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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 91 records · Page 5
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Development and validation of a quantitative proton NMR method for the analysis of pregnenolone

Pregnenolone (PREG) is an endogenous steroid frequently sold as an over-the-counter dietary supplement touted to promote neurological and immunological health. While the PREG dietary supplement is added to the diet for health benefits, there are no FDA approved PREG drugs. However, compounded PREG drug products are available to U.S. patients. The FDA works with state regulatory authorities on the oversight of compounding activities, including developing 503A and 503B lists of bulk substances that compounders are permitted to use. PREG is one of the substances publicly nominated to be included on the 503B list. Compounded hormone therapies such as those using PREG are of interest given the lack of standardization in compounded drug products which may increase the possibility of underdosing, overdosing, or contamination. However, no USP monograph currently exists to evaluate the quality of PREG drug substance or product. To address knowledge gaps and assist in quality control, a simple and rapid quantitative proton nuclear magnetic resonance spectroscopy (qNMR) method for the identification and assay of PREG in different types of PREG products was developed and validated. PREG samples were characterized using 1D 1 H and 2D 1 H– 13 C HSQC NMR spectra. The qNMR assay method (taking approximately 10 min per NMR spectrum) was validated for precision, accuracy, specificity, robustness and linearity per ICH Q2(R1) guidance. The method was validated in a range from 0.032 to 3.2 mg/mL. As a proof of concept, seven PREG bulk substance samples, three tablet and two capsule PREG dietary supplements were assessed by the qNMR analytical procedure. NMR data from all tested samples met the expected criteria for identification and assay. The results demonstrate the potential of qNMR for the quality assessment of different types of PREG samples.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Structure of maize BZR1-type β-amylase BAM8 provides new insights into its noncatalytic adaptation

Plant β-amylase (BAM) proteins play an essential role in growth, development, stress response, and hormone regulation. Despite their typical (β/α) 8 barrel structure as active catalysts in starch breakdown, catalytically inactive BAMs are implicated in diverse yet elusive functions in plants. Further, the noncatalytic BAM7/8 contain N-terminal BZR1 domains and were shown to be involved in the regulation of brassinosteroid signaling and possibly serve as sensors of yet an uncharacterized metabolic signal. While the structures of several catalytically active BAMs have been reported, structural characterization of the catalytically inactive BZR1-type BAMs remain unknown. Here, we determine the crystal structure of β-amylase domain of Zea mays BAM8/BES1/BZR1-5 and provide comprehensive insights into its noncatalytic adaptation. Using structural-guided comparison combined with biochemical analysis and molecular dynamics simulations, we revealed conformational changes in multiple distinct highly conserved regions resulting in rearrangement of the binding pocket. Altogether, this study adds a new layer of understanding to starch breakdown mechanism and elucidates the acquired adjustments of noncatalytic BZR1-type BAMs as putative regulatory domains and/or metabolic sensors in plants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Bacterial effectors mimicking ubiquitin-proteasome pathway tweak plant immunity

Plant pathogenic Gram-negative bacteria evade the host plant immune system by secreting Type III (T3E) and Type IV effector (T4E) proteins into the plant cytoplasm. Mostly T3Es are secreted into the plant cells to establish pathogenicity by affecting the vital plant process viz. metabolic pathways, signal transduction and hormonal regulation. Ubiquitin-26S proteasome system (UPS) exists as one of the important pathways in plants to control plant immunity and various cellular processes by employing several enzymes and enzyme components. Pathogenic and non-pathogenic bacteria are found to secrete effectors into plants with structural and/or functional similarity to UPS pathway components like ubiquitin E3 ligases, F-box domains, cysteine proteases, inhibitor of host UPS or its components, etc. The bacterial effectors mimic UPS components and target plant resistance proteins for degradation by proteasomes, thereby taking control over the host cellular activities as a strategy to exert virulence. Thus, the bacterial effectors circumvent plant cellular pathways leading to infection and disease development. Finally, this review highlights known bacterial T3E and T4E proteins that function and interfere with the ubiquitination pathway to regulate the immune system of plants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Extracellular vesicles in β cell biology: Role of lipids in vesicle biogenesis, cargo, and intercellular signaling

Background: Type 1 diabetes (T1D) is a complex autoimmune disorder whose pathogenesis involves an intricate interplay between ß cells of the pancreatic islet, other islet cells, and cells of the immune system. Direct intercellular communication within the islet occurs via cell surface proteins and indirect intercellular communication has traditionally been as occurring via secreted proteins (e.g., endocrine hormones and cytokines). However, recent literature suggests that extracellular vesicles (EVs) secreted by ß cells constitute an additional and biologically important mechanism for transmitting signals to adjacent ß cells or immune cells. Scope of Review: This review summarizes the general mechanisms of EV formation, with a particular focus on how lipids and lipid signaling pathways influence their formation and cargo. We review the implications of EV release from ß cells for T1D pathogenesis, how EVs and their cargo might be leveraged as biomarkers of the early events leading to T1D, and how EVs might be engineered as a therapeutic candidate to counter T1D outcomes. Major Conclusions: Islet ß cells have been viewed as initiators and propagators of the cellular circuit giving rise to autoimmunity in T1D. In this context, emerging literature suggests that EVs may represent a conduit for communication that holds more comprehensive messaging about the ß cells from which they arise. As the field of EV biology advances, it opens the possibility that intervening with EV formation and cargo loading could be a novel disease-modifying approach in T1D.

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

Do we owe our existence to gravitational waves?

Two heavy elements essential to human biology are thought to have been produced by the astrophysical r-process, which occurs in neutron-rich environments: iodine is a constituent of thyroid hormones that affect many physiological processes including growth and development, body temperature and heart rate, and bromine is essential for tissue development and architecture. Collisions of neutron stars (kilonovae) have been identified as sources of r-process elements including tellurium, which is adjacent to iodine in the periodic table, and lanthanides. Neutron-star collisions arise from energy loss due to gravitational-wave emission from binary systems, leading us to suggest that gravitational waves have played a key role in enabling human life by producing iodine and bromine. We propose probing this proposal by searching in lunar material for live 129 I deposited by a recent nearby kilonova explosion.

Human biochemistry↗
DOE OSTI2025

XERICO as a target for engineering stress-resilient crops: Mechanisms, applications, and future directions

XERICO's capacity to enhance ABA-driven stress responses across diverse crops, its regulatory crosstalk with other hormonal pathways, and its compatibility with advanced genetic engineering tools highlight its central role in sustainable agriculture. Leveraging XERICO in crop improvement programs aligns with the urgent need to mitigate the impacts of climate-induced stress in agriculture, offering a pathway toward resilient and high-yielding crops. Here, by enabling crops to withstand drought and other environmental stresses, XERICO-based biotechnological approaches hold transformative potential for global food security and environmental sustainability.

09 BIOMASS FUELS↗
DOE OSTI2023

Structural asymmetry in FGF23 signaling

Chen et al. have derived cryogenic electron microscopy (cryo-EM) structures of signaling complexes of the endocrine hormone fibroblast growth factor 23 (FGF23) with fibroblast growth factor receptor (FGFR), α-Klotho, and heparin sulfate. Furthermore, these structures are asymmetric, leading to questions concerning in vivo function, and will facilitate structure-based drug design to modulate FGF23 signaling.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Assembly of JAZ–JAZ and JAZ–NINJA complexes in jasmonate signaling

Jasmonates (JAs) are plant hormones with crucial roles in development and stress resilience. They activate MYC transcription factors by mediating the proteolysis of MYC inhibitors called JAZ proteins. In the absence of JA, JAZ proteins bind and inhibit MYC through the assembly of MYC–JAZ–Novel Interactor of JAZ (NINJA)–TPL repressor complexes. However, JAZ and NINJA are predicted to be largely intrinsically unstructured, which has precluded their experimental structure determination. Through a combination of biochemical, mutational, and biophysical analyses and AlphaFold-derived ColabFold modeling, we characterized JAZ–JAZ and JAZ–NINJA interactions and generated models with detailed, high-confidence domain interfaces. We demonstrate that JAZ, NINJA, and MYC interface domains are dynamic in isolation and become stabilized in a stepwise order upon complex assembly. By contrast, most JAZ and NINJA regions outside of the interfaces remain highly dynamic and cannot be modeled in a single conformation. Our data indicate that the small JAZ Zinc finger expressed in Inflorescence Meristem (ZIM) motif mediates JAZ–JAZ and JAZ–NINJA interactions through separate surfaces, and our data further suggest that NINJA modulates JAZ dimerization. This study advances our understanding of JA signaling by providing insights into the dynamics, interactions, and structure of the JAZ–NINJA core of the JA repressor complex.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

MPK6-mediated phosphorylation destabilizes MYC2 and attenuates its transcriptional activity in jasmonate signaling

Given the role of MYC2 as a pivotal regulator in the jasmonate (JA) signaling pathway, influencing the expression of a multitude of downstream genes (Zander et al., 2020), understanding the regulatory dynamics of MYC2 is essential for unraveling plant responses to stress conditions and hormonal signals. Previous studies on the regulation of MYC2 by MPK6 have reported conflicting findings. Takahashi et al. (2007) reported that MPK6 acts as a negative regulator of MYC2, whereas Sethi et al. (2014) proposed a positive regulatory role. Despite these findings, the precise genetic and biochemical mechanisms underlying the MPK6–MYC2 interaction remain poorly understood, highlighting the need for further investigation.

Im, Jong Hee [Michigan State University, East Lans↗
DOE OSTI2021

Fractalkine enhances endometrial receptivity and activates iron transport towards trophoblast cells in an in vitro co-culture system of HEC-1A and JEG-3 cells

Highlights: • Fractalkine activates SOX-17 and the NRF2-Keap-1 system in HEC-1A endometrium cells. • Fractalkine triggers IL-6 and IL-1β cytokine secretions contributing endometrium receptivity. • Fractalkine regulates iron homeostasis of endometrium. • Fractalkine contributes to the iron availability of the trophoblast cells. Endometrium receptivity and successful implantation require a complex network of regulatory factors whom production is strictly controlled especially at the implantation window. Many regulators like steroid hormones, prostaglandins, cytokines, extracellular matrix proteins and downstream cell signalling pathways are involved in the process of embryo-endometrium interaction. Our work reveals the effect of fractalkine (FKN), a unique chemokine on progesterone receptor, SOX-17 and NRF2 expressions in HEC-1A endometrial cell line. FKN activates fractalkine receptor signalling and the expression of SOX-17 through progesterone receptor in HEC-1A endometrial cells, and as a consequence it increases endometrial receptivity. Fractalkine also activates the NRF2-Keap-1 signal transduction pathway regulating the IL-6 and IL-1β cytokine productions, which increase endometrial receptivity, as well. The NRF2 transcription factor increases the expression of the iron exporter ferroportin in HEC-1A cells activating iron release towards JEG-3 trophoblast cells. The iron measurements show that iron content of endometrial cells decreases while heme concentration increases at FKN treatment. At the same time, the trophoblast cells show increased iron uptake and total iron content. Based on our results it seems that FKN enhances the establishment of endometrial receptivity and meanwhile it regulates the iron homeostasis of endometrium contributing to the iron availability of the trophoblast cells and the embryo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Expression of membrane protein disulphide isomerase A1 (PDIA1) disrupt a reducing microenvironment in endometrial epithelium for embryo implantation

Various proteins in the endometrial epithelium are differentially expressed in the receptive phase and play a pivotal role in embryo implantation. The Protein Disulphide Isomerase (PDI) family contains 21 members that function as chaperone proteins through their redox activities. Although total PDIA1 protein expression was high in four common receptive (Ishikawa and RL95-2) and non-receptive (HEC1-B and AN3CA) endometrial epithelial cell lines, significantly higher membrane PDIA1 expression was found in non-receptive AN3CA cells. In Ishikawa cells, oestrogen up-regulated while progesterone down-regulated membrane PDIA1 expression. Moreover, mid-luteal phase hormone treatment down-regulated membrane PDIA1 expression. Furthermore, oestrogen at 10 nM reduced spheroid attachment on Ishikawa cells. Interestingly, inhibition of PDIA1 function by bacitracin or 16F16 increased the spheroid attachment rate onto non-receptive AN3CA cells. Over-expression of PDIA1 in receptive Ishikawa cells reduced the spheroid attachment rate and significantly down-regulated integrin β3 levels, but not integrin αV and E-cadherin. Addition of reducing agent TCEP induced a sulphydryl-rich microenvironment and increased spheroid attachment onto AN3CA cells and human primary endometrial epithelial cells collected at LH+7/8 days. The luminal epithelial cells from human endometrial biopsies had higher PDIA1 protein expression in the proliferative phase than in the secretory phase. Our findings suggest oestrogen and progesterone regulate PDIA1 expression, resulting in the differential expressions of membrane PDIA1 protein to modulate endometrial receptivity. This suggests that membrane PDIA1 expression prior to embryo transfer could be used to predict endometrial receptivity and embryo implantation in women undergoing assisted reproduction treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Phylogenomics reveals convergent evolution of red-violet coloration in land plants and the origins of the anthocyanin biosynthetic pathway

The flavonoids, one of the largest classes of plant secondary metabolites, are found in lineages that span the land plant phylogeny and play important roles in stress responses and as pigments. Perhaps the most well-studied flavonoids are the anthocyanins that have human health benefits and help plants attract pollinators, regulate hormone production, and confer resistance to abiotic and biotic stresses. The canonical biochemical pathway responsible for the production of these pigments is well-characterized for flowering plants yet its conservation across deep divergences in land plants remains debated and poorly understood. Many early land plants such as mosses, liverworts, and ferns produce flavonoid pigments, but their biosynthetic origins and homologies to the anthocyanin pathway remain uncertain. We conducted phylogenetic analyses using full genome sequences representing nearly all major green plant lineages to reconstruct the evolutionary history of the anthocyanin biosynthetic pathway then test the hypothesis that genes in this pathway are present in early land plants. We found that the entire pathway was not intact until the most recent common ancestor of seed plants and that orthologs of many downstream enzymes are absent from seedless plants including mosses, liverworts, and ferns. Our results also highlight the utility of phylogenetic inference, as compared to pairwise sequence similarity, in orthology assessment within large gene families that have complex duplication-loss histories. Here, we suggest that the production of red-violet flavonoid pigments widespread in seedless plants, including the 3-deoxyanthocyanins, requires the activity of novel, as-yet discovered enzymes, and represents convergent evolution of red-violet coloration across land plants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Data-Driven Discovery of Linear Molecular Probes with Optimal Selective Affinity for PFAS in Water

Approaches to tackle the wide and growing variety of highly persistent per- and polyfluoroalkyl substances (PFAS) are of pressing global need because of their detrimental human health effects, such as cancer, birth defects, and hormone imbalance. Sensitive, selective, and easy-to-use real-time sensors to monitor and detect PFAS and sorbents to extract them are critical to meeting government-mandated environmental concentrations. In this work, we combine all-atom molecular dynamics simulations, enhanced sampling, deep representational learning, and Bayesian optimization to perform high-throughput virtual screening for highly sensitive and selective molecular probes. Our molecular design space consists of 3850 linear hydrocarbon chains with varying degrees of halogenation with and without amine- and phosphine-based headgroups. By employing a data-driven search process, we efficiently explore the molecular design space to optimize the sensitivity to perfluorooctanesulfonic acid (PFOS) as a prototypical PFAS analyte and selectivity relative to a sodium dodecyl sulfate (SDS) interferent. We calculate 504 Gibbs free energies of probe-analyte and probe-interferent interactions and identify probes with PFOS association free energies of up to (-ΔG PFOS ) = 9.8 ± 0.2 kJ/mol and selectivities relative to SDS of (-ΔΔG PFOS–SDS ) = 3.1 ± 1.5 kJ/mol. A C 11 Br 23 P(CH 3 ) 2 probe containing 11 backbone brominated carbons and a tertiary phosphine headgroup possesses the most sensitive binding constant to PFOS within the defined search space of K b PFOS = 177.4 ± 12.7, and a semibrominated probe C 5 H 11 C 7 Br 14 N(CH 3 ) 2 containing 12 backbone carbons and a tertiary amine headgroup possesses the highest selectivity relative to SDS of K b PFOS /K b SDS = 4.6 ± 1.7. A retrospective analysis of our data to extract interpretable design rules reveals that the sensitivity of linear hydrogenated probes increases by approximately 1 kJ/mol per C–C bond. The addition or removal of halogen atoms and amine or phosphine headgroups produces nonmonotonic changes in both sensitivity and selectivity with changes to the sensitivity of up to 2.5 kJ/mol. Finally, this work places empirical limitations on the performance of a wide range of linear probes for PFOS detection and offers a generic strategy for high-throughput computational screening to promote selective and sensitive binding.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Melatonin-Induced Modulation of Cholesterol-Enriched Model Neuronal Membranes

Melatonin, a hormone primarily produced by the brain’s pineal gland, not only regulates circadian rhythms, but also influences the structural and biophysical properties of neuronal membranes. Its amphiphilic nature enables direct incorporation into lipid bilayers and preferential interactions with cholesterol-rich lipid rafts, critical hubs for cellular signaling and membrane organization. Despite increasing recognition of its membrane activity, the molecular basis of melatonin’s interactions with coexisting liquid-ordered (L o ) and liquid-disordered (L d ) phases remains unclear. Here, in this study, we combine small-angle neutron scattering (SANS) and all-atom molecular dynamics simulations to examine model neuronal membranes composed of DSPC, DOPC, POPC, and cholesterol. Our results show that melatonin preserves domain morphology while adopting distinct orientations within the bilayer and at the membrane interface, allowing both lateral and transmembrane bridging across lipid phases. These findings establish the molecular underpinnings of melatonin’s modulation of membrane heterogeneity and provide strong support for its receptor-independent actions.

atomistic simulations↗
DOE OSTI2021

A Thioether-Ligated Cupric Superoxide Model with Hydrogen Atom Abstraction Reactivity

The central role of cupric superoxide intermediates proposed in hormone and neurotransmitter biosynthesis by noncoupled binuclear copper monooxygenases like dopamine-β-monooxygenase has drawn significant attention to the unusual methionine ligation of the Cu M (“Cu B ”) active site characteristic of this class of enzymes. The copper–sulfur interaction has proven critical for turnover, raising still-unresolved questions concerning Nature’s selection of an oxidizable Met residue to facilitate C–H oxygenation. We describe herein a model for Cu M , [( TMG N 3 S)Cu I ] + ([1] + ), and its O 2 -bound analog [( TMG N 3 S)Cu II (O 2 •– )] + ([1·O 2 ] + ). The latter is the first reported cupric superoxide with an experimentally proven Cu–S bond which also possesses demonstrated hydrogen atom abstraction (HAA) reactivity. Introduction of O2 to a precooled solution of the cuprous precursor [1]B(C 6 F 5 ) 4 (-135 °C, 2-methyltetrahydrofuran (2-MeTHF)) reversibly forms [1·O 2 ]B(C 6 F 5 ) 4 (UV/vis spectroscopy: λ max 442, 642, 742 nm). Resonance Raman studies (413 nm) using 16 O 2 [ 18 O 2 ] corroborated the identity of [1·O 2 ] + by revealing Cu–O (446 [425] cm –1 ) and O–O (1105 [1042] cm –1 ) stretches, and extended X-ray absorption fine structure (EXAFS) spectroscopy showed a Cu–S interatomic distance of 2.55 Å. HAA reactivity between [1·O 2 ] + and TEMPO–H proceeds rapidly (1.28 × 10 –1 M –1 s –1 , -135 °C, 2-MeTHF) with a primary kinetic isotope effect of kH/kD = 5.4. Comparisons of the O 2 -binding behavior and redox activity of [1] + vs [2] + , the latter a close analog of [1]+ but with all N atom ligation (i.e., N 3 S vs N 4 ), are presented.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Integrative genomics reveals paths to sex dimorphism in Salix purpurea L

Sex dimorphism and gene expression were studied in developing catkins in 159 F 2 individuals from the bioenergy crop Salix purpurea , and potential mechanisms and pathways for regulating sex development were explored. Differential expression, eQTL, bisulfite sequencing, and network analysis were used to characterize sex dimorphism, detect candidate master regulator genes, and identify pathways through which the sex determination region (SDR) may mediate sex dimorphism. Eleven genes are presented as candidates for master regulators of sex, supported by gene expression and network analyses. These include genes putatively involved in hormone signaling, epigenetic modification, and regulation of transcription. eQTL analysis revealed a suite of transcription factors and genes involved in secondary metabolism and floral development that were predicted to be under direct control of the sex determination region. Furthermore, data from bisulfite sequencing and small RNA sequencing revealed strong differences in expression between males and females that would implicate both of these processes in sex dimorphism pathways. These data indicate that the mechanism of sex determination in Salix purpurea is likely different from that observed in the related genus Populus . This further demonstrates the dynamic nature of SDRs in plants, which involves a multitude of mechanisms of sex determination and a high rate of turnover.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding

Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception. However, an inhibitor against this kinase with exquisite selectivity has not reached the market because of the structural similarity between CDKs. In this paper, we describe the development and mechanism of action of type III inhibitors that bind CDK2 with nanomolar affinity. Notably, these anthranilic acid inhibitors exhibit a strong negative cooperative relationship with cyclin binding, which remains an underexplored mechanism for CDK2 inhibition. Furthermore, the binding profile of these compounds in both biophysical and cellular assays demonstrate the promise of this series for further development into a therapeutic selective for CDK2 over highly similar kinases like CDK1. The potential of these inhibitors as contraceptive agents is seen by incubation with spermatocyte chromosome spreads from mouse testicular explants, where they recapitulate Cdk2 -/- and Spdya -/- phenotypes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Structure and growth of plant cell walls

Plant cells build nanofibrillar walls that are central to plant growth, morphogenesis and mechanics. Starting from simple sugars, three groups of polysaccharides, namely, cellulose, hemicelluloses and pectins, with very different physical properties are assembled by the cell to make a strong yet extensible wall. Here, this Review describes the physics of wall growth and its regulation by cellular processes such as cellulose production by cellulose synthase, modulation of wall pH by plasma membrane H + -ATPase, wall loosening by expansin and signalling by plant hormones such as auxin and brassinosteroid. In addition, this Review discusses the nuanced roles, properties and interactions of cellulose, matrix polysaccharides and cell wall proteins and describes how wall stress and wall loosening cooperatively result in cell wall growth.

59 BASIC BIOLOGICAL SCIENCES↗