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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 1,081 records · Page 60
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

A substrate-induced gating mechanism is conserved among Gram-positive IgA1 metalloproteases

The mucosal adaptive immune response is dependent on the production of IgA antibodies and particularly IgA1, yet opportunistic bacteria have evolved mechanisms to specifically block this response by producing IgA1 proteases (IgA1Ps). Our lab was the first to describe the structures of a metal-dependent IgA1P (metallo-IgA1P) produced from Gram-positive Streptococcus pneumoniae both in the absence and presence of its IgA1 substrate through cryo-EM single particle reconstructions. This prior study revealed an active-site gating mechanism reliant on substrate-induced conformational changes to the enzyme that begged the question of whether such a mechanism is conserved among the wider Gram-positive metallo-IgA1P subfamily of virulence factors. Here, we used cryo-EM to characterize the metallo-IgA1P of a more distantly related family member from Gemella haemolysans, an emerging opportunistic pathogen implicated in meningitis, endocarditis, and more recently bacteremia in the elderly. While the substrate-free structures of these two metallo-IgA1Ps exhibit differences in the relative starting positions of the domain responsible for gating substrate, the enzymes have similar domain orientations when bound to IgA1. Together with biochemical studies that indicate these metallo-IgA1Ps have similar binding affinities and activities, these data indicate that metallo-IgA1P binding requires the specific IgA1 substrate to open the enzymes for access to their active site and thus, largely conform to an “induced fit” model.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Targeting Enterococcus faecalis HMG-CoA reductase with a non-statin inhibitor

HMG-CoA reductase (HMGR), a rate-limiting enzyme of the mevalonate pathway in Gram-positive pathogenic bacteria, is an attractive target for development of novel antibiotics. In this study, we report the crystal structures of HMGR from Enterococcus faecalis (efHMGR) in the apo and liganded forms, highlighting several unique features of this enzyme. Statins, which inhibit the human enzyme with nanomolar affinity, perform poorly against the bacterial HMGR homologs. We also report a potent competitive inhibitor (Chembridge2 ID 7828315 or compound 315) of the efHMGR enzyme identified by a high-throughput, in-vitro screening. The X-ray crystal structure of efHMGR in complex with 315 was determined to 1.27 Å resolution revealing that the inhibitor occupies the mevalonate-binding site and interacts with several key active site residues conserved among bacterial homologs. Importantly, 315 does not inhibit the human HMGR. Our identification of a selective, non-statin inhibitor of bacterial HMG-CoA reductases will be instrumental in lead optimization and development of novel antibacterial drug candidates.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A ligand discovery toolbox for the WWE domain family of human E3 ligases

The WWE domain is a relatively under-researched domain found in twelve human proteins and characterized by a conserved tryptophan-tryptophan-glutamate (WWE) sequence motif. Six of these WWE domain-containing proteins also contain domains with E3 ubiquitin ligase activity. The general recognition of poly-ADP-ribosylated substrates by WWE domains suggests a potential avenue for development of Proteolysis-Targeting Chimeras (PROTACs). Here, we present novel crystal structures of the HUWE1, TRIP12, and DTX1 WWE domains in complex with PAR building blocks and their analogs, thus enabling a comprehensive analysis of the PAR binding site structural diversity. Furthermore, we introduce a versatile toolbox of biophysical and biochemical assays for the discovery and characterization of novel WWE domain binders, including fluorescence polarization-based PAR binding and displacement assays, 15 N-NMR-based binding affinity assays and 19 F-NMR-based competition assays. Through these assays, we have characterized the binding of monomeric iso -ADP-ribose ( iso -ADPr) and its nucleotide analogs with the aforementioned WWE proteins. Finally, we have utilized the assay toolbox to screen a small molecule fragment library leading to the successful discovery of novel ligands targeting the HUWE1 WWE domain.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Phylogenetic and ecological drivers of the avian lung mycobiome and its potentially pathogenic component

Vertebrate lungs contain diverse microbial communities, but little is known about the drivers of community composition or consequences for health. Microbiome assembly by processes such as dispersal, coevolution, and host-switching can be probed with comparative surveys; however, few studies exist for lung microbiomes, particularly for the fungal component, the mycobiome. Distinguishing among fungal taxa that are generalist or specialist symbionts, potential pathogens, or incidentally inhaled spores is urgent because of potential for emerging diseases. Here, we characterize the avian lung mycobiome and test the relative influences of environment, phylogeny, and functional traits. We used metabarcoding and culturing from 195 lung samples representing 32 bird species across 20 families. We identified 526 fungal taxa as estimated by distinct sequence types (zOTUs) including many opportunistic pathogens. These were predominantly from the phylum Ascomycota (79%) followed by Basidiomycota (16%) and Mucoromycota (5%). Yeast and yeast-like taxa (Malassezia, Filobasidium, Saccharomyces, Meyerozyma, and Aureobasidium) and filamentous fungi (Cladosporium, Alternaria, Neurospora, Fusarium, and Aspergillus) were abundant. Lung mycobiomes were strongly shaped by environmental exposure, and further modulated by host identity, traits, and phylogenetic affinities. Our results implicate migratory bird species as potential vectors for long-distance dispersal of opportunistically pathogenic fungi.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

A multi-omic characterization of the physiological responses to salt stress in Scenedesmus obliquus UTEX393

Scenedesmus obliquus UTEX393 is a promising microalgal candidate for sustainable biomanufacturing but its limited halotolerance hinders large-scale cultivation in saline environments. To investigate the molecular basis of salt stress responses, we conducted a comprehensive multi-omic analysis integrating genomics, transcriptomics, proteomics, lipidomics, metabolomics, and DNA affinity purification sequencing (DAP-seq). An improved nuclear genome assembly and annotation yielded 19,017 gene models and a 97% BUSCO completeness score, enabling construction of a genome-scale metabolic model. Comparing 15 ppt salinity stress to 5 ppt control, growth and productivity were significantly reduced, accompanied by widespread transcriptomic and proteomic changes. Transcriptomic analysis revealed downregulation of photosynthetic machinery and energy conservation genes, and upregulation of stress-responsive elements such as expansins, flavodoxins, and osmoprotectants. Lipidomic profiling showed accumulation of triacylglycerols (TAGs) and degradation of galactosyl lipids, consistent with a shift toward lipid biosynthesis to mitigate redox imbalance. Depletion of key polar metabolites and branched-chain amino acids suggested a rerouting of central carbon metabolism under stress. DAP-seq identified key transcription factors, including LHY1 and SPL12, that target central metabolic enzymes involved in redox balancing, such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and malate dehydrogenase (MDH). These findings establish a regulatory-metabolic framework linking redox stress to lipid accumulation and reveal potential engineering targets to enhance salt tolerance. Overall, the multi-omic analysis supports the “overflow” hypothesis, where impaired photosynthesis results in excess reducing equivalents being diverted into TAG synthesis and highlights transcriptional regulators as candidates for improving algal robustness in brackish environments.

09 BIOMASS FUELS↗
DOE OSTI2020

Developing scandium and yttrium coordination chemistry to advance theranostic radiopharmaceuticals

The octadentate siderophore analog 3,4,3-LI(1,2-HOPO), denoted 343-HOPO hereafter, is known to have high affinity for both trivalent and tetravalent lanthanide and actinide cations. Here we extend its coordination chemistry to the rare-earth cations Sc$^{3+}$ and Y$^{3+}$ and characterize fundamental metal–chelator binding interactions in solution via UV-Vis spectrophotometry, nuclear magnetic resonance spectroscopy, and spectrofluorimetric metal-competition titrations, as well as in the solid-state via single crystal X-ray diffraction. Sc$^{3+}$ and Y$^{3+}$ binding with 343-HOPO is found to be robust, with both high thermodynamic stability and fast room temperature radiolabeling, indicating that 343-HOPO is likely a promising chelator for in vivo applications with both metals. As a proof of concept, we prepared a $^{86}$Y-343-HOPO complex for in vivo PET imaging, and the results presented herein highlight the potential of 343-HOPO chelated trivalent metal cations for therapeutic and theranostic applications.

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

DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

The development of SARS-CoV-2 main protease (M pro ) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate M pro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of M pro . An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using M pro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of M pro with low nanomolar K i values. Furthermore, these compounds demonstrate efficacy against mutant forms of M pro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

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

N-type molecular doping of a semicrystalline conjugated polymer through cation exchange

Control of electrical doping is indispensable in any semiconductor device, and both efficient hole and electron doping are required for many devices. In organic semiconductors, however, electron doping has been essentially more problematic compared to hole doping because in general organic semiconductors have low electron affinities and require dopants with low ionization potentials that are often air-sensitive. Here, we adapt an efficient molecular doping method, so-called ion-exchange doping, to dope electrons in a polymeric semiconductor. We initially reduce the polymeric semiconductor using one electron transfer from molecular dopants, and then the ionized dopants in the resulting air-unstable films are replaced with secondary ions via cation exchange. Improved ambient stability and crystallinity of the doped polymeric semiconductors are achieved when a specific bulky molecular cation was chosen as the secondary ion, compared to conventional methods. The presented strategy can overcome the trade-off relationship between reducing capability and ambient stability in molecular dopants, and a wider selection of dopant ions will help to realize ambient-stable electron conductors.

36 MATERIALS SCIENCE↗
DOE OSTI2026

SmileyLlama: modifying large language models for directed chemical space exploration

Here we show that large language models (LLMs) can be transformed via supervised fine-tuning of engineered prompts into SmileyLlama for exploring the chemical space of drug molecules. We benchmark SmileyLlama against pretrained LLMs and chemical language models trained from scratch for generating valid and novel drug-like molecules, and use direct preference optimization to both improve SmileyLlama’s adherence to a prompt and as part of the iMiner reinforcement learning framework to predict molecules with optimized three-dimensional conformations and high binding affinity to drug targets. By training an LLM to speak directly as a chemical language model, while retaining most of its natural language capabilities, we show that SmileyLlama can reliably generate molecules with user-specified properties rather than acting only as a chatbot with knowledge of chemistry or as a virtual assistant. While SmileyLlama is geared toward drug discovery, the supervised fine-tuning/direct preference optimization/LLM framework can be extended to other chemical, biological and materials applications.

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

TbasCO: trait-based comparative ‘omics identifies ecosystem-level and niche-differentiating adaptations of an engineered microbiome

A grand challenge in microbial ecology is disentangling the traits of individual populations within complex communities. Various cultivation-independent approaches have been used to infer traits based on the presence of marker genes. However, marker genes are not linked to traits with complete fidelity, nor do they capture important attributes, such as the timing of gene expression or coordination among traits. To address this, we present an approach for assessing the trait landscape of microbial communities by statistically defining a trait attribute as a shared transcriptional pattern across multiple organisms. Leveraging the KEGG pathway database as a trait library and the Enhanced Biological Phosphorus Removal (EBPR) model microbial ecosystem, we demonstrate that a majority (65%) of traits present in 10 or more genomes have niche-differentiating expression attributes. For example, while many genomes containing high-affinity phosphorus transporter pstABCS display a canonical attribute (e.g. up-regulation under phosphorus starvation), we identified another attribute shared by many genomes where transcription was highest under high phosphorus conditions. Taken together, we provide a novel framework for unravelling the functional dynamics of uncultivated microorganisms by assigning trait-attributes through genome-resolved time-series metatranscriptomics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Pinning ångström-size solid ionic channels for rare-earth element separation

High-purity rare-earth elements are essential for modern technologies, yet current solvent extraction processes are energy-intensive and environmentally harmful because of inadequate selectivity and ligand toxicity. Although combining size exclusion and binding affinity can improve lanthanide separation, the role of long-range confinement remains underexplored. Here we report lanthanide separation in aqueous systems using extremely confined manganese oxide solid ionic channels with optimized layer spacing. Different lanthanides induce distinct solid-state phase transformations in manganese oxide, creating a strong driving force for separation. Two lanthanide groups, differing by ~1.4 Å in spacing, were identified and confirmed to be stable by density functional theory. The narrower confinement of heavier Group II lanthanides improves cross-group separation by increasing the dehydration barrier for lighter Group I lanthanides without inducing strong binding. Here, we further developed a strategy to pin the confinement dimensions and enhance same-group separation, increasing enrichment factors for La–Nd and La–Pr pairs from 1.6 ± 0.1 and 1.5 ± 0.1 to 5.4 ± 0.1 and 4.2 ± 0.1, respectively.

Chemical engineering↗
DOE OSTI2025

A bipartite bacterial virulence factor targets the complement system and neutrophil activation

Abstract The complement system and neutrophils constitute the two main pillars of the host innate immune defense against infection by bacterial pathogens. Here, we identify T-Mac, a novel virulence factor of the periodontal pathogen Treponema denticola that allows bacteria to evade both defense systems. We show that T-Mac is expressed as a pre-protein that is cleaved into two functional units. The N-terminal fragment has two immunoglobulin-like domains and binds with high affinity to the major neutrophil chemokine receptors FPR1 and CXCR1, blocking N -formyl-Met-Leu-Phe- and IL-8-induced neutrophil chemotaxis and activation. The C-terminal fragment functions as a cysteine protease with a unique proteolytic activity and structure, which degrades several components of the complement system, such as C3 and C3b. Murine infection studies further reveal a critical T-Mac role in tissue damage and inflammation caused by bacterial infection. Collectively, these results disclose a novel innate immunity-evasion strategy, and open avenues for investigating the role of cysteine proteases and immunoglobulin-like domains of gram-positive and -negative bacterial pathogens.

Kurniyati, Kurni↗
DOE OSTI2025

NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism

Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4’s AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4’s β-hairpin and histidine-helix motifs to the inner mitochondrial membrane. The structure further reveals a similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates. NMR and X-ray scattering (SAXS) solution measurements, mutational analyses, and biochemistry show that the substrate-mimicking AIF-interaction domain shields CHCHD4’s redox-sensitive active site. Disrupting this shield critically activates CHCHD4 substrate affinity and chaperone activity. Regulatory-domain sequestration by NADH-activated AIF directly stimulates chaperone binding and folding, revealing how AIF mediates CHCHD4 mitochondrial import. These results establish AIF as an integral component of the metazoan disulfide relay and point to NADH-activated dimeric AIF as an organizational import center for CHCHD4 and its substrates. Importantly, AIF regulation of CHCHD4 directly links AIF’s cellular NAD(H) sensing to CHCHD4 chaperone function, suggesting a mechanism to balance tissue-specific oxidative phosphorylation (OXPHOS) capacity with NADH availability.

Brosey, Chris A↗
DOE OSTI2020

Strapped calix[4]pyrroles: from syntheses to applications

Supramolecular chemistry is a central topic in modern chemistry. It touches on many traditional disciplines, such as organic chemistry, inorganic chemistry, physical chemistry, materials chemistry, environmental chemistry, and biological chemistry. Supramolecular hosts, inter alia macrocyclic hosts, play critical roles in supramolecular chemistry. Calix[4]pyrroles, non-aromatic tetrapyrrolic macrocycles defined by sp 3 hybridized meso bridges, have proved to be versatile receptors for neutral species, anions, and cations, as well as ion pairs. Compared to the parent system, octamethylcalix[4]pyrrole and its derivatives bearing simple appended functionalities, strapped calix[4]pyrroles typically display enhanced binding affinities and selectivities. In this review, we summarize advances in the design and synthesis of strapped calix[4]pyrroles, as well as their broad utility in molecular recognition, supramolecular extraction, separation technology, ion transport, and as agents capable of inhibiting cancer cell proliferation. Future challenges within this sub-field are also discussed.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Protein coating composition targets nanoparticles to leaf stomata and trichomes

Plant nanobiotechnology has the potential to revolutionize agriculture. However, the lack of effective methods to deliver nanoparticles (NPs) to the precise locations in plants where they are needed impedes these technological innovations. Here, model gold nanoparticles (AuNP) were coated with citrate, bovine serum albumin (BSA) as a protein control, or LM6-M, an antibody with an affinity for functional groups unique to stomata on leaf surfaces to deliver the AuNPs to stomata. One-month-old Vicia faba leaves were exposed via drop deposition to aqueous suspensions of LM6-M-coated AuNPs and allowed to air dry. After rinsing, Au distribution on the leaf surface was investigated by enhanced dark-field microscopy and X-ray fluorescence mapping. While citrate-coated AuNPs randomly covered the plant leaves, LM6M-AuNPs strongly adhered to the stomata and remained on the leaf surface after rinsing, and BSA-AuNPs specifically targeted trichome hairs. To the authors’ knowledge, this is the first report of active targeting of live leaf structures using NPs coated with molecular recognition molecules. Finally, this proof-of-concept study provides a strategy for future targeted nanopesticide delivery research.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Formation of resonances and anionic fragments upon electron attachment to benzaldehyde

Benzaldehyde is a simple aromatic aldehyde and has a wide range of applications in the food, pharmaceutical, and chemical industries. The positive electron affinity of this compound suggests that low-energy electrons can be easily trapped by neutral benzaldehyde. In the present study, we investigated the formation of negative ions following electron attachment to benzaldehyde in the gas-phase. Calculations on elastic electron scattering from benzaldehyde indicate a π* valence bound state of the anion at -0.48 eV and three π* shape resonances (0.78, 2.48 and 5.51 eV). The excited state spectrum of the neutral benzaldehyde is also reported to complement our findings. Using mass spectrometry, we observed the formation of the intact anionic benzaldehyde at ~0 eV. We ascribe the detection of the benzaldehyde anion to stabilization of the π* valence bound state upon dissociative electron attachment to a benzaldehyde dimer. In addition, we report the cross sections for nine fragment anions formed through electron attachment to benzaldehyde. Investigations carried out with partially deuterated benzaldehyde show that the hydrogen loss is site-selective with respect to the incident electron energy. In addition, we propose several dissociation pathways, backed up by quantum chemical calculations on their thermodynamic thresholds. The threshold calculations also support that the resonances formed at higher energies lead to fragment anions observable by mass spectrometry, whereas the resonances at low electron energies decay only by electron autodetachment.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

On the mechanism of soot nucleation

The mechanism of carbon particulate (soot) inception has been a subject of numerous studies and debates. The article begins with a critical review of prior proposals, proceeds to the analysis of factors enabling the development of a meaningful nucleation flux, and then introduces new ideas that lead to the fulfillment of these requirements. In the new proposal, a rotationally-activated dimer is formed in the collision of an aromatic molecule and an aromatic radical; the two react during the lifetime of the dimer to form a stable, doubly-bonded bridge between them, with the reaction rooted in a five-member ring present on the molecule edge. Several such reactions were examined theoretically and the most promising one generated a measurable nucleation flux. The consistency of the proposed model with known aspects of soot particle nanostructure is discussed. Here, the foundation of the new model is fundamentally the H-Abstraction-Carbon-Addition (HACA) mechanism with the reaction affinity enhanced by rotational excitation.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Energetics of CO 2 and H 2 O adsorption on alkaline earth metal doped TiO 2

The process of CO 2 and H 2 O adsorption on the surface of nano-oxide semiconductors is important in the overall performance of artificial photosynthesis and other applications. In this study, we explored the thermodynamics of CO 2 and H 2 O adsorption on TiO 2 as a function of surface chemistry. We applied gas adsorption calorimetry to investigate the energetics of adsorption of those molecules on the surface of anatase nanoparticles. In an attempt to increase TiO 2 surface affinity to CO 2 and H 2 O, TiO 2 was doped with alkaline earth metals (MgO, CaO, SrO, and BaO) by manipulating the chemical synthesis. Adsorption studies using diffuse reflectance infrared spectroscopy at different temperatures indicate that due to the segregation of alkaline earth metals on the surface of TiO 2 nanoparticles, both CO 2 and subsequent H2O adsorption amounts could be increased. CO 2 adsorbs in two different manners, forming carbonates which can be removed at temperatures lower than 700 °C, and a more stable linear adsorption that remains even at 700 °C. Additionally to the surface energetic effects, doping also increased specific surface area, resulting in further improvement in net gas adsorption.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗