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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 163 records · Page 9
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

Hypothesis: Hypoxia induces de novo synthesis of NeuGc gangliosides in humans through CMAH domain substitute

Highlights: • In humans, the key enzyme for NeuGc synthesis, CMAH, is non-functional. • The presence of NeuGc gangliosides in human cancer cells represents an enigma. • We tested the effect of hypoxia by stable isotope labeling in cell culture (SILAC). • Subunit B of respiratory complex II (SDHB) was found upregulated. • Could CMAH be substituted by SDHB, another [Fe{sub 2}S{sub 2}]-containing domain? Immunotherapy is a growing field in cancer research. A privileged tumor-associated antigen that has received much attention is N-glycolyl (NeuGc) GM3. This ganglioside is present in several types of cancer, but is almost undetectable in human healthy tissues. However, its non-hydroxylated variant, NeuAc GM3, is abundant in all mammals. Due to a deletion in the human gene encoding the key enzyme for synthesis of NeuGc, humans, in contrast to other mammals, cannot synthesize NeuGc GM3. Therefore the presence of this ganglioside in human cancer cells represents an enigma. It has been shown that hypoxic conditions trigger the expression of NeuGc gangliosides, which not only serve as attractive targets for cancer therapy, but also as diagnostic and prognostic tumor marker. Here, we confirm hypoxia-induced expression of the NeuGc GM3 ganglioside also in HeLa cells and reveal several candidate proteins, in particular GM3 synthase and subunit B of respiratory complex II (SDHB), that may be involved in the generation of NeuGc GM3 by SILAC-based proteome analysis. These findings have the potential to significantly advance our understanding of how this enigmatic tumor-associated antigen is produced in humans, and also suggest a possible mechanism of action of anti-tumor antibodies that recognize hypoxia markers, such as 14F7.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The dual role of cGMP in oocyte maturation of zebrafish

Highlights: • Activation of the NO/sGC/cGMP pathway could lead to oocyte maturation (OM). • Inhibition of the NO/sGC/cGMP pathway could lead to OM. • NO level increased in follicular cells but remained constant in oocytes during OM. • cGMP level increased in the follicular cells but decreased in oocytes during OM. The roles of cyclic guanosine monophosphate (cGMP) signaling in oocyte maturation attracts much attention in mammals, but its roles in fish are still largely unknown. Using zebrafish as a model, we demonstrated for the first time in fish that cGMP is involved in oocyte maturation, and its functional model in oocyte maturation is different from that of mammals. The intracellular cGMP could be regulated by nitric oxide (NO), we found that all three NO synthase enzymes and four soluble guanylyl cyclases (sGC) are expressed in the zebrafish ovary. Intriguingly, either the activation or inhibition of the NO/sGC/cGMP pathway in fully grown follicles could lead to oocyte maturation. During oocyte maturation, cGMP levels increased in the follicular cell layer but decreased in oocytes, while NO levels increased in follicular cells but remained constant in oocytes. Based on these findings in zebrafish, we propose a hypothetical model on the dual role of cGMP in oocyte maturation: in follicular cells the LH signal could increase the level of NO and cGMP which induces oocyte maturation, while in the oocyte the decreased cGMP level can also induce oocyte maturation. These findings help us to understand the molecular mechanism of fish oocyte maturation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins

Tandem zinc finger (ZF) proteins are the largest and most rapidly diverging family of DNA-binding transcription regulators in mammals. ZFP568 represses a transcript of placental-specific insulin like growth factor 2 (Igf2-P0) in mice. ZFP568 binds a 24-base pair sequence-specific element upstream of Igf2-P0 via the eleven-ZF array. Both DNA and protein conformations deviate from the conventional one finger-three bases recognition, with individual ZFs contacting 2, 3, or 4 bases and recognizing thymine on the opposite strand. These interactions arise from a shortened minor groove caused by an AT-rich stretch, suggesting adaptability of ZF arrays to sequence variations. Despite conservation in mammals, mutations at Igf2 and ZFP568 reduce their binding affinity in chimpanzee and humans. Furthermore, our studies provide important insights into the evolutionary and structural dynamics of ZF-DNA interactions that play a key role in mammalian development and evolution.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Bisphenol A, bisphenol F and bisphenol S affect differently 5α-reductase expression and dopamine–serotonin systems in the prefrontal cortex of juvenile female rats

Background: Early-life exposure to the endocrine disruptor bisphenol A (BPA) affects brain function and behavior, which might be attributed to its interference with hormonal steroid signaling and/or neurotransmitter systems. Alternatively, the use of structural analogs of BPA, mainly bisphenol F (BPF) and bisphenol S (BPS), has increased recently. However, limited in vivo toxicity data exist. Objectives: We investigated the effects of BPA, BPF and BPS on 5α-reductase (5α-R), a key enzyme involved in neurosteroidogenesis, as well as on dopamine (DA)- and serotonin (5-HT)-related genes, in the prefrontal cortex (PFC) of juvenile female rats. Methods: Gestating Wistar rats were treated with either vehicle or 10 μg/kg/day of BPA, BPF or BPS from gestational day 12 to parturition. Then, female pups were exposed from postnatal day 1 through day 21 (PND21), when they were euthanized and RT-PCR, western blot and quantitative PCR-array experiments were performed. Results: BPA decreased 5α-R2 and 5α-R3 mRNA and protein levels, while both BPF and BPS decreased 5α-R3 mRNA levels in PFC at PND21. Further, BPA, BPF and BPS significantly altered, respectively, the transcription of 25, 56 and 24 genes out of the 84 DA and 5-HT-related genes assayed. Of particular interest was the strong induction by all these bisphenols of Cyp2d4, implicated in corticosteroids synthesis. Conclusions: Our results demonstrate for the first time that BPA, BPF and BPS differentially affect 5α-R and genes related to DA/5-HT systems in the female PFC. In vivo evidence of the potential adverse effects of BPF and BPS in the brain of mammals is provided in this work, raising questions about the safety of these chemicals as substitutes for BPA. - Highlights: • Juvenile prefrontal cortex of female rats exposed to bisphenol A, F or S was analyzed. • We provide the first in vivo data of BPF and BPS effects in mammal brain. • BPA, BPF and BPS differently affected dopamine and serotonin-related genes. • 5α-reductase was found as a potential target for BPA action in juvenile female brain.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Framboidal iron oxide: Chondrite-like material from the black mat, Murray Springs, Arizona

At the end of the Pleistocene, many large mammals became extinct in North America1. The three most common theories for this phenomenon include climate change, overkill, or disease. Recently, researchers suggested that an extraterrestrial (ET) event may have caused sudden climate change that devastated these large mammals and had profound effects on the Clovis culture2,3. Critics of the ET event or impact theory note the lack of evidence such as an impact crater, impact material, shocked quartz, or tektites4. Here we present for the first time chemical and textural evidence of impact material from the Clovis-age, Murray Springs black mat layer, Arizona, USA. The impact material contains iron oxide spherules (framboids) in a glassy iron-silica matrix, which is one indicator of a possible meteorite impact. The spherules also contain elevated concentrations of vanadium and little titanium. The chemistry of both the spherules and matrix is consistent with the chemistry of impact material associated with other meteorite impact sites and meteorite showers.

Fayek, Mostafa↗
DOE OSTI2017

Structural Analysis Reveals Features of Ribosome Assembly Factor Nsa1/WDR74 Important for Localization and Interaction with Rix7/NVL2

Ribosome assembly is a complex process that requires hundreds of essential assembly factors, including Rix7 (NVL2 in mammals) and Nsa1 (WDR74 in mammals). Rix7 is a type II double ring, AAA-ATPase, which is closely related to the well-known Cdc48/p97. Previous studies in Saccharomyces cerevisiae suggest that Rix7 mediates the release of Nsa1 from nucleolar pre-60S particles; however, the underlying mechanisms of this release are unknown. Through multiple structural analyses we show that S. cerevisiae Nsa1 is composed of an N-terminal seven-bladed WD40 domain followed by a lysine-rich C terminus that extends away from the WD40 domain and is required for nucleolar localization. Additional co-immunoprecipitation assays with the mammalian homologs identified a well-conserved interface within WDR74 that is important for its association with NVL2. We further show that WDR74 associates with the D1 AAA domain of NVL2, which represents a novel mode of binding of a substrate with a type II AAA-ATPase.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones

Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones are S-oxygenated to the sulfenic acid which can either react with glutathione and initiate a redox-cycle or be oxygenated a second time to the unstable sulfinic acid. In this study, we utilized LC–MS/MS to demonstrate that the oxygenation by hFMO of the thioureas under test terminated at the sulfenic acid. With thiones, hFMO catalyzed the second reaction and the sulfinic acid rapidly lost sulfite to form the corresponding imidazole. Thioureas are often pulmonary toxicants in mammals and, as previously reported by our laboratory, are excellent substrates for hFMO2. This isoform is expressed at high levels in the lung of most mammals, including non-human primates. Genotyping to date indicates that individuals of African (up to 49%) or Hispanic (2–7%) ancestry have at least one allele for functional hFMO2 in lung, but not Caucasians nor Asians. In this study the major metabolite formed by hFMO2 with thioureas from Allergan, Inc. was the sulfenic acid that reacted with glutathione. The majority of thiones were poor substrates for hFMO3, the major form in adult human liver. However, hFMO1, the major isoform expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with K{sub m}s ranging from 7 to 160 μM and turnover numbers of 30–40 min{sup −1}. The product formed was identified by LC–MS/MS as the imidazole. The activities of the mouse and human FMO1 and FMO3 orthologs were in good agreement with the exception of some thiones for which activity was much greater with hFMO1 than mFMO1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Driving in the dark: Deciphering nighttime driver detection of free-ranging roadside wildlife

Wildlife-vehicle collisions are dangerous for motorists; however, few studies have addressed driver detection of roadside animals, and none have evaluated detection of free-ranging wildlife. Here, we used 24 volunteer drivers, infrared videography, a 75-km route, and free-ranging wildlife to quantify factors influencing (1) probability of wildlife detection, (2) detection distance, and (3) probability of dangerous encounters (i.e., detection distance < distance required for braking) for multiple species at night in South Carolina, USA. Detection probability of white-tailed deer (Odocoileus virginianus) was impacted by multiple driver, animal, and roadside factors. Deer detection distances increased by 20.99 m when drivers used high-beam headlights and 23.36 m when deer were moving but decreased by 0.71 m for every minute into a drive. Every encounter with wild pigs (Sus scrofa) and most encounters with small mammals were considered dangerous. Our findings suggest most drivers cannot safely detect deer, wild pigs, and small mammals at night.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Conserved role of ATP synthase in mammalian cilia

Highlights: • ATP synthase localizes to cilia in mammalian cells. • ATP synthase is involved in ciliogenesis. • ATP synthase probably participates in polycystin signalling pathway. We previously found that ATP synthases localize to male-specific sensory cilia and control the ciliary response by regulating polycystin signalling in Caenorhabditis elegans. Herein, we discovered that the ciliary localization of ATP synthase is evolutionarily conserved in mammals. We showed that the ATP synthase subunit F1β is colocalized with the cilia marker acetylated α-tubulin in both mammalian renal epithelial cells (MDCK) and normal mouse cholangiocytes (NMCs). Treatment with ATP synthase inhibitor oligomycin impaired ciliogenesis in MDCK cells, and F1β was co-immunoprecipitated with PKD2 in mammalian cells. Our study provides evidence for the evolutionarily conserved localization of ATP synthase in cilia from worm to mammals. Defects in ATP synthase can lead to ciliary dysfunction, which may be a potential mechanism of polycystic kidney disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Linking international technical specifications for acoustic characterization of marine energy converter sounds with environmental compliance criteria

As new ocean energy technologies emerge and are deployed for testing and operations, sound emissions are a potential concern for environmental effects to marine life. Consistent acoustic measurement and data analysis methods can help promote comparisons of technologies and transferability between project sites. In 2022, acoustic emissions from a prototype scale wave energy converter (WEC) were characterized for a range of environmental conditions and power generation states in the coastal waters off southern California using a set of international technical specifications. Results from the international technical specification analyses were applied to United States regulatory threshold criteria for acoustic impacts to marine mammals and examined in the context of European underwater noise monitoring guidelines. Weighted 24 hour cumulative sound exposure levels SEL24h calculated from the highest power generation state WEC sound pressure levels were often more than 20 dB below threshold criteria for temporary threshold shifts in five relevant marine mammal hearing groups. Following European Union recommendations for analyses and reporting, WEC sound characterization in third octave bands centered at 63 Hz and 125 Hz show clear spatial decay of WEC-generated noise, with more pronounced attenuation at 63 Hz, and a less marked but still detectable gradient at 125 Hz, collectively suggesting a relatively confined acoustic footprint under the observed conditions. The value of the international technical specification approach is highlighted by the isolation of WEC sounds from the surrounding soundscape. This allows for a robust characterization of acoustic emissions through a range of device power generation and sea states. Furthermore, in threshold-based regulatory contexts like the U.S., this facilitates direct evaluation of source contributions, while in broader monitoring frameworks used in the E.U. it provides a reproducible foundation for assessing the contribution of emerging ocean energy technologies to the underwater acoustic environment.

Haxel, Joseph H. (ORCID:0000000273864761)↗
DOE OSTI2018

Crystal structure of the human NK 1 tachykinin receptor

The NK 1 tachykinin G-protein–coupled receptor (GPCR) binds substance P, the first neuropeptide to be discovered in mammals. Through activation of NK 1 R, substance P modulates a wide variety of physiological and disease processes including nociception, inflammation, and depression. Human NK 1 R (hNK 1 R) modulators have shown promise in clinical trials for migraine, depression, and emesis. However, the only currently approved drugs targeting hNK 1 R are inhibitors for chemotherapy-induced nausea and vomiting (CINV). To better understand the molecular basis of ligand recognition and selectivity, we solved the crystal structure of hNK 1 R bound to the inhibitor L760735, a close analog of the drug aprepitant. Our crystal structure reveals the basis for antagonist interaction in the deep and narrow orthosteric pocket of the receptor. We used our structure as a template for computational docking and molecular-dynamics simulations to dissect the energetic importance of binding pocket interactions and model the binding of aprepitant. Furthermore, the structure of hNK 1 R is a valuable tool in the further development of tachykinin receptor modulators for multiple clinical applications.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2011

Canoe binds RanGTP to promote Pins TPR /Mud-mediated spindle orientation

Regulated spindle orientation maintains epithelial tissue integrity and stem cell asymmetric cell division. In Drosophila melanogaster neural stem cells (neuroblasts), the scaffolding protein Canoe (Afadin/Af-6 in mammals) regulates spindle orientation, but its protein interaction partners and mechanism of action are unknown. In this paper, we use our recently developed induced cell polarity system to dissect the molecular mechanism of Canoe-mediated spindle orientation. We show that a previously uncharacterized portion of Canoe directly binds the Partner of Inscuteable (Pins) tetratricopeptide repeat (TPR) domain. The Canoe–PinsTPR interaction recruits Canoe to the cell cortex and is required for activation of the PinsTPR-Mud (nuclear mitotic apparatus in mammals) spindle orientation pathway. We show that the Canoe Ras-association (RA) domains directly bind RanGTP and that both the Canoe RA domains and RanGTP are required to recruit Mud to the cortex and activate the Pins/Mud/dynein spindle orientation pathway.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Relaxed tarantula skeletal muscle has two ATP energy-saving mechanisms

Myosin molecules in the relaxed thick filaments of striated muscle have a helical arrangement in which the heads of each molecule interact with each other, forming the interacting-heads motif (IHM). In relaxed mammalian skeletal muscle, this helical ordering occurs only at temperatures >20°C and is disrupted when temperature is decreased. Recent x-ray diffraction studies of live tarantula skeletal muscle have suggested that the two myosin heads of the IHM (blocked heads [BHs] and free heads [FHs]) have very different roles and dynamics during contraction. Here, we explore temperature-induced changes in the BHs and FHs in relaxed tarantula skeletal muscle. We find a change with decreasing temperature that is similar to that in mammals, while increasing temperature induces a different behavior in the heads. At 22.5°C, the BHs and FHs containing ADP.Pi are fully helically organized, but they become progressively disordered as temperature is lowered or raised. Our interpretation suggests that at low temperature, while the BHs remain ordered the FHs become disordered due to transition of the heads to a straight conformation containing Mg.ATP. Above 27.5°C, the nucleotide remains as ADP.Pi, but while BHs remain ordered, half of the FHs become progressively disordered, released semipermanently at a midway distance to the thin filaments while the remaining FHs are docked as swaying heads. We propose a thermosensing mechanism for tarantula skeletal muscle to explain these changes. Our results suggest that tarantula skeletal muscle thick filaments, in addition to having a superrelaxation–based ATP energy-saving mechanism in the range of 8.5–40°C, also exhibit energy saving at lower temperatures (<22.5°C), similar to the proposed refractory state in mammals.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Museomics Dissects the Genetic Basis for Adaptive Seasonal Coloration in the Least Weasel

Abstract Dissecting the link between genetic variation and adaptive phenotypes provides outstanding opportunities to understand fundamental evolutionary processes. Here, we use a museomics approach to investigate the genetic basis and evolution of winter coat coloration morphs in least weasels (Mustela nivalis), a repeated adaptation for camouflage in mammals with seasonal pelage color moults across regions with varying winter snow. Whole-genome sequence data were obtained from biological collections and mapped onto a newly assembled reference genome for the species. Sampling represented two replicate transition zones between nivalis and vulgaris coloration morphs in Europe, which typically develop white or brown winter coats, respectively. Population analyses showed that the morph distribution across transition zones is not a by-product of historical structure. Association scans linked a 200-kb genomic region to coloration morph, which was validated by genotyping museum specimens from intermorph experimental crosses. Genotyping the wild populations narrowed down the association to pigmentation gene MC1R and pinpointed a candidate amino acid change cosegregating with coloration morph. This polymorphism replaces an ancestral leucine residue by lysine at the start of the first extracellular loop of the protein in the vulgaris morph. A selective sweep signature overlapped the association region in vulgaris, suggesting that past adaptation favored winter-brown morphs and can anchor future adaptive responses to decreasing winter snow. Using biological collections as valuable resources to study natural adaptations, our study showed a new evolutionary route generating winter color variation in mammals and that seasonal camouflage can be modulated by changes at single key genes.

Miranda, Inês↗
DOE OSTI2018

Broad Genomic Sampling Reveals a Smut Pathogenic Ancestry of the Fungal Clade Ustilaginomycotina

Ustilaginomycotina is home to a broad array of fungi including important plant pathogens collectively called smut fungi. Smuts are biotrophs that produce characteristic perennating propagules called teliospores, one of which, Ustilago maydis , is a model genetic organism. Broad exploration of smut biology has been hampered by limited phylogenetic resolution of Ustilaginiomycotina as well as an overall lack of genomic data for members of this subphylum. In this study, we sequenced eight Ustilaginomycotina genomes from previously unrepresented lineages, deciphered ordinal-level phylogenetic relationships for the subphylum, and performed comparative analyses. Unlike other Basidiomycota subphyla, all sampled Ustilaginomycotina genomes are relatively small and compact. Ancestral state reconstruction analyses indicate that teliospore formation was present at the origin of the subphylum. Divergence time estimation dates the divergence of most extant smut fungi after that of grasses (Poaceae). However, we found limited conservation of well-characterized genes related to smut pathogenesis from U. maydis , indicating dissimilar pathogenic mechanisms exist across other smut lineages. The genomes of Malasseziomycetes are highly diverged from the other sampled Ustilaginomycotina, likely due to their unique history as mammal-associated lipophilic yeasts. Despite extensive genomic data, the phylogenetic placement of this class remains ambiguous. Although the sampled Ustilaginomycotina members lack many core enzymes for plant cell wall decomposition and starch catabolism, we identified several novel carbohydrate active enzymes potentially related to pectin breakdown. Finally, ~50% of Ustilaginomycotina species-specific genes are present in previously undersampled and rare lineages, highlighting the importance of exploring fungal diversity as a resource for novel gene discovery.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Chemical Biology And Endomembrane Trafficking In Plants

Endomembrane trafficking is essential for coordinated growth and development in plants and response to environment. In particular, key plasma membrane proteins such as PIN auxin transporters and the BRI1 brassinosteroid receptor translocate dynamically between the endosomes and plasma membrane. We utilized a previously published large‐scale chemical library screening approach in which we identified small molecules that inhibited pollen germination or tube growth. This tip growth requires exocytosis, endocytosis and other endomembrane trafficking processes We then identified groups of small molecules that affect trafficking of PIN auxin transporters and other plasma membrane proteins in Arabidopsis roots. One of these compounds (ES2) targets the essential EXO70A1 component of the exocyst complex in Arabidopsis which is necessary for normal development. In Arabidopsis, there are 23 EXO70 genes (in mammals and yeast they are low copy number) where, among other roles, they appear to be involved in autophagy, cell division and pathogen responses. ES2 targets the exocyst complex in plants as well as mammals including humans where defective recycling/exocytosis have been correlated with disease. To our knowledge, ES2 is the first bioactive compound known to have this specificity. To examine exocytosis and its regulation in more detail, we have examined exo70 mutants, generated EXO70A1 structural data and are examining additional small molecules that may affect recycling/exocytosis. Support or Funding Information Acknowledgement: This work was supported by the US Department of Energy DE‐FG02‐02ER15295 (GRH, NVR).

Hicks, Glenn R.↗