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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 541 records · Page 30
All sourcesNASA NTRSDOE OSTI
NASA NTRS1996

Shape deformation of the organ of Corti associated with length changes of outer hair cell

Cochlear outer hair cells (OHC) are commonly assumed to function as mechanical effectors as well as sensory receptors in the organ of Corti (OC) of the inner ear. OHC in vitro and in organ explants exhibit mechanical responses to electrical, chemical or mechanical stimulation which may represent an aspect of their effector process that is expected in vivo. A detailed description, however, of an OHC effector operation in situ is still missing. Specifically, little is known as to how OHC movements influence the geometry of the OC in situ. Previous work has demonstrated that the motility of isolated OHCs in response to electrical stimulation and to K(+)-gluconate is probably under voltage control and causes depolarisation (shortening) and hyperpolarization (elongation). This work was undertaken to investigate if the movements that were observed in isolated OHC, and which are induced by ionic stimulation, could change the geometry of the OC. A synchronized depolarization of OHC was induced in guinea pig cochleae by exposing the entire OC to artificial endolymph (K+). Subsequent morphometry of mid-modiolar sections from these cochleae revealed that the distance between the basilar membrane (BM) and the reticular lamina (RL) had decreased considerably. Furthermore, in the three upper turns OHC had significantly shortened in all rows. The results suggest that OHC can change their length in the organ of Corti (OC) thus deforming the geometry of the OC. The experiments reveal a tonic force generation within the OC that may change the position of RL and/or BM, contribute to damping, modulate the BM-RL-distance and control the operating points of RL and sensory hair bundles. Thus, the results suggest active self-adjustments of cochlear mechanics by slow OHC length changes. Such mechanical adjustments have recently been postulated to correspond to timing elements of animal communication, speech or music.

Non-NASA Center↗
DOE OSTI2022

Mushroom body input connections form independently of sensory activity in Drosophila melanogaster

Associative brain centers, such as the insect mushroom body, need to represent sensory information in an efficient manner. In Drosophila melanogaster, the Kenyon cells of the mushroom body integrate inputs from a random set of olfactory projection neurons, but some projection neurons—namely those activated by a few ethologically meaningful odors—connect to Kenyon cells more frequently than others. This biased and random connectivity pattern is conceivably advantageous, as it enables the mushroom body to represent a large number of odors as unique activity patterns while prioritizing the representation of a few specific odors. How this connectivity pattern is established remains largely unknown. Here, we test whether the mechanisms patterning the connections between Kenyon cells and projection neurons depend on sensory activity or whether they are hardwired. We mapped a large number of mushroom body input connections in partially anosmic flies—flies lacking the obligate odorant co-receptor Orco—and in wild-type flies. Statistical analyses of these datasets reveal that the random and biased connectivity pattern observed between Kenyon cells and projection neurons forms normally in the absence of most olfactory sensory activity. Finally, this finding supports the idea that even comparatively subtle, population-level patterns of neuronal connectivity can be encoded by fixed genetic programs and are likely to be the result of evolved prioritization of ecologically and ethologically salient stimuli.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Assessment of Potential Dose and Environmental Impacts from Proposed Testing at the INL Radiological Response Training Range

This assessment uses screening-level models to calculate potential environmental impacts from proposed tests at the Idaho National Laboratory (INL) Radiological Response Training Range (RRTR) site. Proposed tests could be conducted using 11 different radioactive material types that include K2O, LaBr3, KBr, Cu, Zr, F, Ga, Ga2O3, NaNO2, Ga-68, and Tc-99m. The tests could potentially release radioactive material to the atmosphere and radionuclides and other contaminants to the soil, which could leach into the unsaturated zone and migrate to the aquifer. Atmospheric transport of radionuclides to potential human receptors and time-integrated air concentrations were calculated with a Gaussian plume model and three years of hourly meteorological data. Potential surface-soil impacts were calculated with the computer program mixing-cell model (MCM). Groundwater impacts were calculated with the computer programs MCM and GWSCREEN. Radiological doses from potential atmospheric releases were calculated for public receptors off the INL Site and for workers at nearby INL facilities. Results were compared to regulatory dose limits. Maximum potential groundwater concentrations were estimated in the aquifer below the NSTR site and compared to drinking water standards or risk-based screening levels for resident tap water. Soil concentrations were calculated and compared to risk-based screening levels for workers and potential future residents. All impacts were estimated assuming 12 tests are conducted annually using all 11 material types for a period of 15 years. This document provides the resources to enable a subject matter expert in the field of environmental assessments to replicate the modeling and calculations. The methodology and parameters are presented in the text. All electronic files, including computer-code input, output, executable files, batch files, scripts, and spreadsheet files are contained in a zip file that can be accessed by selecting “Additional Information” (select Native File) in the INL Electronic Document Management System (EDMS). It is highly unlikely the test scenarios evaluated in this ECAR will adversely impact human health based on comparisons of calculated dose and concentration against regulatory standards and risk-based screening levels. Conservative estimates of dose to workers and the public from atmospheric transport of possible radionuclide releases are far below federal radiation protection standards. Conservative estimates of potential contaminant concentrations in groundwater are less than federal drinking water standards or screening levels. Predicted radionuclide concentrations in surface soils are below risk-based screening levels, except for Ge-68 (material Ga-68) for the worker. The Ge-68 soil concentration can be made less than the worker PRG, if the number of annual tests using Ga-68 is reduced from 12 to 6. However, the sum of ratios still exceeds one because of the high K-40 ratio. If the EF of the worker (number of days the worker is in the contaminated testing area) is reduced from 225 days/yr (default value for full time worker) to 112 days/yr, the Ge-68 ratio is less than one and the sum of ratios is less than one. Actual radiation doses and groundwater and surface-soil concentrations are likely to be much less than those calculated because of the conservative assumptions and parameters employed in the modeling. For example, atmospheric-transport calculations assume the entire inventory of each material type is readily released to the atmosphere and no plume deposition, depletion, or radioactive decay occurs during transport. The calculations also assume the same meteorological conditions (e.g., wind velocity, wind direction, stability class) that produce the maximum 95th percentile concentration (i.e., concentration representing the 95th percentile of a distribution of concentrations derived from 3 years of hourly meteorological data) at each receptor location are the same for all 12 tests during the year, and each receptor is assumed to be present during all 12 tests. The surface-soil assessment assumes the entire inventory of each test is deposited in the top 5 cm of soil. No atmospheric dispersal is assumed, and the radionuclides are subject only to leaching and radioactive decay. The groundwater-pathway modeling is conservative in that it is one-dimensional in the unsaturated zone (no lateral spreading/dilution) and assumes the entire inventory of contaminants infiltrates into the ground at the same location for every test. This is especially conservative for particulate radionuclides because they would have to dissolve or corrode first and some would be dispersed into the atmosphere. The groundwater receptor is also assumed to consume water directly from a hypothetical well positioned in the location of maximum concentration. In addition, conservative degradation rates were used, and volatilization was not considered for the nonradioactive chemical

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2023

Assessment of Potential Dose and Environmental Impacts from Proposed Testing at the INL National Security Test Range

This assessment uses screening-level models to calculate potential environmental impacts from proposed tests at two locations at the Idaho National Laboratory (INL) National Security Test Range (NSTR) site. Proposed tests could be conducted using 11 different radioactive material types that include K 2 O, LaBr 3 , KBr, Cu, Zr, F, Ga, Ga 2 O 3 , NaNO 2 , Ga-68, and Tc-99m. The tests could potentially release radioactive material to the atmosphere and radionuclides and other contaminants to the soil, which could leach into the unsaturated zone and migrate to the aquifer. Atmospheric transport of radionuclides to potential human receptors and time-integrated air concentrations were calculated with a Gaussian plume model and three years of hourly meteorological data. Potential surface-soil impacts were calculated with the computer program mixing-cell model (MCM). Groundwater impacts were calculated with the computer programs MCM and GWSCREEN. Radiological doses from potential atmospheric releases were calculated for public receptors off the INL Site and for workers at nearby INL facilities. Results were compared to regulatory dose limits. Maximum potential groundwater concentrations were estimated in the aquifer below the NSTR site and compared to drinking water standards or risk-based screening levels for resident tap water. Soil concentrations were calculated and compared to risk-based screening levels for workers and potential future residents. All impacts were estimated based on the assumption that 12 tests are conducted annually using all 11 material types for 15 years. This document provides the resources to enable a subject matter expert in the field of environmental assessments to replicate the modeling and calculations. The methodology and parameters are presented in the text. All electronic files, including computer-code input, output, executable files, batch files, scripts, and spreadsheet files, are contained in a zip file that can be accessed by selecting “Additional Information” (select Native File) in the INL Electronic Document Management System (EDMS). It is highly unlikely the test scenarios evaluated in this ECAR will adversely impact human health based on comparisons of calculated dose and concentration against regulatory standards and risk-based screening levels. Conservative estimates of dose to workers and the public from atmospheric transport of possible radionuclide releases are far below federal radiation protection standards. Conservative estimates of potential contaminant concentrations in groundwater are less than federal drinking water standards or screening levels. Predicted radionuclide concentrations in surface soils are below risk-based screening levels, except for Ge-68 (material Ga-68) for the worker. The Ge-68 soil concentration can be made less than the worker PRG, if the number of annual tests using Ga-68 is reduced from 12 to 6. However, the sum of ratios still exceeds one because of the high K-40 ratio. If the EF of the worker (number of days the worker is in the contaminated testing area) is reduced from 225 days/yr (default value for full time worker) to 112 days/yr, the Ge-68 ratio is less than one and the sum of ratios is less than one. Actual radiation doses and groundwater and surface-soil concentrations are likely to be much less than those calculated because of the conservative assumptions and parameters employed in the modeling. For example, atmospheric-transport calculations assume the entire inventory of each material type is readily released to the atmosphere and no plume deposition, depletion, or radioactive decay occurs during transport. The calculations also assume the same meteorological conditions (e.g., wind velocity, wind direction, stability class) that produce the maximum 95th percentile concentration (i.e., concentration representing the 95th percentile of a distribution of concentrations derived from 3 years of hourly meteorological data) at each receptor location are the same for all 12 tests during the year, and each receptor is assumed to be present during all 12 tests. The surface-soil assessment assumes the entire inventory of each test is deposited in the top 5 cm of soil. No atmospheric dispersal is assumed, and the radionuclides are subject only to leaching and radioactive decay. The groundwater-pathway modeling is conservative in that it is one-dimensional in the unsaturated zone (no lateral spreading/dilution) and assumes the entire inventory of contaminants infiltrates into the ground at the same location for every test. This is especially conservative for particulate radionuclides because they would have to dissolve or corrode first and some would be dispersed into the atmosphere. The groundwater receptor is also assumed to consume water directly from a hypothetical well positioned in the location of maximum concentration. In addition, conservative degradation rates were used, and volatilization was not considered for the nonradradioactive chemicals modeled. And finally, the calculations assume all 12 tests will be performed at the same place at both locations, and all 11 radioactive material types will be used for each test. This is conservative because it is anticipated that no more than two material types will be used per test.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2024

Assessment of Potential Dose and Environmental Impacts from Proposed Testing at the INL Radiological Response Training Range

This assessment uses screening level models to calculate potential environmental impacts from proposed tests at the Idaho National Laboratory (INL) Radiological Response Training Range (RRTR) site. Proposed tests could be conducted using 11 different radioactive material types that include K 2 O, LaBr 3 , KBr, Cu, Zr, F, Ga, Ga 2 O 3 , NaNO 2 , Ga-68, and Tc-99m. The tests could potentially release radioactive material to the atmosphere and radionuclides and other contaminants to the soil, which could leach into the unsaturated zone and migrate to the aquifer. Atmospheric transport of radionuclides to potential human receptors and time-integrated air concentrations were calculated with a Gaussian plume model and three years of hourly meteorological data. Potential surface-soil impacts were calculated with the computer program Mixing-Cell Model (MCM). Groundwater impacts were calculated with the computer programs MCM and GWSCREEN. Radiological doses from potential atmospheric releases were calculated for public receptors off the INL Site and for workers at nearby INL facilities. Results were compared to regulatory dose limits. Maximum potential groundwater concentrations were estimated in the aquifer below the NSTR site and compared to drinking water standards or risk-based screening levels for resident tap water. Soil concentrations were calculated and compared to risk-based screening levels for workers and potential future residents. All impacts were estimated based on the assumption that 12 tests are conducted annually using all 11 material types for a period of 15 years. This document provides the resources to enable a subject matter expert in the field of environmental assessments to replicate the modeling and calculations. The methodology and parameters are presented in the text. All electronic files, including computer code input, output, executable files, batch files, scripts, and spreadsheet files are contained in a zip file that can be accessed by selecting “Additional Information” (select Native File) in the INL Electronic Document Management System (EDMS).

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2021

Increased SUMOylation of TCF21 improves its stability and function in human endometriotic stromal cells

Abstract Endometriosis is an estrogen-dependent disease. Our previous study demonstrated that elevated levels of transcription factor 21 (TCF21) in endometriotic tissues enhanced steroidogenic factor-1 (SF-1) and estrogen receptor β (ERβ) expression by forming a heterodimer with upstream stimulatory factor 2 (USF2), allowing these TCF21/USF2 complexes to bind to the promoters of SF-1 and ERβ. Furthermore, TCF21 contributed to the increased proliferation of endometriotic stromal cells (ESCs), suggesting that TCF21 may play a vital role in the pathogenesis of endometriosis. SUMOylation is a posttranslational modification that has emerged as a crucial molecular regulatory mechanism. However, the mechanism regulating TCF21 SUMOylation in endometriosis is incompletely characterized. Thus, this study aimed to explore the effect of TCF21 SUMOylation on its expression and regulation in ovarian endometriosis. We found that the levels of SUMOylated TCF21 were increased in endometriotic tissues and stromal cells compared with eutopic endometrial tissues and stromal cells and enhanced by estrogen. Treatment with the SUMOylation inhibitor ginkgolic acid (GA) and the results of a protein half-life assay demonstrated that SUMOylation can stabilize the TCF21 protein. A coimmunoprecipitation (Co-IP) assay showed that SUMOylation probably increased its interaction with USF2. Further analyses elucidated that SUMOylation of TCF21 significantly increased the binding activity of USF2 to the SF-1 and ERβ promoters. Moreover, the SUMOylation motifs in TCF21 affected the proliferation ability of ESCs. The results of this study suggest that SUMOylation plays a critical role in mediating the high expression of TCF21 in ESCs and may participate in the development of endometriosis.

Zhu, Jingwen↗
DOE OSTI2021

NF-κB Blockade by NEMO Binding Domain Peptide Ameliorates Inflammation and Neurobehavioral Sequelae After Cranial Radiation Therapy in Juvenile Mice

Cranial radiation therapy (CRT) is a common treatment for pediatric brain tumor patients. However, side effects include significant neurobehavioral dysfunction in survivors. This dysfunction may in part be caused by inflammation, including increased production of tumor necrosis factor alpha (TNFα) and its receptor TNFR1, which can activate the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB). The TNFα blockade abrogates this inflammatory response, although it presents immunologic risks. Thus, modulation of pathway subsets may be preferable. Here, we test whether inhibition of NF-κB activation using an NF-κB essential modulator binding domain (NBD) peptide mitigates CRT-induced neuroinflammation and improves behavioral outcomes.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Muscone suppresses inflammatory responses and neuronal damage in a rat model of cervical spondylotic myelopathy by regulating Drp1‐dependent mitochondrial fission

Abstract Cervical spondylotic myelopathy (CSM) is a common cause of disability with few treatments. Aberrant mitochondrial dynamics play a crucial role in the pathogenesis of various neurodegenerative diseases. Thus, regulation of mitochondrial dynamics may offer therapeutic benefit for the treatment of CSM. Muscone, the active ingredient of an odoriferous animal product, exhibits anti‐inflammatory and neuroprotective effects for which the underlying mechanisms remain obscure. We hypothesized that muscone might ameliorate inflammatory responses and neuronal damage by regulating mitochondrial dynamics. To this end, the effects of muscone on a rat model of chronic cervical cord compression, as well as activated BV2 cells and injured neurons, were assessed. The results showed that muscone intervention improved motor function compared with vehicle‐treated rats. Indeed, muscone attenuated pro‐inflammatory cytokine expression, neuronal‐apoptosis indicators in the lesion area, and activation of the nod‐like receptor family pyrin domain‐containing 3 inflammasome, nuclear transcription factor‐κB, and dynamin‐related protein 1 in Iba1‐ and βIII‐tubulin‐labeled cells. Compared with vehicle‐treated rats, compression sites of muscone‐treated animals exhibited elongated mitochondrial morphologies in individual cell types and reduced reactive oxygen species. In vitro results indicated that muscone suppressed microglial activation and neuronal damage by regulating related‐inflammatory or apoptotic molecules. Moreover, muscone inhibited dynamin‐related protein 1 activation in activated BV2 cells and injured neurons, whereby it rescued mitochondrial fragmentation and reactive oxygen species production, which regulate a wide range of inflammatory and apoptotic molecules. Our findings reveal that muscone attenuates neuroinflammation and neuronal damage in rats with chronic cervical cord compression by regulating mitochondrial fission events, suggesting its promise for CSM therapy. image

Zhou, Long‐yun↗
NASA NTRS2002

Immunoglobulin Fc gamma receptor promotes immunoglobulin uptake, immunoglobulin-mediated calcium increase, and neurotransmitter release in motor neurons

Receptors for the Fc portion of immunoglobulin G (IgG; FcgammaRs) facilitate IgG uptake by effector cells as well as cellular responses initiated by IgG binding. In earlier studies, we demonstrated that amyotrophic lateral sclerosis (ALS) patient IgG can be taken up by motor neuron terminals and transported retrogradely to the cell body and can alter the function of neuromuscular synapses, such as increasing intracellular calcium and spontaneous transmitter release from motor axon terminals after passive transfer. In the present study, we examined whether FcgammaR-mediated processes can contribute to these effects of ALS patient immunoglobulins. F(ab')(2) fragments (which lack the Fc portion) of ALS patient IgG were not taken up by motor axon terminals and were not retrogradely transported. Furthermore, in a genetically modified mouse lacking the gamma subunit of the FcR, the uptake of whole ALS IgG and its ability to enhance intracellular calcium and acetylcholine release were markedly attenuated. These data suggest that FcgammaRs appear to participate in IgG uptake into motor neurons as well as IgG-mediated increases in intracellular calcium and acetylcholine release from motor axon terminals. Copyright 2002 Wiley-Liss, Inc.

Non-NASA Center↗
DOE OSTI2023

Structure of human TRPV4 in complex with GTPase RhoA

Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4α-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a π-to-α transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2009

Changes of Gene Expression in the Apoptosis Pathway in Lncap and PC3 Cells Exposed to X-Rays or Protons

Radio-resistant or recurrent prostate cancer represents a serious health risk for approximately 20%-30% of patients treated with primary radiation therapy for clinically localized prostate cancer. In our current studies, we investigated the expressions of apoptosis related gene expression profile (84 genes) in two distinct prostate cell lines Lncap (P53+ and AR+) and PC3 (P53- and AR-) before and after exposure to X-rays or protons, using cDNA PCR arrays. In Lncap cells, 10Gy X-ray radiation significantly induced the expression of 19 out of 84 genes at 4h after irradiation. The changed genes were mostly in death and death receptor domain families, TNF ligand and receptor families, and apoptotic group of the BCL2 family, especially in P53 related genes, such as FAS, BAX, BAK1 and GADD45A. In PC3, X-rays only induced the expression of 3 genes, including an increased expression of BIRC3. There was no difference of the X-ray mediated cell killing in both cell lines using the cell cycle analysis. However, these X-ray-induced gene expression differences between PC3 and Lncap may explain the phenotype of PC3 cells that shows more tolerant not only to radiation, but also to other apoptosis inducing and sensitizing reagents. To compare the effectiveness of cell killing with X-rays, we also exposed PC3 cells to 10Gy protons at the Bragg peak region. Protons did not induce more apoptosis than X-rays for the same dose. In comparison to X-rays, protons significantly altered expressions of 13 genes in PC3, which included decreased expressions of anti-apoptosis genes (BCL2 and BCL2L2), and increased expressions of death and death receptor domain family genes, TNF ligand and receptor family and several kinases (FAS, DAPK1 and RIPK2). These data suggest that proton treatment is more effective in influencing the apoptosis pathways in PC3 cells than X-rays, thus protons may be more effective in the treatment of specific prostate tumor.

Zhang, Ye↗
DOE OSTI2020

Auxin‐induced actin cytoskeleton rearrangements require AUX1

Summary The actin cytoskeleton is required for cell expansion and implicated in cellular responses to the phytohormone auxin. However, the mechanisms that coordinate auxin signaling, cytoskeletal remodeling and cell expansion are poorly understood. Previous studies examined long‐term actin cytoskeleton responses to auxin, but plants respond to auxin within minutes. Before this work, an extracellular auxin receptor – rather than the auxin transporter AUXIN RESISTANT 1 (AUX1) – was considered to precede auxin‐induced cytoskeleton reorganization. In order to correlate actin array organization and dynamics with degree of cell expansion, quantitative imaging tools established baseline actin organization and illuminated individual filament behaviors in root epidermal cells under control conditions and after indole‐3‐acetic acid (IAA) application. We evaluated aux1 mutant actin organization responses to IAA and the membrane‐permeable auxin 1‐naphthylacetic acid (NAA). Cell length predicted actin organization and dynamics in control roots; short‐term IAA treatments stimulated denser and more parallel, longitudinal arrays by inducing filament unbundling within minutes. Although AUX1 is necessary for full actin rearrangements in response to auxin, cytoplasmic auxin (i.e. NAA) stimulated a lesser response. Actin filaments became more ‘organized’ after IAA stopped elongation, refuting the hypothesis that ‘more organized’ actin arrays universally correlate with rapid growth. Short‐term actin cytoskeleton response to auxin requires AUX1 and/or cytoplasmic auxin.

AUX1↗
NASA NTRS1995

Integrin-extracellular matrix interactions in connective tissue remodeling and osteoblast differentiation

The differentiaton of bone cells is a complex multistep process. Bone is somewhat unusual in that it is very actively and continually remodeled in the adult and that maintenance of its mass in the mature organism is exquisitely sensitive to mechanical as well as chemical signals. Bone is also unique because it consists of a very large amount of extracellular matrix (ECM) that is mineralized. The integrin family of ECM receptors has been shown to play an important role in tissue morphogenesis in several systems. Our studies on the regulation of matrix remodeling enzymes by integrins in rabbit synovial fibroblasts show that two b1 integrin fibronectin (FN) receptor complexes (alpha 5 beta 1 and alpha 4 beta 1) cooperate in detecting subtle changes in the composition of the ECM. As a result of signal transduction by these integrins, the levels of mRNA and protein for several members of the metalloproteinase family are regulated in these cells. We have also used antibody and RGD peptide perturbation studies to determine the significance of cell/ECM interactions to normal osteogenesis. We found that interactions between the cell binding domain of FN and integrins are required for both normal morphogenesis and gene expression in cultured osteoblasts that differentiate to form bone-like tissue in culture. These data lead us to propose that beta 1 integrins play an important role in osteoblast differentiation as well as in bone remodeling.

NASA Discipline Number 26-10↗
DOE OSTI2021

Polymersomes Decorated with the SARS-CoV-2 Spike Protein Receptor-Binding Domain Elicit Robust Humoral and Cellular Immunity

The COVID-19 pandemic underscores the need for rapid, safe, and effective vaccines. In contrast to some traditional vaccines, nanoparticle-based subunit vaccines are particularly efficient in trafficking antigens to lymph nodes, where they induce potent immune cell activation. Here, we developed a strategy to decorate the surface of oxidation-sensitive polymersomes with multiple copies of the SARS-CoV-2 spike protein receptor-binding domain (RBD) to mimic the physical form of a virus particle. We evaluated the vaccination efficacy of these surface-decorated polymersomes (RBD surf ) in mice compared to RBD-encapsulated polymersomes (RBD encap ) and unformulated RBD (RBD free ), using monophosphoryl-lipid-A-encapsulated polymersomes (MPLA PS) as an adjuvant. While all three groups produced high titers of RBD-specific IgG, only RBD surf elicited a neutralizing antibody response to SARS-CoV-2 comparable to that of human convalescent plasma. Moreover, RBD surf was the only group to significantly increase the proportion of RBD-specific germinal center B cells in the vaccination-site draining lymph nodes. Both RBD surf and RBD encap drove similarly robust CD4 + and CD8 + T cell responses that produced multiple Th1-type cytokines. We conclude that a multivalent surface display of spike RBD on polymersomes promotes a potent neutralizing antibody response to SARS-CoV-2, while both antigen formulations promote robust T cell immunity.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

cGAS-like receptors sense RNA and control 3'2'-cGAMP signalling in Drosophila

Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger cG[2'–5']pA[3'–5']p (2'3'-cGAMP) and controls activation of innate immunity in mammalian cells. Animal genomes typically encode multiple proteins with predicted homology to cGAS, but the function of these uncharacterized enzymes is unknown. Here we show that cGAS-like receptors (cGLRs) are innate immune sensors that are capable of recognizing divergent molecular patterns and catalysing synthesis of distinct nucleotide second messenger signals. Crystal structures of human and insect cGLRs reveal a nucleotidyltransferase signalling core shared with cGAS and a diversified primary ligand-binding surface modified with notable insertions and deletions. We demonstrate that surface remodelling of cGLRs enables altered ligand specificity and used a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster. We show that RNA recognition activates Drosophila cGLR1 to synthesize the novel product cG[3'–5']pA[2'–5']p (3'2'-cGAMP). A crystal structure of Drosophila stimulator of interferon genes (dSTING) in complex with 3'2'-cGAMP explains selective isomer recognition, and 3'2'-cGAMP induces an enhanced antiviral state in vivo that protects from viral infection. Similar to radiation of Toll-like receptors in pathogen immunity, our results establish cGLRs as a diverse family of metazoan pattern recognition receptors.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Sorafenib derivatives-functionalized gold nanoparticles confer protection against tumor angiogenesis and proliferation via suppression of EGFR and VEGFR-2

Sorafenib is a multi-kinase inhibitor that has been highlighted as a tumor suppressor due to its anti-proliferative and anti-angiogenic properties, whereas the clinical application of Sorafenib is restricted by the side effects it may cause. The past decade has witnessed the development of a series of sorafenib derivatives to improve the clinical performance of sorafenib. Gold nanoparticles (AuNPs) have been widely utilized in drug delivery systems due to their unique properties, including biocompatible nature, simple preparation, and easy surface modification. Herein, this study is aimed to investigate the anti-tumor effects of new sorafenib derivatives-capped gold nanoparticles (AuNPs-New Sor) in tumor formation and metastasis as well as the underlying mechanisms. Initially, new sorafenib derivatives were constructed and combined with AuNPs to form AuNPs-New Sor, and the properties of synthesized AuNPs-New Sor were identified in a mouse model of tumorigenesis. The effect of AuNPs-New Sor on tumor vascular normalization was investigated by assessing vascular permeability and perfusion rate. Next, we evaluated the effect of AuNPs-New Sor on migration and viability of tumor cells and human umbilical vein endothelial cells (HUVECs) as well as on HUVEC angiogenesis in vitro. A melanoma mouse model was further established for in vivo substantiation of the anti-tumor effect of AuNPs-New Sor. According to the results, AuNPs could deliver new sorafenib derivatives into tumor tissues and downregulate the expression of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), thereby suppressing tumor migration, EMT, and angiogenesis in vitro. In addition, AuNPs-New Sor displayed competitive anti-tumor activities in vivo. Taken together, AuNPs-New Sor may attenuate tumor development and angiogenesis through downregulation of EGFR and VEGFR-2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Simultaneous Targeting of RSK and AKT Efficiently Inhibits YB-1-Mediated Repair of Ionizing Radiation-Induced DNA Double-Strand Breaks in Breast Cancer Cells

Y-box binding protein 1 (YB-1) overexpression is associated with chemotherapy- and radiation therapy resistance. Ionizing radiation (IR), receptor tyrosine kinase ligands, and mutation in KRAS gene stimulate activation of YB-1. YB-1 accelerates the repair of IR-induced DNA double-strand breaks (DSBs). Ribosomal S6 kinase (RSK) is the main kinase inducing YB-1 phosphorylation. We investigated the impact of RSK targeting on DSB repair and radiosensitivity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2024

Eucalyptus Wood Smoke Extract Elicits a Dose-Dependent Effect in Brain Endothelial Cells

The frequency, duration, and size of wildfires have been increasing, and the inhalation of wildfire smoke particles poses a significant risk to human health. Epidemiological studies have shown that wildfire smoke exposure is positively associated with cognitive and neurological dysfunctions. However, there is a significant gap in knowledge on how wildfire smoke exposure can affect the blood–brain barrier and cause molecular and cellular changes in the brain. Our study aims to determine the acute effect of smoldering eucalyptus wood smoke extract (WSE) on brain endothelial cells for potential neurotoxicity in vitro. Primary human brain microvascular endothelial cells (HBMEC) and immortalized human brain endothelial cell line (hCMEC/D3) were treated with different doses of WSE for 24 h. WSE treatment resulted in a dose-dependent increase in IL-8 in both HBMEC and hCMEC/D3. RNA-seq analyses showed a dose-dependent upregulation of genes involved in aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (NRF2) pathways and a decrease in tight junction markers in both HBMEC and hCMEC/D3. When comparing untreated controls, RNA-seq analyses showed that HBMEC have a higher expression of tight junction markers compared to hCMEC/D3. In summary, our study found that 24 h WSE treatment increases IL-8 production dose-dependently and decreases tight junction markers in both HBMEC and hCMEC/D3 that may be mediated through the AhR and NRF2 pathways, and HBMEC could be a better in vitro model for studying the effect of wood smoke extract or particles on brain endothelial cells.

60 APPLIED LIFE SCIENCES↗