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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 379 records · Page 21
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Robust T cell activation requires an eIF3-driven burst in T cell receptor translation

Activation of T cells requires a rapid surge in cellular protein synthesis. However, the role of translation initiation in the early induction of specific genes remains unclear. Here, we show human translation initiation factor eIF3 interacts with select immune system related mRNAs including those encoding the T cell receptor (TCR) subunits TCRA and TCRB. Binding of eIF3 to the TCRA and TCRB mRNA 3’-untranslated regions (3’-UTRs) depends on CD28 coreceptor signaling and regulates a burst in TCR translation required for robust T cell activation. Use of the TCRA or TCRB 3’-UTRs to control expression of an anti-CD19 chimeric antigen receptor (CAR) improves the ability of CAR-T cells to kill tumor cells in vitro. These results identify a new mechanism of eIF3-mediated translation control that can aid T cell engineering for immunotherapy applications.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

B cell receptor-induced IL-10 production from neonatal mouse CD19 + CD43 - cells depends on STAT5-mediated IL-6 secretion

Newborns are unable to reach the adult-level humoral immune response partly due to the potent immunoregulatory role of IL-10. Increased IL-10 production by neonatal B cells has been attributed to the larger population of IL-10-producting CD43 + B-1 cells in neonates. Here, we show that neonatal mouse CD43 - non-B-1 cells also produce substantial amounts of IL-10 following B cell antigen receptor (BCR) activation. In neonatal mouse CD43 - non-B-1 cells, BCR engagement activated STAT5 under the control of phosphorylated forms of signaling molecules Syk, Btk, PKC, FAK, and Rac1. Neonatal STAT5 activation led to IL-6 production, which in turn was responsible for IL-10 production in an autocrine/paracrine fashion through the activation of STAT3. In addition to the increased IL-6 production in response to BCR stimulation, elevated expression of IL-6Rα expression in neonatal B cells rendered them highly susceptible to IL-6-mediated STAT3 phosphorylation and IL-10 production. Finally, IL-10 secreted from neonatal mouse CD43 - non-B-1 cells was sufficient to inhibit TNF-α secretion by macrophages. Our results unveil a distinct mechanism of IL-6-dependent IL-10 production in BCR-stimulated neonatal CD19 + CD43 - B cells.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Compositions and methods for modulating kinase activity

The present invention features an antibody mimetic, or an antigen binding fragment thereof, that specifically binds to an allosteric site of Aurora A kinase, therapeutic compositions comprising this antibody mimetic, and the use of the monobody to modulate Aurora A kinase for the treatment of cancer.

Kern, Dorothee↗
DOE OSTI2022

Chimeric OspA genes, proteins and methods of use thereof

The invention relates to the development of chimeric OspA molecules for use in a new Lyme vaccine. More specifically, the chimeric OspA molecules comprise the proximal portion from one OspA serotype, together with the distal portion from another OspA serotype, while retaining antigenic properties of both of the parent polypeptides. The chimeric OspA molecules are delivered alone or in combination to provide protection against a variety of Borrelia genospecies. The invention also provides methods for administering the chimeric OspA molecules to a subject in the prevention and treatment of Lyme disease or borreliosis.

Crowe, Brian A.↗
DOE OSTI2023

Synthetic anti-plague antibodies

Monoclonal antibodies that specifically bind the F1 antigen of Yersinia pestis with high affinity are described. Use of the monoclonal antibodies for the detection of Y. pestis infection and the diagnosis of plague are also described. Immunoconjugates of the monoclonal antibodies and a radionuclide can also be used for the treatment of a Y. pestis infection.

Lillo, Antonietta Maria↗
DOE OSTI2024

Production of High Specific Activity 155 Tb, 161 Tb and 203 Pb for Research and Clinical Applications: Effective Target Design, Target Material Recycling and Radioisotope Separation (Final Technical Report)

The overall objectives of this project were (1) to develop methods for the production and separation of a diagnostic and therapeutic or “theranostic” pair of radioisotopes, terbium-155 ( 155 Tb) and terbium-161 ( 161 Tb) and (2) to train graduate students and postdoctoral fellows in technologies and methods used in radionuclide production. Radionuclides can be incorporated into drugs called radiopharmaceuticals that target a specific disease (e.g., cancer). The need for theranostic radionuclides is escalating with the clinical translation of radiopharmaceuticals due to their implementation in personalized medicine, which has demonstrated enhanced patient treatments. High purity and high specific activity radionuclides are critical for theranostic agent development, for example to maintain diagnostic image quality, to minimize radiation dose to the patient, and to increase uptake in the targeted tissue (e.g., tumor), especially in the case of receptor- and antigen-targeted agents. The 155 Tb (diagnostic) and 161 Tb (therapeutic) radioisotopes that were generated through this project are a theranostic pair with demonstrated potential for the development and translation into individualized, targeted, and dosimetry-driven radiotherapies. However, the development of such radiotherapies has been hindered by the lack of a routine and reliable supply of these isotopes in the United States. Methods for the production, separation, and supply of 155 Tb and 161 Tb were investigated and developed in this project. Further, the strong emphasis throughout the project on the training of graduate students and postdoctoral fellows has helped to ensure and enhance the nuclear science workforce through the training of the next generation of highly qualified scientists in nuclear and radiochemistry. This grant also continued a collaboration between scientists at the University of Washington (UW), the University of Missouri (MU) and Brookhaven National Laboratory (BNL). All three institutions were involved in the project, but to different degrees on the various tasks through which the overall objectives were met.

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2021

Neutralizing Antibodies to SARS-CoV-2 Selected from a Human Antibody Library Constructed Decades Ago

Combinatorial antibody libraries not only effectively reduce antibody discovery to a numbers game, but enable documentation of the history of antibody responses in an individual. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has prompted a wider application of this technology to meet the public health challenge of pandemic threats in the modern era. Herein, a combinatorial human antibody library constructed 20 years before the coronavirus disease 2019 (COVID-19) pandemic is used to discover three highly potent antibodies that selectively bind SARS-CoV-2 spike protein and neutralize authentic SARS-CoV-2 virus. Compared to neutralizing antibodies from COVID-19 patients with generally low somatic hypermutation (SHM), these three antibodies contain over 13–22 SHMs, many of which are involved in specific interactions in their crystal structures with SARS-CoV-2 spike receptor binding domain. The identification of these somatically mutated antibodies in a pre-pandemic library raises intriguing questions about the origin and evolution of these antibodies with respect to their reactivity with SARS-CoV-2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Structural basis of glycan276-dependent recognition by HIV-1 broadly neutralizing antibodies

Recognition of N-linked glycan at residue N276 (glycan276) at the periphery of the CD4-binding site (CD4bs) on the HIV-envelope trimer is a formidable challenge for many CD4bs-directed antibodies. To understand how this glycan can be recognized, here we isolate two lineages of glycan276-dependent CD4bs antibodies. Antibody CH540-VRC40.01 (named for donor-lineage.clone) neutralizes 81% of a panel of 208 diverse strains, while antibody CH314-VRC33.01 neutralizes 45%. Cryo-electron microscopy (cryo-EM) structures of these two antibodies and 179NC75, a previously identified glycan276-dependent CD4bs antibody, in complex with HIV-envelope trimer reveal substantially different modes of glycan276 recognition. Despite these differences, binding of glycan276-dependent antibodies maintains a glycan276 conformation similar to that observed in the absence of glycan276-binding antibodies. By contrast, glycan276-independent CD4bs antibodies, such as VRC01, displace glycan276 upon binding. These results provide a foundation for understanding antibody recognition of glycan276 and suggest its presence may be crucial for priming immunogens seeking to initiate broad CD4bs recognition.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Shaping Nanobodies and Intrabodies against Proteoforms

Proteoforms expand genomic diversity and direct developmental processes. While high-resolution mass spectrometry has accelerated characterization of proteoforms, molecular techniques working to bind, and disrupt the function of specific proteoforms have lagged behind. In this study, we worked to develop intrabodies capable of binding specific proteoforms. Herein we employed a synthetic camelid nanobody library expressed in yeast to identify nanobody binders of different SARS-CoV-2 receptor binding domain (RBD) proteoforms. Importantly, employment of the positive and negative selection mechanism inherent to the synthetic system allowed for amplification of nanobody-expressing yeast that bind to the original (Wuhan strain RBD) but not the E484K (Beta variant) mutation. Nanobodies raised against specific RBD proteoforms were validated by yeast-2-hybrid analysis and sequence comparisons. These results provide a clear framework for development of proteoform-specific nanobodies and intrabodies.

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

Supramolecular Motion Enables Chondrogenic Bioactivity of a Cyclic Peptide Mimetic of Transforming Growth Factor-β1

Transforming growth factor (TGF)-β1 is a multifunctional protein that is essential in many cellular processes that include fibrosis, inflammation, chondrogenesis, and cartilage repair. In particular, cartilage repair is important to avoid physical disability since this tissue does not have the inherent capacity to regenerate beyond full development. We report here on supramolecular coassemblies of two peptide amphiphile molecules, one containing a TGF-β1 mimetic peptide, and another which is one of two constitutional isomers lacking bioactivity. Using human articular chondrocytes, we investigated the bioactivity of the supramolecular copolymers of each isomer displaying either the previously reported linear form of the mimetic peptide or a novel cyclic analogue. Based on fluorescence depolarization and 1 H NMR spin–lattice relaxation times, we found that coassemblies containing the cyclic compound and the most dynamic isomer exhibited the highest intracellular TGF-β1 signaling and gene expression of cartilage extracellular matrix components. Here, we conclude that control of supramolecular motion is emerging as an important factor in the binding of synthetic molecules to receptors that can be tuned through chemical structure.

Antigens↗
DOE OSTI2021

Cas9-derived peptides presented by MHC Class II that elicit proliferation of CD4 + T-cells

CRISPR–Cas9 mediated genome editing offers unprecedented opportunities for treating human diseases. There are several reports that demonstrate pre-existing immune responses to Cas9 which may have implications for clinical development of CRISPR-Cas9 mediated gene therapy. Here we use 209 overlapping peptides that span the entire sequence of Staphylococcus aureus Cas9 (SaCas9) and human peripheral blood mononuclear cells (PBMCs) from a cohort of donors with a distribution of Major Histocompatibility Complex (MHC) alleles comparable to that in the North American (NA) population to identify the immunodominant regions of the SaCas9 protein. We also use an MHC Associated Peptide Proteomics (MAPPs) assay to identify SaCas9 peptides presented by MHC Class II (MHC-II) proteins on dendritic cells. Using these two data sets we identify 22 SaCas9 peptides that are both presented by MHC-II proteins and stimulate CD4 + T-cells.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Specificity remains a major challenge to current therapeutic strategies for cancer. Mutation associated neoantigens (MANAs) are products of genetic alterations, making them highly specific therapeutic targets. MANAs are HLA-presented (pHLA) peptides derived from intracellular mutant proteins that are otherwise inaccessible to antibody-based therapeutics. Here, we describe the cryo-EM structure of an antibody-MANA pHLA complex. Specifically, we determine a TCR mimic (TCRm) antibody bound to its MANA target, the KRAS G12V peptide presented by HLA-A*03:01. Hydrophobic residues appear to account for the specificity of the mutant G12V residue. We also determine the structure of the wild-type G12 peptide bound to HLA-A*03:01, using X-ray crystallography. Based on these structures, we perform screens to validate the key residues required for peptide specificity. These experiments led us to a model for discrimination between the mutant and the wild-type peptides presented on HLA-A*03:01 based exclusively on hydrophobic interactions.

36 MATERIALS SCIENCE↗