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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 739 records · Page 41
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Integrative mapping reveals molecular features underlying the mechanism of nucleocytoplasmic transport

Nuclear pore complexes (NPCs) enable rapid, selective, and robust nucleocytoplasmic transport. To explain how transport emerges from the system components and their interactions, we used experimental data and theoretical information to construct an integrative Brownian dynamics model of transport through an NPC, coupled to a kinetic model of transport in the cell. The model recapitulates key aspects of transport for a wide range of molecular cargoes, including preribosomes and viral capsids. Our model quantifies how flexible phenylalanine-glycine (FG) repeat proteins create an entropic barrier to passive diffusion and how this barrier is selectively lowered in facilitated diffusion by the many transient interactions of nuclear transport receptors with the FG repeats. Selective transport is enhanced by “fuzzy” multivalent interactions, redundant FG repeat mass, coupling to the energy-dependent RanGTP concentration gradient, and exponential dependence of transport kinetics on the transport barrier. Our model will facilitate rational modulation of the NPC and its artificial mimics.

Raveh, Barak [School of Computer Science and Engin↗
DOE OSTI2025

Pooled PPIseq: Screening the SARS-CoV-2 and human interface with a scalable multiplexed protein-protein interaction assay platform

Protein-Protein Interactions (PPIs) are a key interface between virus and host, and these interactions are important to both viral reprogramming of the host and to host restriction of viral infection. In particular, viral-host PPI networks can be used to further our understanding of the molecular mechanisms of tissue specificity, host range, and virulence. At higher scales, viral-host PPI screening could also be used to screen for small-molecule antivirals that interfere with essential viral-host interactions, or to explore how the PPI networks between interacting viral and host genomes co-evolve. Current high-throughput PPI assays have screened entire viral-host PPI networks. However, these studies are time consuming, often require specialized equipment, and are difficult to further scale. Here, we develop methods that make larger-scale viral-host PPI screening more accessible. This approach combines the mDHFR split-tag reporter with the iSeq2 interaction-barcoding system to permit massively-multiplexed PPI quantification by simple pooled engineering of barcoded constructs, integration of these constructs into budding yeast, and fitness measurements by pooled cell competitions and barcode-sequencing. We applied this method to screen for PPIs between SARS-CoV-2 proteins and human proteins, screening in triplicate >180,000 ORF-ORF combinations represented by >1,000,000 barcoded lineages. Our results complement previous screens by identifying 74 putative PPIs, including interactions between ORF7A with the taste receptors TAS2R41 and TAS2R7, and between NSP4 with the transmembrane KDELR2 and KDELR3. We show that this PPI screening method is highly scalable, enabling larger studies aimed at generating a broad understanding of how viral effector proteins converge on cellular targets to effect replication.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1972

Theoretical aspects of color vision

The three color receptors of Young-Helmholtz and the opponent colors type of information processing postulated by Hering are both present in the human visual system. This mixture accounts for both the phenomena of color matching or hue discrimination and such perceptual qualities of color as the division of the spectrum into color bands. The functioning of the cells in the visual system, especially within the retina, and the relation of this function to color perception are discussed.

Wolbarsht, M. L.↗
NASA NTRS2003

Expression and function of FGF10 in mammalian inner ear development

We have investigated the expression of FGF10 during ear development and the effect of an FGF10 null mutation on ear development. Our in situ hybridization data reveal expression of FGF10 in all three canal crista sensory epithelia and the cochlea anlage as well as all sensory neurons at embryonic day 11.5 (E11.5). Older embryos (E18.5) displayed strong graded expression in all sensory epithelia. FGF10 null mutants show complete agenesis of the posterior canal crista and the posterior canal. The posterior canal sensory neurons form initially and project rather normally by E11.5, but they disappear within 2 days. FGF10 null mutants have no posterior canal system at E18.5. In addition, these mutants have deformations of the anterior and horizontal cristae, reduced formation of the anterior and horizontal canals, as well as altered position of the remaining sensory epithelia with respect to the utricle. Hair cells form but some have defects in their cilia formation. No defects were detected in the organ of Corti at the cellular level. Together these data suggest that FGF10 plays a major role in ear morphogenesis. Most of these data are consistent with earlier findings on a null mutation in FGFR2b, one of FGF10's main receptors. Copyright 2003 Wiley-Liss, Inc.

NASA Discipline Developmental Biology↗
NASA NTRS1991

Plant gravity sensing

This review of plant gravity sensing examines sensing in organ gravitropism, sensing in single-cell gravitropism, and nongravitropic sensing. Topics related to sensing in organ gravitropism are (1) identification of the gravitropic susceptors, including intracellular asymmetry in equilibrium position and after reorientation, susceptor signal-to-noise ratio, signal integration over threshold stimulation periods, intracellular asymmetry and gravitropic competence, and starch deficiency and gravitropic competence; (2) possible root statocytes and receptors, including identification of presumptive statocytes, cytology, and possible receptors and models of sensing; and (3) negatively gravitropic organs, including identification and distribution of presumptive statocytes and cytology and possible receptors. Topics related to nongravitropic sensing include gravitaxis, reaction wood, gravimorphogenesis, other gravity-influenced organ movements, and cytoplasmic streaming.

Non-NASA Center↗
DOE OSTI2021

The minor pilin PilV provides a conserved adhesion site throughout the antigenically variable meningococcal type IV pilus

Type IV pili (T4P) are among the most widespread adhesive factors in prokaryotes. In pathogenic Neisseria, the major pilin, which provides the structural framework for the filamentous T4P, undergoes antigenic variation allowing the bacteria to evade the humoral immune response without impacting host-cell adhesion. Here, we show that a minor pilin, PilV, is distributed throughout the pilus and contributes to Neisseria meningitidis adhesion and that antibodies to PilV block meningococcal adhesion in vivo. Our results provide a mechanism whereby N. meningitidis varies its immunodominant major pilin to escape antibody recognition while maintaining conserved sites throughout the pilus for host receptor binding. They further suggest a strategy to prevent or block deadly N. meningitidis infections by targeting this minor pilin.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Investigating the Theranostic Potential of Elementally Matched [ 43 Sc]Sc-PSMA-617 and [ 47 Sc]Sc-PSMA-617

The theranostic approach, which employs diagnostic radiopharmaceuticals to select patients who would benefit from targeted radiotherapy agents, has become an invaluable strategy for effective medical care. Scandium radionuclides offer the advantage of forming elementally matched and chemically identical diagnostic and therapeutic compounds, making them ideal candidates for this strategy. PSMA-617 is an established prostate-specific membrane antigen targeting agent and can be used as a proof of concept to investigate 43 Sc, the diagnostic nuclide, and 47 Sc, the therapeutic nuclide, as a theranostic pair. Methods: Cellular uptake, competitive binding assays, and internalization studies were carried out using LNCaP or PC-3 cell lines. [ 43 Sc]Sc-PSMA-617 was used in PET imaging studies in LNCaP or PC-3 tumor models, with time points ranging from 1–9 h. LNCaP tumor-bearing mice injected with [ 47 Sc]Sc-PSMA-617 were imaged using SPECT up to 48 h. A longitudinal study was carried out using LNCaP tumor-bearing mice imaged with [ 43 Sc]Sc-PSMA-617 prior to receiving a therapeutic dose of [ 47 Sc]Sc-PSMA-617. Results: 43 Sc and 47 Sc were incorporated into PSMA-617 at radiochemical yields of >99%. Cellular uptake studies demonstrated high uptake and specificity to PSMA receptors for [ 47 Sc]Sc-PSMA-617. In vivo PET studies showed specificity of [ 43 Sc]Sc-PSMA-617 while SPECT studies demonstrated tumor retention of [ 47 Sc]Sc-PSMA-617 up to 48 h. [ 47 Sc]Sc-PSMA-617 demonstrated therapeutic efficacy by delaying tumor growth and increasing survival rates from a single administered dose in xenograft models. More importantly, the PET results from [ 43 Sc]Sc-PSMA-617 PET were highly correlated with the therapeutic response from [ 47 Sc]Sc-PSMA-617, showing that 43 Sc PET data can predict therapeutic outcomes in individual animals from 47 Sc agents, even in animals sharing a genetic background and implanted with tumors from the same cell line. Conclusions: Two chemically identical, PSMA-targeting radioscandium pharmaceuticals demonstrated in vivo stability, specificity and retention in PSMA+ tumor models. A theranostic study showed that a higher 43 Sc PET SUVmean was strongly correlated to therapeutic response from the 47 Sc agent, demonstrating that 43 Sc and 47 Sc can be used as an elementally matched theranostic pair.

Biodistribution↗
DOE OSTI2023

Structure-based design of nanobodies that inhibit seeding of Alzheimer’s patient–extracted tau fibrils

Despite much effort, antibody therapies for Alzheimer’s disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood–brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

GDF15: a potential therapeutic target for type 1 diabetes

Type 1 Diabetes (T1D) is a pancreatic disease, which is marked by immune-mediated ? cell destruction causing hyperglycemic phenotype. Recently, our team has demonstrated the beneficial role of GDF15 in preventing T1D-associated insulitis. Therefore, in this review, we discuss the therapeutic potential of GDF15 in treating T1D and map the promising avenues demanding increased focus in this field. Areas covered: Several therapeutic options exist for management of T1D, however, the demand for new and efficient therapies persists, particularly for interventions that may prevent or delay disease onset. Growth differentiation factor 15 (GDF15) is a known diabetes biomarker which has shown impressive tissue-protective actions across a broad range of metabolic disorders. There is a tremendous amount of overlap between the two topics (GDF15 & T1D), however, the connections were uncharted. We discuss all these connections and the possibility of exploiting them to make GDF15 a T1D therapy. Expert Opinion: The newly discovered GDF15 primary receptor and associated signaling pathway has accelerated the excitement by making it a druggable target. However, the there exists a huge gap in knowledge regarding the mechanism by which GDF15 functions in the peripheral tissues. In this context, reports of GDF15 receptor in pancreas, gives a convincing argument of direct GDF15 effect. Further, GDF15’s role in regulating mitochondrial, ER and metabolic stress, makes it an ideal T1D candidate.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

cotH Genes Are Necessary for Normal Spore Formation and Virulence in Mucor lusitanicus

Mucormycosis is an invasive fungal infection caused by certain members of the fungal order of Mucorales. The species most frequently identified as the etiological agents of mucormycosis belong to the genera Rhizopus , Lichtheimia , and Mucor . The frequency of systemic mucormycosis has been increasing, mainly because of increasing numbers of susceptible patients. Furthermore, Mucorales display intrinsic resistance to the majority of routinely used antifungal agents (e.g., echinocandins and short-tailed azoles), which limits the number of possible therapeutic options. All the above-mentioned issues urge the improvement of molecular identification methods and the discovery of new antifungal targets and strategies. Spore coat proteins (CotH) constitute a kinase family present in many pathogenic bacteria and fungi and participate in the spore formation in these organisms. Moreover, some of them can act as virulence factors being receptors of the human GRP78 protein during Rhizopus delemar-induced mucormycosis. We identified 17 cotH -like genes in the Mucor lusitanicus genome database. Successful disruption of five cotH genes in Mucor was performed using the CRISPR-Cas9 system. The CotH3 and CotH4 proteins play a role in adaptation to different temperatures as well as in developing the cell wall structure. We also show CotH4 protein is involved in spore wall formation by affecting the total chitin content and, thus, the composition of the spore wall. The role of CotH3 and CotH4 proteins in virulence was confirmed in two invertebrate models and a diabetic ketoacidosis (DKA) mouse model.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR

Abstract Bromodomain and extraterminal (BET) proteins are extensively studied in multiple pathologies, including cancer. BET proteins modulate transcription of various genes, including those synonymous with cancer, such as MYC. Thus, BET inhibitors are a major area of drug development efforts. (+)-JQ1 (JQ1) is the prototype inhibitor and is a common tool to probe BET functions. While showing therapeutic promise, JQ1 is not clinically usable, partly due to metabolic instability. Here, we show that JQ1 and the BET-inactive (−)-JQ1 are agonists of pregnane X receptor (PXR), a nuclear receptor that transcriptionally regulates genes encoding drug-metabolizing enzymes such as CYP3A4, which was previously shown to oxidize JQ1. A PXR-JQ1 co-crystal structure identified JQ1′s tert-butyl moiety as a PXR anchor and explains binding by (−)-JQ1. Analogs differing at the tert-butyl lost PXR binding, validating our structural findings. Evaluation in liver cell models revealed both PXR-dependent and PXR-independent modulation of CYP3A4 expression by BET inhibitors. We have characterized a non-BET JQ1 target, a mechanism of physiological JQ1 instability, a biological function of (−)-JQ1, and BET-dependent transcriptional regulation of drug metabolism genes.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1999

Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter uptake and release and produces learning and memory deficits in rats

A substantial body of evidence indicates that aged-related changes in the fluidity and lipid composition of the plasma membrane contribute to cellular dysfunction in humans and other mammalian species. In the CNS, reductions in neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity) have been attributed to age as well as the presence of the beta-amyloid peptide-25-35, known to play an important role in the neuropathology of Alzheimer's disease (AD). These PMO increases may influence neurotransmitter synthesis, receptor binding, and second messenger systems as well as signal transduction pathways. The effects of neuronal PMO on learning and memory processes have not been adequately investigated, however. Based on the hypothesis that an increase in PMO may alter a number of aspects of synaptic transmission, we investigated several neurochemical and behavioral effects of the membrane ordering agent, PF-68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced [3H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced nicotine stimulated [3H]NE release. The compound (800-2400 microg/kg, i.p., resulting in nmoles/mg SDS extractable protein in the brain) decreased step-through latencies and increased the frequencies of crossing into the unsafe side of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68 increased the latencies and swim distances required to locate a hidden platform and reduced the time spent and distance swam in the previous target quadrant during transfer (probe) trials. PF-68 did not impair performance of a well-learned working memory task, the rat delayed stimulus discrimination task (DSDT), however. Studies with 14C-labeled PF-68 indicated that significant (pmoles/mg wet tissue) levels of the compound entered the brain from peripheral (i.p.) injection. No PF-68 related changes were observed in swim speeds or in visual acuity tests in water maze experiments, rotorod performance, or in tests of general locomotor activity. Furthermore, latencies to select a lever in the DSDT were not affected. These results suggest that PF-68 induced deficits in learning and memory without confounding peripheral motor, sensory, or motivational effects at the tested doses. Furthermore, none of the doses induced a conditioned taste aversion to a novel 0.1% saccharin solution indicating a lack of nausea or gastrointestinal malaise induced by the compound. The data indicate that increases in neuronal plasma membrane order may have significant effects on neurotransmitter function as well as learning and memory processes. Furthermore, compounds such as PF-68 may also offer novel tools for studying the role of neuronal PMO in mnemonic processes and changes in PMO resulting from age-related disorders such as AD.

Poloxamer/pharmacology↗
NASA NTRS2001

Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury

The p38 stress-activated protein kinase pathway is involved in regulation of phosphorylation of Hsp25, which in turn regulates actin filament dynamic in non-neuronal cells. We report that p38, Hsp25 and Akt signaling pathways were specifically activated in spinal motor neurons after sciatic nerve axotomy. The activation of the p38 kinase was required for induction of Hsp25 expression. Furthermore, Hsp25 formed a complex with Akt, a member of PI-3 kinase pathway that prevents neuronal cell death. Together, our observations implicate Hsp25 as a central player in a complex system of signaling that may both promote regeneration of nerve fibers and prevent neuronal cell death in the injured spinal cord.

NASA Discipline Developmental Biology↗
DOE OSTI2022

Engineered human antibodies for the opsonization and killing of Staphylococcus aureus

Gram-positive organisms with their thick envelope cannot be lysed by complement alone. Nonetheless, antibody-binding on the surface can recruit complement and mark these invaders for uptake and killing by phagocytes, a process known as opsonophagocytosis. The crystallizable fragment of immunoglobulins (Fcγ) is key for complement recruitment. The cell surface of S. aureus is coated with Staphylococcal protein A (SpA). SpA captures the Fcγ domain of IgG and interferes with opsonization by anti-S. aureus antibodies. In principle, the Fcγ domain of therapeutic antibodies could be engineered to avoid the inhibitory activity of SpA. However, the SpA-binding site on Fcγ overlaps with that of the neonatal Fc receptor (FcRn), an interaction that is critical for prolonging the half-life of serum IgG. This evolutionary adaptation poses a challenge for the exploration of Fcγ mutants that can both weaken SpA–IgG interactions and retain stability. Here, we use both wild-type and transgenic human FcRn mice to identify antibodies with enhanced half-life and increased opsonophagocytic killing in models of S. aureus infection and demonstrate that antibody-based immunotherapy can be improved by modifying Fcγ. Our experiments also show that by competing for FcRn-binding, staphylococci effectively reduce the half-life of antibodies during infection. These observations may have profound impact in treating cancer, autoimmune, and asthma patients colonized or infected with S. aureus and undergoing monoclonal antibody treatment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Metabolic Signaling Cascades Prompted by Glutaminolysis in Cancer

Aberrant glutamatergic signaling has been implicated in altered metabolic activity and the demand to synthesize biomass in several types of cancer including melanoma. In the last decade, there has been a significant contribution to our understanding of metabolic pathways. An increasing number of studies are now emphasizing the importance of glutamate functioning as a signaling molecule and a building block for cancer progression. To that end, our group has previously illustrated the role of glutamatergic signaling mediated by metabotropic glutamate receptor 1 (GRM1) in neoplastic transformation of melanocytes in vitro and spontaneous development of metastatic melanoma in vivo. Glutamate, the natural ligand of GRM1, is one of the most abundant amino acids in humans and the predominant excitatory neurotransmitter in the central nervous system. Elevated levels of glutaminolytic mitochondrial tricarboxylic acid (TCA) cycle intermediates, especially glutamate, have been reported in numerous cancer cells. Herein, we highlight and critically review metabolic bottlenecks that are prevalent during tumor evolution along with therapeutic implications of limiting glutamate bioavailability in tumors.

Shah, Raj (ORCID:0000000204400189)↗
NASA NTRS2002

Retinoid quantification by HPLC/MS(n)

Retinoic acid (RA) mediates most of the biological effects of vitamin A that are essential for vertebrate survival. It acts through binding to receptors that belong to the nuclear receptor transcription factor superfamily (Mangelsdorf et al. 1994). It is also a highly potent vertebrate teratogen. To determine the function and effects of endogenous and exogenous RA, it is important to have a highly specific, sensitive, accurate, and precise analytical procedure. Current analyses of RA and other retinoids are labor intensive, of poor sensitivity, have limited specificity, or require compatibility with RA reporter cell lines (Chen et al. 1995. BIOCHEM: Pharmacol. 50: 1257-1264; Creech Kraft et al. 1994. BIOCHEM: J. 301: 111-119; Lanvers et al. 1996. J. Chromatogr. B Biomed. Appl. 685: 233-240; Maden et al. 1998. DEVELOPMENT: 125: 4133-4144; Wagner et al. 1992. DEVELOPMENT: 116: 55-66). This paper describes an HPLC/mass spectrometry/mass spectrometry product ion scan (HPLC/MS(n)) procedure for the analysis of retinoids that employs atmospheric pressure chemical ionization MS. The retinoids are separated by normal-phase column chromatography with a linear hexane-isopropanol-dioxane gradient. Each retinoid is detected by a unique series of MS(n) functions set at optimal collision-induced dissociation energy (30% to 32%) for all MS(n) steps. The scan events are divided into three segments, based on HPLC elution order, to maximize the mass spectrometer duty cycle. The all-trans, 9-cis, and 13-cis RA isomers are separated, if desired, by an isocratic hexane-dioxane-isopropanol mobile phase. This paper describes an HPLC/MS(n) procedure possessing high sensitivity and specificity for retinoids.

NASA Discipline Developmental Biology↗