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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 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Temporal responsiveness of adipose-derived stem/stromal cell immune plasticity

Highlights: • Adipose-derived stem cells modulate immune responses in a plastic manner. • The persistence of pro- and anti-inflammatory phenotypes was explored over time. • IL-6 was present at all time points; IDO1 was induced after cytokine stimulation. • Phenotypes persisted 96–168 h after returning to control conditions. • Macrophages showed reaction to ASC culture but without time effect. We determined the role of time in adipose-derived stem/stromal cell (ASC) response to a model inflammatory environment. ASCs and other mesenchymal stem/stromal cells exhibit immune plasticity. We evaluated the persistence of pro- and anti-inflammatory phenotypes for ASCs exposed to a sustained or pulse inflammatory stimulus. Using qPCR, flow cytometry, and immunocytochemistry, we monitored the temporal expression and up-regulation patterns of a pro-inflammatory gene (caspase 1), a pleiotropic gene/protein (interleukin 6, IL-6), and an anti-inflammatory gene/protein (indoleamine 2, 3-dioxygenase, IDO1) after exposing ASCs to the cytokines tumor necrosis factor-α and interferon-γ. In response to sustained cytokine stimulation, we discovered that time played a role in the balance of pro- and anti-inflammatory ASC phenotypes. IL-6 was present at all time points for both cytokine-stimulated and non-stimulated conditions, whereas IDO1 was heterogeneously up-regulated in stimulated conditions at later time points. After a pulse stimulus, ASC immunoresponse remained consistent for 96–168 h. As a final measure of immune plasticity, we cultured cytokine-stimulated ASCs with blood-derived macrophages to observe macrophage polarization. While the presence of ASCs altered macrophage phenotype, there was no dependency on the length of ASC cytokine exposure time.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A Single Immunization with Spike-Functionalized Ferritin Vaccines Elicits Neutralizing Antibody Responses against SARS-CoV-2 in Mice

The development of a safe and effective SARS-CoV-2 vaccine is a public health priority. We designed subunit vaccine candidates using self-assembling ferritin nanoparticles displaying one of two multimerized SARS-CoV-2 spikes: full-length ectodomain (S-Fer) or a C-terminal 70 amino-acid deletion (SΔC-Fer). Ferritin is an attractive nanoparticle platform for production of vaccines, and ferritin-based vaccines have been investigated in humans in two separate clinical trials. We confirmed proper folding and antigenicity of spike on the surface of ferritin by cryo-EM and binding to conformation-specific monoclonal antibodies. After a single immunization of mice with either of the two spike ferritin particles, a lentiviral SARS-CoV-2 pseudovirus assay revealed mean neutralizing antibody titers at least 2-fold greater than those in convalescent plasma from COVID-19 patients. Additionally, a single dose of SΔC-Fer elicited significantly higher neutralizing responses as compared to immunization with the spike receptor binding domain (RBD) monomer or spike ectodomain trimer alone. After a second dose, mice immunized with SΔC-Fer exhibited higher neutralizing titers than all other groups. Taken together, these results demonstrate that multivalent presentation of SARS-CoV-2 spike on ferritin can notably enhance elicitation of neutralizing antibodies, thus constituting a viable strategy for single-dose vaccination against COVID-19.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2017

Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations

A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env + B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env¯ upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env + (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A monomeric mycobacteriophage immunity repressor utilizes two domains to recognize an asymmetric DNA sequence

Regulation of bacteriophage gene expression involves repressor proteins that bind and downregulate early lytic promoters. A large group of mycobacteriophages code for repressors that are unusual in also terminating transcription elongation at numerous binding sites (stoperators) distributed across the phage genome. Here we provide the X-ray crystal structure of a mycobacteriophage immunity repressor bound to DNA, which reveals the binding of a monomer to an asymmetric DNA sequence using two independent DNA binding domains. The structure is supported by small-angle X-ray scattering, DNA binding, molecular dynamics, and in vivo immunity assays. We propose a model for how dual DNA binding domains facilitate regulation of both transcription initiation and elongation, while enabling evolution of other superinfection immune specificities.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A multiscale model of immune surveillance in micrometastases gives insights on cancer patient digital twins

Abstract Metastasis is the leading cause of death in patients with cancer, driving considerable scientific and clinical interest in immunosurveillance of micrometastases. We investigated this process by creating a multiscale mathematical model to study the interactions between the immune system and the progression of micrometastases in general epithelial tissue. We analyzed the parameter space of the model using high-throughput computing resources to generate over 100,000 virtual patient trajectories. We demonstrated that the model could recapitulate a wide variety of virtual patient trajectories, including uncontrolled growth, partial response, and complete immune response to tumor growth. We classified the virtual patients and identified key patient parameters with the greatest effect on the simulated immunosurveillance. We highlight the lessons derived from this analysis and their impact on the nascent field of cancer patient digital twins (CPDTs). While CPDTs could enable clinicians to systematically dissect the complexity of cancer in each individual patient and inform treatment choices, our work shows that key challenges remain before we can reach this vision. In particular, we show that there remain considerable uncertainties in immune responses, unreliable patient stratification, and unpredictable personalized treatment. Nonetheless, we also show that in spite of these challenges, patient-specific models suggest strategies to increase control of clinically undetectable micrometastases even without complete parameter certainty.

Mathematical & Computational Biology↗
DOE OSTI2018

Legionella pneumophila inhibits immune signalling via MavC-mediated transglutaminase-induced ubiquitination of UBE2N

The bacterial pathogen Legionella pneumophila modulates host immunity using effectors translocated by its Dot/Icm transporter to facilitate its intracellular replication. A number of these effectors employ diverse mechanisms to interfere with protein ubiquitination, a post-translational modification essential for immunity. Here, we have found that L. pneumophila induces monoubiquitination of the E2 enzyme UBE2N by its Dot/Icm substrate MavC(Lpg2147). We demonstrate that MavC is a transglutaminase that catalyses covalent linkage of ubiquitin to Lys92 and Lys94 of UBE2N via Gln40. Similar to canonical transglutaminases, MavC possess deamidase activity that targets ubiquitin at Gln40. We identified Cys74 as the catalytic residue for both ubiquitination and deamidation activities. Furthermore, ubiquitination of UBE2N by MavC abolishes its activity in the formation of K63-type polyubiquitin chains, which dampens NF-? B signalling in the initial phase of bacterial infection. Our results reveal an unprecedented mechanism of modulating host immunity by modifying a key ubiquitination enzyme by ubiquitin transglutamination.

Gan, Ninghai (ORCID:0000000172384056)↗
DOE OSTI2015

Bulk elastic waves with unidirectional backscattering-immune topological states in a time-dependent superlattice

Recent progress in electronic and electromagnetic topological insulators has led to the demonstration of one way propagation of electron and photon edge states and the possibility of immunity to backscattering by edge defects. Unfortunately, such topologically protected propagation of waves in the bulk of a material has not been observed. We show, in the case of sound/elastic waves, that bulk waves with unidirectional backscattering-immune topological states can be observed in a time-dependent elastic superlattice. The superlattice is realized via spatial and temporal modulation of the stiffness of an elastic material. Bulk elastic waves in this superlattice are supported by a manifold in momentum space with the topology of a single twist Möbius strip. Our results demonstrate the possibility of attaining one way transport and immunity to scattering of bulk elastic waves.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2019

Biosynthesis and secretion of the microbial sulfated peptide RaxX and binding to the rice XA21 immune receptor

Significance Despite the importance of immune receptors in the biology of plants and animals, the precise biochemical mechanisms leading to the biosynthesis and secretion of the peptide activators of these immune receptors remain unexplored. Here, we describe the biosynthesis, processing, and secretion of a peptide activator that binds a rice immune receptor. Our studies also reveal that this peptide activator is a member of an important class of peptides present in both eukaryotic and prokaryotic species. Thus, these results provide a major advance in our knowledge of the biology of peptide ligands.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Time-dependent heterogeneity leads to transient suppression of the COVID-19 epidemic, not herd immunity

Significance Epidemics generally spread through a succession of waves that reflect factors on multiple timescales. Here, we develop a general approach bridging across these timescales and demonstrate how to incorporate population heterogeneity into a wide class of epidemiological models. We demonstrate that a fragile state of transient collective immunity emerges during early, high-paced stages of the epidemic, leading to suppression of individual epidemic waves. However, this state is not an indication of lasting herd immunity: Subsequent waves may emerge due to stochastic changes in individual social activity. Parameters of transient collective immunity are estimated using empirical data from the COVID-19 epidemic in several US locations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Plant immunity: Rice XA21-mediated resistance to bacterial infection

Significance The mechanisms plants employ to resist infection were unknown until just a few decades ago. We now understand that plants utilize diverse classes of immune receptors to recognize and respond to pathogenic microbes and pests. This paper describes the development of the plant immunity field, from early studies on the genetics of disease resistance to our increasing knowledge of how plant receptors interact with their microbial ligands, with an emphasis on the rice immune receptor XA21 and its bacterial ligand.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

A periplasmic zinc capture protein enhances the resistance of Neisseria gonorrhoeae to nutritional immunity

During microbial infection, mammalian hosts reduce the availability of free metals such as zinc in a process known as nutritional immunity. Pathogens counteract nutritional immunity by expressing gene products that enhance growth in metal-limited conditions. One of the most transcriptionally induced genes in zinc-limited Neisseria gonorrhoeae , ngo1049, encodes a DUF4198 family protein we have named Zcp. This family of proteins is widely distributed in Gram-negative bacteria. Here, we provide the first structural, biochemical, and functional characterization of a DUF4198 protein. Zcp is a periplasmic, homodimeric substrate-binding protein (SBP), which binds one zinc ion per subunit with submicromolar affinity. We identified a zinc binding pocket in each subunit, composed of three histidine residues. Zcp enables maximal growth of N. gonorrhoeae in zinc-limited conditions but is dispensable for zinc uptake, in contrast to the cluster A-I SBP ZnuA, which is required for zinc import. The growth defect of zcp mutant N. gonorrhoeae is rescued by zinc supplementation. Zcp associates with proteins with roles in maintaining cell envelope integrity, and N. gonorrhoeae lacking zcp is more sensitive to envelope-targeting antimicrobials. Zcp enables infectivity of human epithelial cells and neutrophils by zinc-limited N. gonorrhoeae . We conclude that N. gonorrhoeae produces Zcp to buffer periplasmic zinc, which enables ZnuA to balance import of different metals and ensures the bioavailability of zinc for extracytoplasmic zinc-requiring proteins, as part of the coordinated response to host-imposed nutritional immunity.

Liyayi, Ian K. [Department of Microbiology, Immuno↗
DOE OSTI2020

Peripheral blood hematology, plasma biochemistry, and the optimization of an in vitro immune-based assay in the brown watersnake ( Nerodia taxispilota )

Reptiles represent a phylogenetic lineage that provides a unique link between ectothermic anamniotes and endothermic amniotes. Compared to mammalian and avian species, our understanding of the reptilian immune system is greatly lacking. This gap in knowledge is largely due to an absence of established immune-based assays or specific reagents for these species. In the present study, brown watersnakes (Nerodia taxispilota) were live-captured in the wild, sexed, weighed, measured, bled via the caudal vein and released. At 24 hr post-collection, peripheral blood leukocytes were enriched and evaluated with an established mammalian in-vitro lymphocyte proliferation assay. Snake peripheral blood leukocyte enrichment yielded > 90% lymphocytes with viabilities averaging 81.5%. Baseline physiologic data for N. taxispilota, including hematology and total solids, leukocyte differentials, cell recovery and plasma biochemistry, were also collected. Cells cultured with Concanavalin A exhibited significantly increased proliferation at both 72 and 96 hr. Furthermore, these preliminary results show that enriched peripheral blood from wild-caught N. taxispilota provides a sufficient yield of leukocytes that can be cultured and functionally evaluated using a standard mammalian in-vitro immune-based assay.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Logistics of defense: The contribution of endomembranes to plant innate immunity

Phytopathogens cause plant diseases that threaten food security. Unlike mammals, plants lack an adaptive immune system and rely on their innate immune system to recognize and respond to pathogens. Plant response to a pathogen attack requires precise coordination of intracellular traffic and signaling. Spatial and/or temporal defects in coordinating signals and cargo can lead to detrimental effects on cell development. The role of intracellular traffic comes into a critical focus when the cell sustains biotic stress. In this review, we discuss the current understanding of the post-immune activation logistics of plant defense. Specifically, we focus on packaging and shipping of defense-related cargo, rerouting of intracellular traffic, the players enabling defense-related traffic, and pathogen-mediated subversion of these pathways. We highlight the roles of the cytoskeleton, cytoskeleton–organelle bridging proteins, and secretory vesicles in maintaining pathways of exocytic defense, acting as sentinels during pathogen attack, and the necessary elements for building the cell wall as a barrier to pathogens. We also identify points of convergence between mammalian and plant trafficking pathways during defense and highlight plant unique responses to illustrate evolutionary adaptations that plants have undergone to resist biotic stress.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Herbaspirillum rubrisubalbicans as a Phytopathogenic Model to Study the Immune System of Sorghum bicolor

Herbaspirillum rubrisubalbicans is the causal agent of red stripe disease (RSD) and mottle stripe disease of sorghum and sugarcane, respectively. In all, 63 genotypes of Sorghum bicolor were inoculated with H. rubrisubalbicans, with 59 showing RSD symptoms. Quantitative trait loci (QTL) analysis in a recombinant inbred line (RIL) population identified several QTL associated with variation in resistance to RSD. RNA sequencing analysis identified a number of genes whose transcript levels were differentially regulated during H. rubrisubalbicans infection. Among those genes that responded to H. rubrisubalbicans inoculation were many involved in plant–pathogen interactions such as leucine-rich repeat receptors, mitogen-activated protein kinase 1, calcium-binding proteins, transcriptional factors (ethylene-responsive element binding factor), and callose synthase. Pretreatment of sorghum leaves with the pathogen-associated molecular pattern (PAMP) molecules flg22 and chitooctaose provided protection against subsequent challenge with the pathogen, suggesting that PAMP-triggered immunity plays an important role in the sorghum immunity response. These data present baseline information for the use of the genetically tractable H. rubrisubalbicans–sorghum pathosystem for the study of innate immunity and disease resistance in this important grain and bioenergy crop. Information gained from the use of this system is likely to be informative for other monocots, including those more intractable for experimental study (e.g., sugarcane).

Biochemistry & Molecular Biology↗
DOE OSTI2018

The effect of dietary ginseng polysaccharide supplementation on porcine milk‐derived esRNAs involved in the host immune responses

Abstract Ginseng polysaccharides (GPS) have been well known as an immune modulator. This study was conducted to investigate the effects of dietary supplemental GPS on the immune responses involved in sow’s milk‐derived exosomal shuttle RNAs (esRNAs) using RNA‐Seq and miRNA‐Seq. Of the 213 identified miRNA types, a total of 26 conserved miRNAs were differently expressed in response to GPS supplementation, including 10 up‐regulated and 16 down‐regulated miRNAs in GPS feeding group. In addition, exosomal transcriptome analysis identified 14,696 protein‐coding genes in sow’s milk exosomes, and 283 genes with 204 and 79 candidates showing up and down‐regulation were significantly responded to GPS supplementation. Integrated analysis of each differently expressed miRNA with significantly expressed genes further revealed the presence of 51 highly conserved miRNA–gene interactions that were annotated to be related to immunoregulatory functions. This work provided an important advance in the functional identification of dietary GPS supplementation and more fundamental information about how GPS promoted the immune response and healthy growth of the infant from mothers at molecular levels.

Sun, Jiajie↗
DOE OSTI2020

The essential effector SCRE1 in Ustilaginoidea virens suppresses rice immunity via a small peptide region

Summary The biotrophic fungal pathogen Ustilaginoidea virens causes rice false smut, a newly emerging plant disease that has become epidemic worldwide in recent years. The U. virens genome encodes many putative effector proteins that, based on the study of other pathosystems, could play an essential role in fungal virulence. However, few studies have been reported on virulence functions of individual U. virens effectors. Here, we report our identification and characterization of the secreted cysteine‐rich protein SCRE1, which is an essential virulence effector in U. virens . When SCRE1 was heterologously expressed in Magnaporthe oryzae , the protein was secreted and translocated into plant cells during infection. SCRE1 suppresses the immunity‐associated hypersensitive response in the nonhost plant Nicotiana benthamiana . Induced expression of SCRE1 in rice also inhibits pattern‐triggered immunity and enhances disease susceptibility to rice bacterial and fungal pathogens. The immunosuppressive activity is localized to a small peptide region that contains an important ‘cysteine‐proline‐alanine‐arginine‐serine’ motif. Furthermore, the scre1 knockout mutant generated using the CRISPR/Cas9 system is attenuated in U. virens virulence to rice, which is greatly complemented by the full‐length SCRE1 gene. Collectively, this study indicates that the effector SCRE1 is able to inhibit host immunity and is required for full virulence of U. virens .

Zhang, Nan↗
DOE OSTI2024

Waning immunity and IgG4 responses following bivalent mRNA boosting

Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.

Science & Technology - Other Topics↗
DOE OSTI2016

Transcriptomic and proteomic insights into innate immunity and adaptations to a symbiotic lifestyle in the gutless marine worm Olavius algarvensis

The gutless marine worm Olavius algarvensis has a completely reduced digestive and excretory system, and lives in an obligate nutritional symbiosis with bacterial symbionts. While considerable knowledge has been gained of the symbionts, the host has remained largely unstudied. We generated transcriptomes and proteomes of O. algarvensis to better understand how this annelid worm gains nutrition from its symbionts, how it adapted physiologically to a symbiotic lifestyle, and how its innate immune system recognizes and responds to its symbiotic microbiota. Key adaptations to the symbiosis include (i) the expression of gut-specific digestive enzymes despite the absence of a gut, most likely for the digestion of symbionts in the host's epidermal cells; (ii) a modified hemoglobin that may bind hydrogen sulfide produced by two of the worm’s symbionts; and (iii) the expression of a very abundant protein for oxygen storage, hemerythrin, that could provide oxygen to the symbionts and the host under anoxic conditions. In addition, we identified a large repertoire of proteins involved in interactions between the worm's innate immune system and its symbiotic microbiota, such as peptidoglycan recognition proteins, lectins, fibrinogen-related proteins, Toll and scavenger receptors, and antimicrobial proteins.We also show how this worm, over the course of evolutionary time, has modified widely-used proteins and changed their expression patterns in adaptation to its symbiotic lifestyle and describe expressed components of the innate immune system in a marine oligochaete. These results provide further support for the recent realization that animals have evolved within the context of their associations with microbes and that their adaptive responses to symbiotic microbiota have led to biological innovations.

Wippler, Juliane↗