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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 793 records · Page 44
All sourcesNASA NTRSDOE OSTI
DOE OSTI2014

The crystal structure of S. cerevisiae Sad1, a catalytically inactive deubiquitinase that is broadly required for pre-mRNA splicing

Sad1 is an essential splicing factor initially identified in a genetic screen in Saccharomyces cerevisiae for snRNP assembly defects. Based on sequence homology, Sad1, or USP39 in humans, is predicted to comprise two domains: a zinc finger ubiquitin binding domain (ZnF-UBP) and an inactive ubiquitin-specific protease (iUSP) domain, both of which are well conserved. The role of these domains in splicing and their interaction with ubiquitin are unknown. We first used splicing microarrays to analyze Sad1 function in vivo and found that Sad1 is critical for the splicing of nearly all yeast intron-containing genes. By using in vitro assays, we then showed that it is required for the assembly of the active spliceosome. To gain structural insights into Sad1 function, we determined the crystal structure of the full-length protein at 1.8 Å resolution. In the structure, the iUSP domain forms the characteristic ubiquitin binding pocket, though with an amino acid substitution in the active site that results in complete inactivation of the enzymatic activity of the domain. The ZnF-UBP domain of Sad1 shares high structural similarly to other ZnF-UBPs; however, Sad1’s ZnF-UBP does not possess the canonical ubiquitin binding motif. Given the precedents for ZnF-UBP domains to function as activators for their neighboring USP domains, we propose that Sad1’s ZnF-UBP acts in a ubiquitin-independent capacity to recruit and/or activate Sad1’s iUSP domain to interact with the spliceosome.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

The UPR Branch IRE1- bZIP60 in Plants Plays an Essential Role in Viral Infection and Is Complementary to the Only UPR Pathway in Yeast

The unfolded protein response (UPR) signaling network encompasses two pathways in plants, one mediated by inositol-requiring protein-1 (IRE1)-bZIP60 mRNA and the other by site-1/site-2 proteases (S1P/S2P)-bZIP17/bZIP28. As the major sensor of UPR in eukaryotes, IRE1, in response to endoplasmic reticulum (ER) stress, catalyzes the unconventional splicing of HAC1 in yeast, bZIP60 in plants and XBP1 in metazoans. Recent studies suggest that IRE1p and HAC1 mRNA, the only UPR pathway found in yeast, evolves as a cognate system responsible for the robust UPR induction. However, the functional connectivity of IRE1 and its splicing target in multicellular eukaryotes as well as the degree of conservation of IRE1 downstream signaling effectors across eukaryotes remains to be established. Here, we report that IRE1 and its substrate bZIP60 function as a strictly cognate enzymesubstrate pair to control viral pathogenesis in plants. Moreover, we show that the S1P/ S2P-bZIP17/bZIP28 pathway, the other known branch of UPR in plants, does not play a detectable role in virus infection, demonstrating the distinct function of the IRE1-bZIP60 pathway in plants. Furthermore, we provide evidence that bZIP60 and HAC1, products of the enzyme-substrate duet, rather than IRE1, are functionally replaceable to cope with ER stress in yeast. Taken together, we conclude that the downstream signaling of the IRE1- mediated splicing is evolutionarily conserved in yeast and plants, and that the IRE1-bZIP60 UPR pathway not only confers overlapping functions with the other UPR branch in fundamental biology but also may exert a unique role in certain biological processes such as virus-plant interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Quantile-dependent expressivity of postprandial lipemia

“Quantile-dependent expressivity” describes an effect of the genotype that depends upon the level of the phenotype (e.g., whether a subject’s triglycerides are high or low relative to its population distribution). Prior analyses suggest that the effect of a genetic risk score (GRS) on fasting plasma triglyceride levels increases with the percentile of the triglyceride distribution. Postprandial lipemia is well suited for testing quantile-dependent expressivity because it exposes each individual’s genotype to substantial increases in their plasma triglyceride concentrations. Ninety-seven published papers were identified that plotted mean triglyceride response vs. time and genotype, which were converted into quantitative data. Separately, for each published graph, standard least-squares regression analysis was used to compare the genotype differences at time t (dependent variable) to average triglyceride concentrations at time t (independent variable) to assess whether the genetic effect size increased in association with higher triglyceride concentrations and whether the phenomenon could explain purported genetic interactions with sex, diet, disease, BMI, and drugs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Varroa destructor mites vector and transmit pathogenic honey bee viruses acquired from an artificial diet

The ectoparasitic mite Varroa destructor is one of the most destructive pests of the honey bee (Apis mellifera) and the primary biotic cause of colony collapse in many regions of the world. These mites inflict physical injury on their honey bee hosts from feeding on host hemolymph and fat body cells/cellular components, and serve as the vector for deadly honey bee viruses, including Deformed wing virus (DWV) and the related Varroa destructor virus-1 (VDV-1) (i.e., DWV-like viruses). Studies focused on elucidating the dynamics of Varroa-mediated vectoring and transmission of DWV-like viruses may be confounded by viruses present in ingested host tissues or the mites themselves. Here we describe a system that includes an artificial diet free of insect tissue-derived components for maintaining Varroa mites for in vitro experimentation. Using this system, together with the novel engineered cDNA clone-derived genetically tagged VDV-1 and wild-type DWV, we demonstrated for the first time that Varroa mites provided an artificial diet supplemented with engineered viruses for 36 hours could acquire and transmit sufficient numbers of virus particles to establish an infection in virus-naïve hosts. While the in vitro system described herein provides for only up to five days of mite survival, precluding study of the long-term impacts of viruses on mite health, the system allows for extensive insights into the dynamics of Varroa-mediated vectoring and transmission of honey bee viruses.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Evaluation of 6-OxP-CD, an Oxime-based cyclodextrin as a viable medical countermeasure against nerve agent poisoning: Experimental and molecular dynamic simulation studies on its inclusion complexes with cyclosarin, soman and VX

The ability of the cyclodextrin-oxime construct 6-OxP-CD to bind and degrade the nerve agents Cyclosarin (GF), Soman (GD) and S -[2-[Di(propan-2-yl)amino]ethyl] O -ethyl methylphosphonothioate (VX) has been studied using 31 P-nuclear magnetic resonance (NMR) under physiological conditions. While 6-OxP-CD was found to degrade GF instantaneously under these conditions, it was found to form an inclusion complex with GD and significantly improve its degradation (t 1/2 ~ 2 hrs) relative over background (t 1/2 ~ 22 hrs). Consequently, effective formation of the 6-OxP-CD:GD inclusion complex results in the immediate neutralization of GD and thus preventing it from inhibiting its biological target. In contrast, NMR experiments did not find evidence for an inclusion complex between 6-OxP-CD and VX, and the agent’s degradation profile was identical to that of background degradation (t 1/2 ~ 24 hrs). As a complement to this experimental work, molecular dynamics (MD) simulations coupled with Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations have been applied to the study of inclusion complexes between 6-OxP-CD and the three nerve agents. These studies provide data that informs the understanding of the different degradative interactions exhibited by 6-OxP-CD with each nerve agent as it is introduced in the CD cavity in two different orientations (up and down). For its complex with GF, it was found that the oxime in 6-OxP-CD lies in very close proximity (P GF …O Oxime ~ 4–5 Å) to the phosphorus center of GF in the ‘down GF ’ orientation for most of the simulation accurately describing the ability of 6-OxP-CD to degrade this nerve agent rapidly and efficiently. Further computational studies involving the center of masses (COMs) for both components (GF and 6-OxP-CD) also provided some insight on the nature of this inclusion complex. Distances between the COMs (ΔCOM) lie closer in space in the ‘down GF ’ orientation than in the ‘up GF ’ orientation; a correlation that seems to hold true not only for GF but also for its congener, GD. In the case of GD, calculations for the ‘down GD ’ orientation showed that the oxime functional group in 6-OxP-CD although lying in close proximity (P GD …O Oxime ~ 4–5 Å) to the phosphorus center of the nerve agent for most of the simulation, adopts another stable conformation that increase this distance to ~ 12–14 Å, thus explaining the ability of 6-OxP-CD to bind and degrade GD but with less efficiency as observed experimentally (t 1/2 ~ 4 hr. vs. immediate). Lastly, studies on the VX:6-OxP-CD system demonstrated that VX does not form a stable inclusion complex with the oxime-bearing cyclodextrin and as such does not interact in a way that is conducive to an accelerated degradation scenario. Collectively, these studies serve as a basic platform from which the development of new cyclodextrin scaffolds based on 6-OxP-CD can be designed in the development of medical countermeasures against these highly toxic chemical warfare agents.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Assessing springtime vertebrate prey of sympatric mesopredators in the southeastern United States using metabarcoding analysis

Coyotes (Canis latrans) colonized the eastern United States over the last century and formed a 3-species predator guild with bobcats (Lynx rufus) and gray foxes (Urocyon cinereoargenteus) across much of the southeastern United States. Diets among the three species vary along with respective impacts on game species such as white-tailed deer (Odocoileus virginianus) and wild turkeys (Meleagris gallopavo). To determine predation impacts on vertebrate prey and dietary overlap in consumption of prey items, we assessed diets of coyote, bobcat, and gray fox during spring, coinciding with white-tailed deer fawning and wild turkey nesting and brood rearing. We sampled across three sites along the Savannah River in South Carolina from mid-May through mid-June of 2020–2021. We collected 180 scat samples along 295.9 kilometers (71.1–122.4 km/site) of unpaved secondary roads and used DNA metabarcoding to determine vertebrate diet items. We identified predator species of scat using DNA metabarcoding and species-specific mtDNA fragment analysis (153 were coyote, 20 bobcat, and seven gray fox). Overall, we found evidence that two species, coyote and bobcat, consumed deer while all three consumed turkeys. Frequency of deer in the diet varied across sites for coyotes from 62–86% and wild turkey was present with a frequency of occurrence of 9% for coyotes, 5% for bobcats, and 14% for gray fox. Vertebrate diet specialization was evident across predator species with high frequency of deer in coyote diets, rabbits and small mammals in bobcat diets, and herpetofauna in gray fox diets. During deer fawning and wild turkey nesting and brood rearing, dietary overlap appears to be mediated by disparate selection of prey items, which reduced competition among coyotes, bobcats, and gray foxes. Use of DNA metabarcoding may augment our understanding of dietary preferences within this predator guild by providing increased resolution of diet composition among important game species.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Basics of Neutrons for First Responders

These are slides from a presentation on the basics of neutrons. A few topics covered are: common origins of terrestrial neutron radiation, neutron sources, neutron energy, interactions, detecting neutrons, gammas from neutron interactions, neutron signatures in gamma-ray spectra, neutrons and NaI, neutron fluence to dose (msV), instruments' response to neutrons.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2024

CORN (Crop Optimization Realized through Neuralnets)

Traditional models of predicting plant traits are limited because they often rely on linear assumptions that do not fully capture the complexity of biological interactions and DNA-based markers which are static across environments. This project generated a set of RNA-based data from large multi-environment field trials and combined it with advanced machine learning techniques to account for these complex interactions and improve the accuracy of predictions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA

New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis . The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Mechanism Across Scales: A Holistic Modeling Framework Integrating Laboratory and Field Studies for Microbial Ecology

Over the last century, leaps in technology for imaging, sampling, detection, high-throughput sequencing, and -omics analyses have revolutionized microbial ecology to enable rapid acquisition of extensive datasets for microbial communities across the ever-increasing temporal and spatial scales. The present challenge is capitalizing on our enhanced abilities of observation and integrating diverse data types from different scales, resolutions, and disciplines to reach a causal and mechanistic understanding of how microbial communities transform and respond to perturbations in the environment. This type of causal and mechanistic understanding will make predictions of microbial community behavior more robust and actionable in addressing microbially mediated global problems. To discern drivers of microbial community assembly and function, we recognize the need for a conceptual, quantitative framework that connects measurements of genomic potential, the environment, and ecological and physical forces to rates of microbial growth at specific locations. We describe the Framework for Integrated, Conceptual, and Systematic Microbial Ecology (FICSME), an experimental design framework for conducting process-focused microbial ecology studies that incorporates biological, chemical, and physical drivers of a microbial system into a conceptual model. Through iterative cycles that advance our understanding of the coupling across scales and processes, we can reliably predict how perturbations to microbial systems impact ecosystem-scale processes or vice versa. We describe an approach and potential applications for using the FICSME to elucidate the mechanisms of globally important ecological and physical processes, toward attaining the goal of predicting the structure and function of microbial communities in chemically complex natural environments.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Investigation of the Impact of Lipid Acyl Chain Saturation on Fusion Peptide Interactions with Lipid Bilayers

The interaction of many peptides with lipid bilayer membranes strongly depends on the lipid composition. Here, a study of the impact of unsaturated lipid acyl chains on the interaction of a derivative of the HIV-1 fusion peptide with lipid bilayer vesicles is presented. Lipid bilayer vesicles composed of mixtures of lipids with two saturated acyl chains and lipids and one saturated and one unsaturated acyl chain, but identical head groups, were studied. The dependence of the peptide conformation on the unsaturated lipid content was probed by circular dichroism spectroscopy, while the impact of the peptide on the bilayer structure was determined by small-angle neutron scattering. The impact of the peptide on the lipid bilayer vesicle dynamics was investigated using neutron spin echo spectroscopy. Molecular dynamics simulations were used to characterize the behavior of the systems studied to determine if there were clear differences in their physical properties. The results reveal that the peptide–bilayer interaction is not a simple function of the unsaturated lipid acyl chain content of the bilayer. Instead, the peptide behavior is more consistent with that seen for the bilayer containing only unsaturated lipids, which is supported by lipid-specific interactions revealed by the simulations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Structural Basis of Clostridium perfringens Enterotoxin Activation and Oligomerization by Trypsin

Clostridium perfringens enterotoxin (CpE) is a β-pore forming toxin that disrupts gastrointestinal homeostasis in mammals by binding membrane protein receptors called claudins. Although structures of CpE fragments bound to claudins have been determined, the mechanisms that trigger CpE activation and oligomerization that lead to the formation of cytotoxic β-pores remain undetermined. Proteolysis of CpE in the gut by trypsin has been shown to play a role in this and subsequent cytotoxicity processes. Here, we report solution structures of full-length and trypsinized CpE using small-angle X-ray scattering (SAXS) and crystal structures of trypsinized CpE and its C-terminal claudin-binding domain (cCpE) using X-ray crystallography. Mass spectrometry and SAXS uncover that removal of the CpE N-terminus by trypsin alters the CpE structure to expose areas that are normally unexposed. Crystal structures of trypsinized CpE and cCpE reveal unique dimer interfaces that could serve as oligomerization sites. Moreover, comparisons of these structures to existing ones predict the functional implications of oligomerization in the contexts of cell receptor binding and β-pore formation. This study sheds light on trypsin’s role in altering CpE structure to activate its function via inducing oligomerization on its path toward cytotoxic β-pore formation. Its findings can incite new approaches to inhibit CpE-based cytotoxicity with oligomer-disrupting therapeutics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Immune activation during Pseudomonas infection causes local cell wall remodeling and alters AGP accumulation

The plant cell boundary generally comprises constituents of the primary and secondary cell wall (CW) that are deposited sequentially during development. Although it is known that the CW acts as a barrier against phytopathogens and undergoes modifications to limit their invasion, the extent, sequence, and requirements of the pathogen-induced modifications of the CW components are still largely unknown, especially at the level of the polysaccharide fraction. To address this significant knowledge gap, we adopted the compatible Pseudomonas syringae–Arabidopsis thaliana system. We found that, despite systemic signaling actuation, Pseudomonas infection leads only to local CW modifications. Furthermore, by utilizing a combination of CW and immune signaling-deficient mutants infected with virulent or non-virulent bacteria, we demonstrated that the pathogen-induced changes in CW polysaccharides depend on the combination of pathogen virulence and the host's ability to mount an immune response. This results in a pathogen-driven accumulation of CW hexoses, such as galactose, and an immune signaling-dependent increase in CW pentoses, mainly arabinose, and xylose. Our analyses of CW changes during disease progression also revealed a distinct spatiotemporal pattern of arabinogalactan protein (AGP) deposition and significant modifications of rhamnogalacturonan sidechains. Furthermore, genetic analyses demonstrated a critical role of AGPs, specifically of the Arabinoxylan Pectin Arabinogalactan Protein1, in limiting pathogen growth. Collectively, our results provide evidence for the actuation of significant remodeling of CW polysaccharides in a compatible host-pathogen interaction, and, by identifying AGPs as critical elements of the CW in plant defense, they pinpoint opportunities to improve plants against diverse pathogens.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Interaction of NaOH solutions with silica surfaces

Sodium adsorption on silica surfaces depends on the solution counter-ion. Here, we use NaOH solutions to investigate basic environments. Sodium adsorption on hydroxylated silica surfaces from NaOH solutions were investigated through molecular dynamics with a dissociative force field, allowing for the development of secondary molecular species. Furthermore, across the NaOH concentrations (0.01 M – 1.0 M), ~50% of the Na + ions were concentrated in the surface region, developing silica surface charges between –0.01 C/m 2 (0.01 M NaOH) and –0.76 C/m 2 (1.0 M NaOH) due to surface site deprotonation. Five inner-sphere adsorption complexes were identified, including monodentate, bidentate, and tridentate configurations and two additional structures, with Na + ions coordinated by bridging oxygen and hydroxyl groups or water molecules. Coordination of Na + ions by bridging oxygen atoms indicates partial or complete incorporation of Na + ions into the silica surface. Residence time analysis identified that Na + ions coordinated by bridging oxygen atoms stayed adsorbed onto the surface four times longer than the mono/bi/tridentate species, indicating formation of relatively stable and persistent Na + ion adsorption structures. Such inner-sphere complexes form only at NaOH concentrations of > 0.5 M. Na + adsorption and lifetimes have implications for the stability of silica surfaces.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

BIPSPI+: Mining Type-Specific Datasets of Protein Complexes to Improve Protein Binding Site Prediction

Computational approaches for predicting protein-protein interfaces are extremely useful for understanding and modelling the quaternary structure of protein assemblies. In particular, partner-specific binding site prediction methods allow delineating the specific residues that compose the interface of protein complexes. In recent years, new machine learning and other algorithmic approaches have been proposed to solve this problem. However, little effort has been made in finding better training datasets to improve the performance of these methods. With the aim of vindicating the importance of the training set compilation procedure, in this work we present BIPSPI+, a new version of our original server trained on carefully curated datasets that outperforms our original predictor. We show how prediction performance can be improved by selecting specific datasets that better describe particular types of protein interactions and interfaces (e.g. homo/hetero). In addition, our upgraded web server offers a new set of functionalities such as the sequence-structure prediction mode, hetero- or homo-complex specialization and the guided docking tool that allows to compute 3D quaternary structure poses using the predicted interfaces. BIPSPI+ is freely available at https://bipspi.cnb.csic.es.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Impact of spatial organization on a novel auxotrophic interaction among soil microbes

Here, a key prerequisite to achieve a deeper understanding of microbial communities and to engineer synthetic ones is to identify the individual metabolic interactions among key species and how these interactions are affected by different environmental factors. Deciphering the physiological basis of species–species and species–environment interactions in spatially organized environments requires reductionist approaches using ecologically and functionally relevant species. To this end, we focus here on a defined system to study the metabolic interactions in a spatial context among the plant-beneficial endophytic fungus Serendipita indica , and the soil-dwelling model bacterium Bacillus subtilis . Focusing on the growth dynamics of S. indica under defined conditions, we identified an auxotrophy in this organism for thiamine, which is a key co-factor for essential reactions in the central carbon metabolism. We found that S. indica growth is restored in thiamine-free media, when co-cultured with B. subtilis . The success of this auxotrophic interaction, however, was dependent on the spatial and temporal organization of the system; the beneficial impact of B. subtilis was only visible when its inoculation was separated from that of S. indica either in time or space. These findings describe a key auxotrophic interaction in the soil among organisms that are shown to be important for plant ecosystem functioning, and point to the potential importance of spatial and temporal organization for the success of auxotrophic interactions. These points can be particularly important for engineering of minimal functional synthetic communities as plant seed treatments and for vertical farming under defined conditions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Design and construction of 3D printed devices to investigate active and passive bacterial dispersal on hydrated surfaces

Background: To disperse in water-unsaturated environments, such as the soil, bacteria rely on the availability and structure of water films forming on biotic and abiotic surfaces, and, especially, along fungal mycelia. Dispersal along such “fungal highways” may be driven both by mycelial physical properties and by interactions between bacteria and fungi. However, we still do not have a way to disentangle the biotic and abiotic elements. Results: We designed and 3D printed two devices establishing stable liquid films that support bacteria dispersal in the absence of biotic interactions. The thickness of the liquid film determined the presence of hydraulic flow capable of transporting non-motile cells. In the absence of flow, only motile cells can disperse in the presence of an energy source. Non-motile cells could not disperse autonomously without flow but dispersed as “hitchhikers” when co-inoculated with motile cells. Conclusions: The 3D printed devices can be used as an abiotic control to study bacterial dispersal on hydrated surfaces, such as plant roots and fungal hyphae networks in the soil. By teasing apart the abiotic and biotic dimensions, these 3D printed devices will stimulate further research on microbial dispersal in soil and other water-unsaturated environments.

3D printing↗