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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 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Engineering well-expressed, V2-immunofocusing HIV-1 envelope glycoprotein membrane trimers for use in heterologous prime-boost vaccine regimens

HIV-1 vaccine immunofocusing strategies may be able to induce broadly-reactive neutralizing antibodies (NAbs). Here, we engineered a panel of diverse, membrane-resident native HIV-1 trimers vulnerable to two broad targets—the V2 apex and fusion peptide (FP). Selection criteria included i) high expression and ii) infectious function, so that trimer neutralization sensitivity can be profiled in pseudovirus (PV) assays. Initially, we boosted the expression of 17 candidate trimers by truncating gp41 and introducing a gp120-gp41 SOS disulfide to prevent gp120 shedding. "Repairs" were made to fill glycan holes and eliminate other strain-specific aberrations. A new neutralization assay allowed PV infection when our standard assay was insufficient. Trimers with exposed V3 loops, a target of non-NAbs, were discarded. To try to increase V2-sensitivity, we removed clashing glycans and modified the C-strand. Notably, a D167N mutation improved V2-sensitivity in several cases. Glycopeptide analysis of JR-FL trimers revealed near complete sequon occupation and that filling the N197 glycan hole was well-tolerated. In contrast, sequon optimization and inserting/removing glycans at other positions frequently had global "ripple" effects on glycan maturation and sequon occupation throughout the gp120 outer domain and gp41. V2 MAb CH01 selectively bound to trimers with small high mannose glycans near the base of the V1 loop, thereby avoiding clashes. Knocking in a rare N49 glycan was found to perturb gp41 glycans, increasing FP NAb sensitivity—and sometimes improving expression. Finally, a biophysical analysis of VLPs revealed that i) ~25% of particles bear Env spikes, ii) spontaneous particle budding is high and only increases 4-fold upon Gag transfection, and iii) Env+ particles express ~30–40 spikes. Taken together, we identified 7 diverse trimers with a range of sensitivities to two targets to allow rigorous testing of immunofocusing vaccine concepts.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

High-Energy Solid-State Lithium Batteries with Organic Cathode Materials (Final Report)

Organic materials made from abundant elements via low-energy processes are emerging as sustainable and low-cost alternatives to transition metal oxides as the electrode materials for high- energy batteries in the wake of supply chain and environmental issues associated with critical materials during the transition to clean energy. Organic insertion materials (OIMs) offer material- level energy comparable to transition metal oxides, but they have durability difficulties owing to dissolving in common liquid electrolytes. Combining ceramic-based solid electrolytes with organic electrode materials is one intriguing solution. The goal of this project is to design and synthesize high-energy OIMs, to understand the chemical dynamics and mechanical properties at the OIM-sulfide interface during electrochemical cycling, and to develop methods for constructing the optimum cathode microstructure, which will lead to improved electrochemical performance. The project team has accomplished the following over the last four years: (a) demonstrating that the mechanical softness of organic electrode materials is uniquely beneficial in suppressing crack formation at the electrode-electrolyte interface during cell operation; (b) understanding the interaction between cathode microstructure and the mechanical properties of individual components; and (c) establishing predictive control of cathode microstructure by tuning the mechanical properties of solid electrolytes and OIMs; (d) determining the chemical combability of sulfide electrolyte with high-energy OIMs and finally (f) laying out a road map toward a specific energy of 500 Wh kg -1 for solid-state lithium batteries. 14 publications resulted from this project.

25 ENERGY STORAGE↗
DOE OSTI2024

Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca 2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2 –/– female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2 –/– female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4 + T cells and Granzyme-B in CD8 + T cells. We also found fewer FOXP3 + T-regulatory cells and Ly49G + NK and Ly49G + NKT cells in female Tusc2 –/– brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2 –/– hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2 + dynamics. Overall, the data suggest that dysregulation of Ca 2+ -dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2 –/– mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca 2+ - signaling pathways in the brain should be explored to improve cognitive health.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

3D-printed B 4 C collimation for neutron pressure cells

A design for an incident-beam collimator for the Paris–Edinburgh pressure cell is described here. This design can be fabricated from reaction-bonded B 4 C but also through fast turnaround, inexpensive 3D-printing. 3D-printing thereby also offers the opportunity of composite collimators whereby the tip closest to the sample can exhibit even better neutronic characteristics. Here, we characterize four such collimators: one from reaction-bonded B 4 C, one 3D-printed and fully infiltrated with cyanoacrylate, a glue, one with a glue-free tip, and one with a tip made from enriched 10 B 4 C. The collimators are evaluated on the Spallation Neutrons and Pressure Diffractometer of the Spallation Neutron Source and the Wide-Angle Neutron Diffractometer at the High Flux Isotope Reactor, both at Oak Ridge National Laboratory. This work clearly shows that 3D-printed collimators perform well and also that composite collimators improve performance even further. Beyond use in the Paris–Edinburgh cell, these findings also open new avenues for collimator designs as clearly more complex shapes are possible through 3D printing. An example of such is shown here with a collimator made for single-crystal samples measured inside a diamond anvil cell. These developments are expected to be highly advantageous for future experimentation in high pressure and other extreme environments and even for the design and deployment of new neutron scattering instruments.

47 OTHER INSTRUMENTATION↗
DOE OSTI2023

The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition

Cbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment. A Cbl-b inhibitor, Nx-1607, is currently in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirm potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing the compound’s interaction with both the TKBD and LHR, but not the RING domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Coupling Kinesin Spindle Protein and Aurora B Inhibition with Apoptosis Induction Enhances Oral Cancer Cell Killing

Many proteins regulating mitosis have emerged as targets for cancer therapy, including the kinesin spindle protein (KSP) and Aurora kinase B (AurB). KSP is crucial for proper spindle pole separation during mitosis, while AurB plays roles in chromosome segregation and cytokinesis. Agents targeting KSP and AurB selectively affect dividing cells and have shown significant activity in vitro. However, these drugs, despite advancing to clinical trials, often yield unsatisfactory outcomes as monotherapy, likely due to variable responses driven by cyclin B degradation and apoptosis signal accumulation networks. Accumulated data suggest that combining emerging antimitotics with various cytostatic drugs can enhance tumor-killing effects compared to monotherapy. Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. The combination of BH3-mimetics with both KSP and AurB inhibitors synergistically induced substantial cell death, primarily through apoptosis. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness.

Silva, João P. N. (ORCID:0000000344554286)↗
DOE OSTI2022

Screen-Printed Contacts for Crystalline Silicon Solar Cells: An Overview

Over the years, the photovoltaic market, worldwide, has been witnessing a double-digit growth rate. The silicon solar cell manufacturing technology has evolved to utilize raw materials optimally to address this growth. One of the ways in which manufacturers are addressing the challenge is by increasing the cell size and making thinner wafers. With this change in parameters, understanding the metal contact formation in solar cells becomes paramount to improve their efficiency. Screen printing is a widely used method to form metal contacts on solar cells and is ideally suited for large-volume manufacturing. This paper presents a review of the (a) role of screen printing in various solar cell architectures and (b) existing models for current conduction and contact formation mechanisms. An alternate approach to current conduction and contact formation mechanism in silicon solar cells is proposed.

contacts↗
DOE OSTI2024

Host cells and methods for producing hydroxytyrosol

The present invention provides for a composition comprising: (a) a first host cell capable of producing L-DOPA; and (b) a modified host cell is capable of converting L-DOPA into hydroxytyrosol (HTy); wherein any one or both of the first host cell and second host cell is a genetically modified host cell.

Yoshida, Erika↗
DOE OSTI2024

Exotic edge states of C 3 high-fold fermions in honeycomb lattices

A generalization of the graphene honeycomb model to the case where each site in the honeycomb lattice contains a n -fold degenerate set of eigenstates of the C 3 symmetry has been recently proposed to describe several systems, including triangulene crystals and photonic lattices. These generalized honeycomb models are defined by ( n a , n b ) , the number of C 3 eigenstates in the a and b sites of the unit cell, resulting in n a + n b bands. Thus, the (1,1) case gives the coventional honeycomb model that describes the two low-energy bands in graphene. Generalizations, such as (2,1), (2,2), and (3,3) display several nontrivial features, such as coexisting graphenelike Dirac cones with flat bands, both at zero and finite energy, as well as robust degeneracy points where a flat band and a parabolic band meet at the Γ point. Here we explore the edge states of this class of crystals, using as reference triangulene crystals, and we find several types of edge states absent in the conventional (1,1) honeycomb case, associated to the nontrivial features of the two-dimensional bands of the high-fold case. First, we find dispersive edge states associated to the finite-energy flat bands, that occur both at the armchair and zigzag termination. Second, in the case of noncentrosymmetric triangulene crystals that lead to a S = 1 Dirac band, we have a bonding-antibonding pair of dispersive edge states, localized in the same edge so that their energy splitting is reduced as their localization increases, opposite to the conventional behavior of pairs of states localized in opposite edges. Third, for the (3,3) case, that hosts a gap separating a pair of flat conduction and valence bands, we find nondispersive edge states with E = 0 in all edge terminations. Published by the American Physical Society 2024

Madail, L. (ORCID:0000000208457748)↗
DOE OSTI2023

Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics

Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic patterns, we developed an agent-based model that includes intracellular virion production cycles reflecting the cyclic nature of each individual virus lifecycle. The model fits the data well predicting an increase in production cycles initially starting with a long production cycle of 1 virion per 20 hours that gradually reaches 1 virion per hour after approximately 3–4 days before virion production increases dramatically to reach to a steady state rate of 4 virions per hour per cell. Together, modeling suggests that it is the cyclic nature of the virus lifecycle combined with an initial slow but increasing rate of HBV production from each cell that plays a role in generating the observed multiphasic HBV kinetic patterns in humanized mice.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Structural Characterization of Alzheimer DNA Promoter Sequences from the Amyloid Precursor Gene in the Presence of Thioflavin T and Analogs

Understanding DNA-ligand binding interactions requires ligand screening, crystallization, and structure determination. In order to obtain insights into the amyloid peptide precursor (APP) gene-Thioflavin T (ThT) interaction, single crystals of two DNA sequences 5'-GCCCACCACGGC-3' (PDB 8ASK) and d(CCGGGGTACCCCGG) 2 (PDB 8ASH) were grown in the presence of ThT or its analogue 2-((4-(dimethylamino)benzylidene)amino)-3,6-dimethylbenzo[d]thiazol-3-ium iodide (XRB). Both structures were solved by molecular replacement. In the case of 8ASK, the space group was H3 with unit cell dimensions of a = b = 64.49 Å, c = 46.19 Å. Phases were obtained using a model generated by X3DNA. The novel 12-base-pair B-DNA structure did not have extra density for the ThT ligand. The 14-base-pair A-DNA structure with bound ThT analog XRB was isomorphous with previously the obtained apo-DNA structure 5WV7 (space group was P 4 1 2 1 2 with unit cell dimensions a = b = 41.76 Å, c = 88.96 Å). Binding of XRB to DNA slightly changes the DNA's buckle parameters at the CpG regions. Comparison of the two conformations of the XRB molecule: alone and bound to DNA indicates that the binding results from the freedom of rotation of the two aromatic rings.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Cxcl12 Deletion in Mesenchymal Cells Increases Bone Turnover and Attenuates the Loss of Cortical Bone Caused by Estrogen Deficiency in Mice

ABSTRACT CXCL12 is abundantly expressed in reticular cells associated with the perivascular niches of the bone marrow (BM) and is indispensable for B lymphopoiesis. Cxcl12 promotes osteoclastogenesis and has been implicated in pathologic bone resorption. We had shown earlier that estrogen receptor α deletion in osteoprogenitors and estrogen deficiency in mice increase Cxcl12 mRNA and protein levels in the BM plasma, respectively. We have now generated female and male mice with conditional deletion of a Cxcl12 allele in Prrx1 targeted cells (Cxcl12∆Prrx1) and show herein that they have a 90% decrease in B lymphocytes but increased erythrocytes and adipocytes in the marrow. Ovariectomy increased the expression of Cxcl12 and B-cell number in the Cxcl12f/f control mice, but these effects were abrogated in the Cxcl12∆Prrx1 mice. Cortical bone mass was not affected in Cxcl12∆Prrx1 mice. Albeit, the cortical bone loss caused by ovariectomy was greatly attenuated. Most unexpectedly, the rate of bone turnover in sex steroid–sufficient female or male Cxcl12∆Prrx1 mice was dramatically increased, as evidenced by a more than twofold increase in several osteoblast- and osteoclast-specific mRNAs, as well as increased mineral apposition and bone formation rate and increased osteoclast number in the endosteal surface. The magnitude of the Cxcl12∆Prrx1-induced changes were much greater than those caused by ovariectomy or orchidectomy in the Cxcl12f/f mice. These results strengthen the evidence that CXCL12 contributes to the loss of cortical bone mass caused by estrogen deficiency. Moreover, they reveal for the first time that in addition to its effects on hematopoiesis, CXCL12 restrains bone turnover—without changing the balance between resorption and formation—by suppressing osteoblastogenesis and the osteoclastogenesis support provided by cells of the osteoblast lineage. © 2020 American Society for Bone and Mineral Research.

Ponte, Filipa (ORCID:0000000197133640)↗
DOE OSTI2022

Cryotrapping peroxide in the active site of human mitochondrial manganese superoxide dismutase crystals for neutron diffraction

Structurally identifying the enzymatic intermediates of redox proteins has been elusive due to difficulty in resolving the H atoms involved in catalysis and the susceptibility of ligand complexes to photoreduction from X-rays. Cryotrapping ligands for neutron protein crystallography combines two powerful tools that offer the advantage of directly identifying hydrogen positions in redox-enzyme intermediates without radiolytic perturbation of metal-containing active sites. However, translating cryogenic techniques from X-ray to neutron crystallography is not straightforward due to the large crystal volumes and long data-collection times. Here, methods have been developed to visualize the evasive peroxo complex of manganese superoxide dismutase (MnSOD) so that all atoms, including H atoms, could be visualized. The subsequent cryocooling and ligand-trapping methods resulted in neutron data collection to 2.30 Å resolution. The P 6 1 22 crystal form of MnSOD is challenging because it has some of the largest unit-cell dimensions ( a = b = 77.8, c = 236.8 Å) ever studied using high-resolution cryo-neutron crystallography. The resulting neutron diffraction data permitted the visualization of a dioxygen species bound to the MnSOD active-site metal that was indicative of successful cryotrapping.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Generalized hydrodynamic analysis of transport through a finite open nanopore for two-component single-file systems

Single-file diffusion (SFD) in finite open nanopores is characterized by nonzero spatially varying tracer diffusion coefficients within a generalized hydrodynamic description. This contrasts with infinite SFD systems where tracer diffusivity vanishes. In standard tracer counterpermeation (TCP) analysis, two reservoirs, each containing a different species, are connected to opposite ends of a finite pore. Here, we implement an extended TCP analysis to allow the two reservoirs to contain slightly different mixtures of the two species. Then, determination of diffusion fluxes through the pore allows extraction of diffusion coefficients for near-constant partial concentrations of the two species. This analysis is applied for a lattice-gas model describing two-component SFD through a finite linear pore represented by a one-dimensional array of cells. Two types of particles, A and B, can hop only to adjacent empty cells with generally different rates, $h_A$ and $h_B$. Particles are noninteracting other than exclusion of multiple cell occupancy. Results reveal generalized hydrodynamic tracer diffusion coefficients which adopt small values inversely proportional to pore length in the pore center, but which are strongly enhanced near pore openings.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
DOE OSTI2020

Concurrent evaluation of autophagy induction and Burkholderia infection at the single cell level

Autophagy is a natural, regulated cellular process that "cleans up" cellular debris by degrading and recycling dysfunctional proteins. There is a high potential impact of exploiting the benefits of autophagy to complement existing treatments, but little has been done to date on bacterial pathogens of defense concern such as Burkholderia pseudomallei, a highly virulent Select Agent pathogen that is intrinsically resistant to most classes of antibiotics. Assessment of autophagy in the context of infection typically requires use of multiple technologies in combination (e.g., Western analysis paired with microscopy or flow cytometry) as applied to heterogeneous populations of cells. To address this, we have developed a dual target reporter cell line (RAW264.7 LC3-BFP:mPlum, GFP-RelA) that enables concurrent visualization of infection and autophagy induction. We assessed the effect of clinically approved small molecule inducers of autophagy on infection by Burkholderia thailendensis, a closely related but less virulent surrogate for B. pseudomallei. The reporter cells were first infected with a B. thailendensis strain that constitutively expresses GFP, then treated with one of four known autophagy inducers (rapamycin, niclosamide, bromhexine HC1, or flubendazole) for 4 hours. Confocal fluorescence imaging was used to quantify autophagy stimulation at the single cell level. Autophagy maturation was observed as a decrease in BFP LC3 puncta with a concurrent increase in mPlum LC3 puncta. B. thailendensis infection was assessed by monitoring translocation of GFP-RelA (an NFkB subunit) into the nucleus and through quantitating the intracellular bacterial presence in single cells. Preliminary results indicate that bromhexine HC1 and niclosamide may hinder B. thailendensis' ability to replicate intracellularly and reduce overall bacterial survival.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

X-ray Ptychography Imaging of Human Chromosomes After Low-dose Irradiation

Abstract Studies of the structural and functional role of chromosomes in cytogenetics have spanned more than 10 decades. In this work, we take advantage of the coherent X-rays available at the latest synchrotron sources to extract the individual masses of all 46 chromosomes of metaphase human B and T cells using hard X-ray ptychography. We have produced ‘X-ray karyotypes’ of both heavy metal–stained and unstained spreads to determine the gain or loss of genetic material upon low-level X-ray irradiation doses due to radiation damage. The experiments were performed at the I-13 beamline, Diamond Light Source, Didcot, UK, using the phase-sensitive X-ray ptychography method.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Synthesis and ion-irradiation tolerance of the Dy2TiO5 polymorphs

In developing improvements in nuclear fuels, work has been conducted in replacing boron with lanthanides to act as neutron absorbent materials. To further this development for the first time the three major polymorphs of Dy2TiO5 have been fabricated as bulk, single-phase materials in a systematic study. Crystal structure refinement has been carried out from powder x-ray diffraction data, with further structural detail attained via electron diffraction. A cubic phase, defect-pyrochlore, Fd-3m space group, was found with cell parameter a = 10.2996 (1) angstrom and oxygen x48f positional parameter = 0.331 (1). Dy2TiO5 was also fabricated as a bulk, single-phase compound with hexagonal symmetry, P6(3)/mmc space group, with cell parameters a = b = 3.6307(2), c = 11.8963(8) angstrom. The radiation response for each of the polymorphs has been investigated in-situ via 1 MeV Kr - ion-irradiation and transmission electron microscopy characterisation at the IVEM-TANDEM facility, Argonne National Laboratory. Critical temperatures, T-c, for maintaining crystallinity during irradiation were determined and showed Dy2TiO5 with either orthorhombic or cubic symmetry to perform the best, with the lowest T-c values of 711 and 761 K respectively when compared with the hexagonal form. These relatively low T-c values may be attributed to different characteristics for each phase; high anti-site defect formation energy for the orthorhombic symmetry, and the ability to accommodate disorder for the cubic symmetry.

Burnable poison↗