated luminescence of Al2O3:C

This paper examines the effect of high-dose irradiation on the optically stimulated luminescence (OSL) of Al2O3:C, principally on the shape of the OSL decay curve and on the OSL sensitivity. The effect of the degree of deep trap filling on the OSL was also studied by monitoring the sensitivity changes after doses of beta irradiation and after step-annealing of samples previously irradiated with high doses. The OSL response to dose shows a linear-supralinear-saturation behavior, with a decrease in the response for doses higher than those required for saturation. This behavior correlates with the sensitivity changes observed in the samples annealed only to 773 K, which show sensitization for doses up to 20-50 Gy and desensitization for higher doses. Data from the step-annealing study leads to the suggestion that the sensitization is caused by the filling of deep electron traps, which become thermally unstable at 1100-1200 K, whereas the desensitization is caused by the filling of deep hole traps, which become thermally unstable at 800-875 K, along with a concomitant decrease in the concentration of recombination centers (F+ -centers). Changes in the shape of the OSL decay curves are also observed at high doses, the decay becoming faster as the dose increases. These changes in the OSL decay curves are discussed in terms of multiple overlapping components, each characterized by different photoionization cross-sections. However, using numerical solutions of the rate equations for a simple model consisting of a main trap and a recombination center, it is shown that the kinetics of OSL process may also be partially responsible for the changes in the OSL curves at high doses in Al2O3:C. Finally, the implication of these results for the dosimetry of heavy charged particles is discussed. c2004 Elsevier Ltd. All rights reserved.

Heavy Ions↗
NASA NTRS2010

NASA-Navy Telemedicine: Autogenic Feedback Training Exercises for Motion Sickness

Airsickness is the most significant medical condition affecting naval aviation training. A 2001 study showed that airsickness was reported in 81% of naval aviation students and was associated with 82% of below average flight scores. The cost to a single training air-wing was over $150,000 annually for fuel and maintenance costs alone. Resistent cases are sent to the Naval Aerospace Medical Institute (NAMI) for evaluation and desensitization in the self-paced airsickness desensitization (SPAD) program. This approach is 75% successful, but can take up to 8 weeks at a significant travel cost. NASA Ames Research Center's Autogenic Feedback Training Exercises (AFTE) uses physiological and biofeedback training for motion sickness prevention. It has a remote capability that has been used from Moffett Field, CA to Atlanta, GA . AFTE is administered in twelve (30-minute) training sessions. The success rate for the NASA AFTE program has been over 85%. Methods: Implementation Phases: Phase I: Transfer NASA AFTE to NAMI; NASA will remotely train aviation students at NAMI. Phase II: NAMI-centered AFTE application with NASA oversight. Phase III: NAMI-centered AFTE to remotely train at various Navy sites. Phase IV: NAMI to offer Tri-service application and examine research opportunities. Results: 1. Use available telemedicine connectivity between NAMI and NASA. 2. Save over $2,000 per student trained. 3. Reduce aviation training attrition. 4. Provide standardization of multi-location motion sickness training. 5. Future tri-service initiatives. 6. Data to NASA and Navy for QA and research opportunities.

Acromite, Michael T.↗
DOE OSTI2024

VPS26 Moonlights as a β-Arrestin-like Adapter for a 7-Transmembrane RGS Protein in Arabidopsis thaliana

Extracellular signals perceived by 7-transmembrane (7TM)-spanning receptors initiate desensitization that involves the removal of these receptors from the plasma membrane. Agonist binding often evokes phosphorylation in the flexible C-terminal region and/or intracellular loop 3 of many 7TM G-protein-coupled receptors in animal cells, which consequently recruits a cytoplasmic intermediate adaptor, β-arrestin, resulting in clathrin-mediated endocytosis (CME) and downstream signaling such as transcriptional changes. Some 7TM receptors undergo CME without recruiting β-arrestin, but it is not clear how. Arrestins are not encoded in the Arabidopsis thaliana genome, yet Arabidopsis cells have a well-characterized signal-induced CME of a 7TM protein, designated Regulator of G Signaling 1 (AtRGS1). Here we show that a component of the retromer complex, Vacuolar Protein Sorting-Associated 26 (VPS26), binds the phosphorylated C-terminal region of AtRGS1 as a VPS26A/B heterodimer to form a complex that is required for downstream signaling. We propose that VPS26 moonlights as an arrestin-like adaptor in the CME of AtRGS1.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Kainate receptor channel opening and gating mechanism

Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission. Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism. Although structures of kainate receptor domains and subunit assemblies are available, the mechanism of kainate receptor gating remains poorly understood. Here we present cryo-electron microscopy structures of the kainate receptor GluK2 in the presence of the agonist glutamate and the positive allosteric modulators lectin concanavalin A and BPAM344. Concanavalin A and BPAM344 inhibit kainate receptor desensitization and prolong activation by acting as a spacer between the amino-terminal and ligand-binding domains and a stabilizer of the ligand-binding domain dimer interface, respectively. Channel opening involves the kinking of all four pore-forming M3 helices. Our structures reveal the molecular basis of kainate receptor gating, which could guide the development of drugs for treatment of neurological disorders.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Small-molecule modulation of β-arrestins

β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt β-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and β-arrestin-dependent physiological functions while sparing G protein–receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin–receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.

Kahsai, Alem W. [Duke University, Durham, NC (Unit↗
DOE OSTI2021

Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1

Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Here, combining functional, crystallographic, computational and mutational approaches, we show that two structurally distinct small molecules potently and allosterically inhibit channel activation and desensitization by binding at the acidic pocket and stabilizing the closed state of rat/chicken ASIC1. Our work identifies a previously unidentified binding site, elucidates a molecular mechanism of small molecule modulation of ASIC gating, and demonstrates directly the structural basis of such modulation, providing mechanistic and structural insight into ASIC gating, modulation and therapeutic targeting.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Heterogeneous energetic material damage simulator (HEDS): A deep learning approach to simulate damage–sensitivity linkages

Damage in the microstructures of energetic materials (EMs), such as propellants and plastic bonded explosives (PBXs), can significantly alter their response to external loads. Both sensitization and desensitization can occur, causing concerns with safety and performance in the field; predictive models that connect damage and the sensitivity of EMs can enable design and provide confidence in their robustness and reliability. However, modeling of damage evolution is challenging for real microstructures of EMs; samples of damaged EMs are difficult to obtain, thereby hindering experiments and direct numerical simulations to determine the sensitivity of EMs at various stages of damage. Here, we develop an approach to generate synthetic, i.e., in silico produced, damaged microstructures for use in simulations to connect damage levels to sensitivity. The development of the present workflow to generate and impose varying levels of damage in microstructures, known as HEDS (Heterogeneous Energetic Material Damage Simulator), begins with a small set of images of damaged PBXs and combines a collection of deep neural network techniques to generate microstructures with varying levels of damage. By making the synthetic microstructures conform closely to those observed in available real, imaged microstructures, we develop an ensemble of damaged microstructures that can be used for in silico shock experiments. HEDS develops these microstructure ensembles as level set fields, which are directly employed in a sharp interface Eulerian hydrocode where shock simulations are performed to quantify the energy release rate from hotspot fields generated in the microstructure. These capabilities can be useful for the analysis and assessment of changes in the sensitivity of EMs and to design formulations that are less susceptible to damage-induced changes in sensitivity and performance.

Fang, Irene (ORCID:0009000844557122)↗
DOE OSTI2022

X-ray structure of a human cardiac muscle troponin C/troponin I chimera in two crystal forms

The X-ray crystal structure of a human cardiac muscle troponin C/troponin I chimera has been determined in two different crystal forms and shows a conformation of the complex that differs from that previously observed by NMR. The chimera consists of the N-terminal domain of troponin C (cTnC; residues 1–80) fused to the switch region of troponin I (cTnI; residues 138–162). In both crystal forms, the cTnI residues form a six-turn α-helix that lays across the hydrophobic groove of an adjacent cTnC molecule in the crystal structure. In contrast to previous models, the cTnI helix runs in a parallel direction relative to the cTnC groove and completely blocks the calcium desensitizer binding site of the cTnC–cTnI interface.

59 BASIC BIOLOGICAL SCIENCES↗