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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 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Association of post-COVID phenotypic manifestations with new-onset psychiatric disease

Acute COVID-19 infection can be followed by diverse clinical manifestations referred to as Post Acute Sequelae of SARS-CoV2 Infection (PASC). Studies have shown an increased risk of being diagnosed with new-onset psychiatric disease following a diagnosis of acute COVID-19. However, it was unclear whether non-psychiatric PASC-associated manifestations (PASC-AMs) are associated with an increased risk of new-onset psychiatric disease following COVID-19. A retrospective electronic health record (EHR) cohort study of 2,391,006 individuals with acute COVID-19 was performed to evaluate whether non-psychiatric PASC-AMs are associated with new-onset psychiatric disease. Data were obtained from the National COVID Cohort Collaborative (N3C), which has EHR data from 76 clinical organizations. EHR codes were mapped to 151 non-psychiatric PASC-AMs recorded 28–120 days following SARS-CoV-2 diagnosis and before diagnosis of new-onset psychiatric disease. Association of newly diagnosed psychiatric disease with age, sex, race, pre-existing comorbidities, and PASC-AMs in seven categories was assessed by logistic regression. There were significant associations between a diagnosis of any psychiatric disease and five categories of PASC-AMs with odds ratios highest for neurological, cardiovascular, and constitutional PASC-AMs with odds ratios of 1.31, 1.29, and 1.23 respectively. Secondary analysis revealed that the proportions of 50 individual clinical features significantly differed between patients diagnosed with different psychiatric diseases. Our study provides evidence for association between non-psychiatric PASC-AMs and the incidence of newly diagnosed psychiatric disease. Significant associations were found for features related to multiple organ systems. This information could prove useful in understanding risk stratification for new-onset psychiatric disease following COVID-19. Prospective studies are needed to corroborate these findings.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Galectin-1 secreted by bone marrow-derived mesenchymal stem cells mediates anti-inflammatory responses in acute airway disease

The hallmarks of allergic airway disease (AAD) include infiltration of inflammatory cells into the bronchoalveolar space. Bone marrow derived mesenchymal stem cells (BMSCs) show anti-inflammatory properties in AAD. In addition, galectin-1 (Gal-1) is a lectin significantly upregulated upon inflammation and is also known to mediate potential anti-inflammatory responses. We hypothesized that BMSCs regulated inflammatory responses by secretion of Gal-1 during AAD pathogenesis. BMSCs were isolated from murine femurs and tibiae and adoptively transferred into an ovalbumin-induced AAD mouse model. Knockdown of Gal-1 in BMSCs was performed using shRNA. Flow cytometry, ELISAs, and immunohistology were performed to analyze inflammatory responses in mice, and a Transwell system was used to establish an in vitro co-culture system of lung epithelial cells (MLE-12) and BMSCs. Administration of BMSCs significantly upregulated Gal-1 expression upon inflammation and decreased infiltration of inflammatory cells and secretion of proinflammatory cytokines in vivo. In addition, we showed that this function was mediated by reduced activation of the MAPK p38 signaling pathway. Similar observations were found using an in vitro lipopolysaccharide-induced model when MLE-12 cells were co-cultured with BMSCs. Gal-1 secretion by BMSCs alleviated inflammatory responses observed in AAD and hence provides a promising therapeutic alternative to AAD patients insensitive to conventional drug treatments.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Spatial metabolomics and lipidomics in kidney disease

Kidney disease is a global health issue that affects over 850 million people, and early detection is key to preventing severe disease and complications. Kidney diseases are associated with complex dysregulation of lipid metabolism. Spatial metabolomics through mass spectrometry imaging (MSI) enables spatial mapping of the lipids in tissue and includes a variety of techniques that can be used to image lipids. In the kidney MSI studies often seek to resolve individual functional tissue units such as glomeruli and proximal tubules. Several different MSI techniques such as matrix-assisted laser desorption/ionization and desorption electrospray ionization have been used to characterize lipids and small molecules in chronic kidney disease, acute kidney injury, genetic kidney disease, and cancer. In this review we provide several examples of how spatial metabolomics data can provide critical information concerning localization of changes in disease states. Additionally, when combined with pathology, measurements, transcriptomics, or proteomics, the metabolomic changes can illuminate underlying mechanisms and provide new clinical insights.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

The effects of chronic diseases on plutonium urinary excretion in former workers of the Mayak Production Association

The radiochemical analysis of plutonium activity in urine is the main method for indirect estimation of doses of internal exposure from plutonium incorporation in professional workers. It was previously shown that late-in-life acute diseases, particularly those that affect the liver, can promote accelerated rates of release of plutonium from the liver with enhanced excretion rates. This initial study examines the relationships of some chronic diseases on plutonium excretion as well as the terminal relative distribution of plutonium between the liver and skeleton. Fourteen cases from former workers at the Mayak Production Association (Mayak PA) who provided from 4–9 urine plutonium bioassays for plutonium, had an autopsy conducted after death, and had sufficient clinical records to document their health status were used in this study. Enhanced plutonium excretion was associated with more serious chronic diseases, including cardiovascular diseases and other diseases that involved the liver. These chronic diseases were also associated with relatively less plutonium found in the liver relative to the skeleton determined by analyses conducted after autopsy. These data further document health conditions that affect plutonium biokinetics and organ deposition and retention patterns and suggest that health status should be considered when conducting plutonium bioassays as these may alter subsequent dosimetry and risk models.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Neonatal Zika virus infection causes transient perineuronal net degradation

Perineuronal nets (PNNs) form a specialized extracellular matrix that predominantly surrounds parvalbumin (PV)-expressing GABAergic inhibitory interneurons and help regulate neuronal activity. Their formation early in the postnatal period is regulated by neuronal signaling and glial activation raising concerns that part of the long-term effects ascribed to perinatal viral infections could be mediated by altered PNN formation. Previously, we developed a model of neonatal Zika virus (ZIKV) infection where mice have lifelong neurological sequelae that includes motor disfunction and reduced anxiety coupled with a persistent low-grade expression in proinflammatory markers despite resolving the acute infection. Here, we demonstrate that ZIKV infection to P1 neonatal mice results in a reduction of PNN formation during the acute disease with significant reduction in Wisteria floribunda agglutinin (WFA) staining at the peak of infection [15 days post infection (dpi)] that persisted after the symptoms resolved (30 dpi). At 60 dpi, when there is residual inflammation in the CNS, the number of WFA + cells and the level of WFA staining as well as levels of aggrecan and brevican in the brains of convalescent mice were not different from those in uninfected controls, however, there was increased frequency of PNNs with an immature phenotype. Over time the impact of the perinatal infection became less evident and there were no clear differences in PNN morphology between the groups at 1 year post infection. Of note, the reduction in PNNs during acute ZIKV infection was not associated with decreased mRNA levels of aggrecan or brevican, but increased levels of degraded aggrecan and brevican indicating increased PNN degradation. These changes were associated with increased expression of matrix metalloproteinase 12 (MMP12) and MMP19, but not MMP9, a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) or ADAMTS5. Together our findings indicate that infection at the time of PNN development interferes with PNN formation, but the nets can reform once the infection and inflammation subside.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Exposing structural variations in SARS-CoV-2 evolution

The mutation of SARS-CoV-2 influences viral function as residue replacements affect both physiochemical properties and folding conformations. Although a large amount of data on SARS-CoV-2 is available, the investigation of how viral functions change in response to mutations is hampered by a lack of effective structural analysis. Here, we exploit the advances of protein structure fingerprint technology to study the folding conformational changes induced by mutations. With integration of both protein sequences and folding conformations, the structures are aligned for SARS-CoV to SARS-CoV-2, including Alpha variant (lineage B.1.1.7) and Delta variant (lineage B.1.617.2). The results showed that the virus evolution with change in mutational positions and physicochemical properties increased the affinity between spike protein and ACE2, which plays a critical role in coronavirus entry into human cells. Additionally, these structural variations impact vaccine effectiveness and drug function over the course of SARS-CoV-2 evolution. The analysis of structural variations revealed how the coronavirus has gradually evolved in both structure and function and how the SARS-CoV-2 variants have contributed to more severe acute disease worldwide.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Breast Conservation in Women with Autoimmune Disease: The Role of Active Autoimmune Disease and Hypofractionation on Acute and Late Toxicity in a Case-Controlled Series

Autoimmune connective tissue disease (CTD) has historically represented a relative contraindication to breast conservation (BC) among patients with early-stage breast cancer. Controversy exists regarding the use of hypofractionated radiation therapy (RT) among patients with CTDs. We evaluated acute and late toxicity in patients with breast cancer and CTD treated with BC.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Wearable Sensors Measure Ankle Joint Changes of Patients with Parkinson’s Disease before and after Acute Levodopa Challenge

Background . Previous studies found levodopa could improve the activity of the ankle joints of patients with Parkinson’s disease (PD). But ankle joint movement is composed of four motion ranges. The specific changes of four motion ranges in PD remain unknown. Objective . The purpose of this study was to decompose the complex ankle joint movement, measure ankle joint changes before and after the acute levodopa challenge test (ALCT), and investigate the effects of these parameters on gait performance. Methods . 29 PD patients and 30 healthy control subjects (HC) completed the Instrumented Stand and Walk (ISAW) test and gait parameters were collected by the JiBuEn gait analysis system. The percentage of improvement of gait data and the UPDRS III in the on-drug condition (ON) were determined with respect to the off-drug condition (OFF). Results . We observed a reduction in the heel strike angle (HS), 3-plantarflexion (3-PF) angle, and 4-dorsiflexion (4-DF) angle of ankle joints. We did not find significant difference in the toe-off angle (TO), 1-plantarflexion (1-PF) angle, and 2-dorsiflexion (2-DF) angle among three groups. Stride length improvement rate was significantly correlated with HS ( r s = 0.616, P < 0.001 ) and 3-PF ( r s = 0.639, P < 0.001 ) improvement rates. The improvement in the sum of rigidity items (UPDRS motor subsection item 22) was also correlated with HS ( r s = 0.389, P = 0.037 ) and 3-PF ( r s = 0.373, P = 0.046 ) improvement rates. Conclusions . Exogenous levodopa supplementation can significantly reduce the rigidity of patients with PD, improve their 3-PF and 4-DF of ankle joint kinematic parameters, and ultimately enhance their gait.

Wu, Zhuang↗
DOE OSTI2021

Viral Load Kinetics of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospitalized Individuals With Coronavirus Disease 2019

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) kinetics remain understudied, including the impact of remdesivir. In hospitalized individuals, peak sputum viral load occurred in week 2 of symptoms, whereas viremia peaked within 1 week of symptom-onset, suggesting early systemic seeding of SARS-CoV-2. Remdesivir treatment was associated with faster viral decay.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Deletion of the H108R Gene Reduces Virulence of the Pandemic Eurasia Strain of African Swine Fever Virus with Surviving Animals Being Protected against Virulent Challenge

African swine fever virus (ASFV) is the etiological agent of African swine fever (ASF), a devastating disease affecting domestic and wild swine and currently causing a global pandemic, severely affecting swine production. Here, we demonstrate that the deletion of the previously uncharacterized ASFV gene, H108R from the highly virulent ASFV-Georgia2007 (ASFV-G) genome strain, reduces virulence in domestic swine. ASFV-G-DH108R, a recombinant virus with the H108R gene deleted, was used to evaluate the involvement of the H108R gene for ASFV replication and virulence in swine. ASFV-G-DH108R showed a delayed replication in swine macrophage cultures. A group of five pigs, intramuscularly inoculated with 102 HAD50 of ASFV-G-DH108R, was observed over a 28-day period and compared with a similar group of animals inoculated with similar doses of the parental virulent virus. While all animals inoculated with ASFV-G developed an acute fatal disease, ASFV-G-DH108R inoculated animals, with the exception of one animal showing a protracted but fatal form of the disease, all survived the infection, remaining clinically healthy during the observational period. The surviving animals presented protracted viremias with lower virus titers compared with those of animals inoculated with the parental virus, and all of them developed a strong virus-specific antibody response. Importantly, all animals surviving ASFV-G-DAH108R infection were protected when challenged with the virulent parental strain, ASFV-G. This report constitutes the first evidence that the H108R gene is involved in ASFV virulence in swine and that the deletion of this gene may be used as a tool to increase the attenuation of currently experimental vaccines to improve their safety profiles.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Modeling the Influenza A NP-vRNA-Polymerase Complex in Atomic Detail

Seasonal flu is an acute respiratory disease that exacts a massive toll on human populations, healthcare systems and economies. The disease is caused by an enveloped Influenza virus containing eight ribonucleoprotein (RNP) complexes. Each RNP incorporates multiple copies of nucleoprotein (NP), a fragment of the viral genome (vRNA), and a viral RNA-dependent RNA polymerase (POL), and is responsible for packaging the viral genome and performing critical functions including replication and transcription. A complete model of an Influenza RNP in atomic detail can elucidate the structural basis for viral genome functions, and identify potential targets for viral therapeutics. In this work we construct a model of a complete Influenza A RNP complex in atomic detail using multiple sources of structural and sequence information and a series of homology-modeling techniques, including a motif-matching fragment assembly method. Our final model provides a rationale for experimentally-observed changes to viral polymerase activity in numerous mutational assays. Further, our model reveals specific interactions between the three primary structural components of the RNP, including potential targets for blocking POL-binding to the NP-vRNA complex. The methods developed in this work open the possibility of elucidating other functionally-relevant atomic-scale interactions in additional RNP structures and other biomolecular complexes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A phase 2 study of sorafenib combined with conventional therapies in refractory central nervous system leukemia

Background Patients with refractory central nervous system leukemia (CNSL) have a dismal prognosis and lack effective therapy. Case reports have shown that sorafenib is effective against brain metastases, including leukemia. Methods To explore the efficacy of sorafenib combined with conventional therapies for refractory CNSL, a phase 2 study was conducted. The primary end point was the complete remission rate (CRR) within 8 weeks of treatment. Secondary end points included the overall response rate (ORR), event‐free survival (EFS), overall survival (OS), and adverse events (AEs). Results Twenty‐six patients with refractory CNSL were enrolled; they included 17 with isolated CNSL, 7 with hematological relapse, and 2 with another extramedullary relapse. After 8 weeks of treatment, 21 patients achieved complete remission, 2 achieved partial remission, and 3 achieved no remission for a CRR of 80.8% (95% CI, 62.1%‐91.5%) and an ORR of 88.5% (95% CI, 71.0%‐96.0%). Twenty patients survived, and 6 died. The 2‐year EFS and OS rates were 75.0% (95% CI, 54.5%‐88.3%) and 76.9% (95% CI, 54.2%‐90.4%), respectively. Six patients experienced grade 3 or 4 treatment‐related AEs, including moderate chronic graft‐vs‐host disease (n = 3), grade 3 or 4 acute graft‐vs‐host disease (n = 2), and grade 3 skin rash (n = 1). No treatment‐related deaths occurred during the therapy of refractory CNSL. Conclusions Sorafenib combined with conventional therapies is effective and safe for refractory CNSL. Lay Summary Sorafenib combined with conventional therapies is effective and safe for refractory central nervous system leukemia.

Chen, Xiaoxia↗
DOE OSTI2020

Inducible epithelial resistance against acute Sendai virus infection prevents chronic asthma‐like lung disease in mice

Background and Purpose Respiratory viral infections play central roles in the initiation, exacerbation and progression of asthma in humans. An acute paramyxoviral infection in mice can cause a chronic lung disease that resembles human asthma. We sought to determine whether reduction of Sendai virus lung burden in mice by stimulating innate immunity with aerosolized Toll‐like receptor (TLR) agonists could attenuate the severity of chronic asthma‐like lung disease. Experimental Approach Mice were treated by aerosol with 1‐μM oligodeoxynucleotide (ODN) M362, an agonist of the TLR9 homodimer, and 4‐μM Pam2CSK4 (Pam2), an agonist of the TLR2/6 heterodimer, within a few days before or after Sendai virus challenge. Key Results Treatment with ODN/Pam2 caused ~75% reduction in lung Sendai virus burden 5 days after challenge. The reduction in acute lung virus burden was associated with marked reductions 49 days after viral challenge in eosinophilic and lymphocytic lung inflammation, airway mucous metaplasia, lumenal mucus occlusion and hyperresponsiveness to methacholine. Mechanistically, ODN/Pam2 treatment attenuated the chronic asthma phenotype by suppressing IL‐33 production by type 2 pneumocytes, both by reducing the severity of acute infection and by down‐regulating Type 2 (allergic) inflammation. Conclusion and Implications These data suggest that treatment of susceptible human hosts with aerosolized ODN and Pam2 at the time of a respiratory viral infection might attenuate the severity of the acute infection and reduce initiation, exacerbation and progression of asthma.

Goldblatt, David L.↗
DOE OSTI2022

Microcystin-LR aerosol induces inflammatory responses in healthy human primary airway epithelium

Harmful algal blooms plague bodies of freshwater globally. These blooms are often composed of outgrowths of cyanobacteria capable of producing the heptapeptide Microcystin-LR (MC-LR) which is a well-known hepatotoxin. Recently, MC-LR has been detected in aerosols generated from lake water. However, the risk for human health effects due to MC-LR inhalation exposure have not been extensively investigated. In this study, we exposed a fully differentiated 3D human airway epithelium derived from 14 healthy donors to MC-LR-containing aerosol for 3 minutes per day for 3 days. Concentrations of MC-LR ranged from 100 pM to 1 µM. Although there were little to no detrimental alterations in measures of the airway epithelial function (i.e. cell survival, tissue integrity, mucociliary clearance, or cilia beating frequency), a distinct shift in the transcriptional activity was found. Genes related to inflammation were found to be upregulated such as C-C motif chemokine 5 (CCL5; log2FC = 0.56 , p = 0.02) and C-C chemokine receptor type 7 (CCR7; log2FC = 0.83, p = 0.03). Functionally, conditioned media from MC-LR exposed airway epithelium was also found to have significant chemo-attractive properties for primary human neutrophils. Additionally, increases were found in the concentration of secreted chemokine proteins in the conditioned media such as CCL1 (log2FC = 5.07 , p = 0.0001) and CCL5 (log2FC = 1.02, p = 0.046). These results suggest that MC-LR exposure to the human airway epithelium is capable of inducing an inflammatory response that may potentiate acute or chronic disease.

3D human airway epithelium↗
DOE OSTI2021

A Novel Glutathione S-Transferase Gtt2 Class (VpGSTT2) Is Found in the Genome of the AHPND/EMS Vibrio parahaemolyticus Shrimp Pathogen

Glutathione S-transferases are a family of detoxifying enzymes that catalyze the conjugation of reduced glutathione (GSH) with different xenobiotic compounds using either Ser, Tyr, or Cys as a primary catalytic residue. We identified a novel GST in the genome of the shrimp pathogen V. parahaemolyticus FIM- S1708+, a bacterial strain associated with Acute Hepatopancreatic Necrosis Disease (AHPND)/Early Mortality Syndrome (EMS) in cultured shrimp. This new GST class was named Gtt2. It has an atypical catalytic mechanism in which a water molecule instead of Ser, Tyr, or Cys activates the sulfhydryl group of GSH. The biochemical properties of Gtt2 from Vibrio parahaemolyticus (VpGSTT2) were characterized using kinetic and crystallographic methods. Recombinant VpGSTT2 was enzymatically active using GSH and CDNB as substrates, with a specific activity of 5.7 units/mg. Low affinity for substrates was demonstrated using both Michaelis–Menten kinetics and isothermal titration calorimetry. The crystal structure showed a canonical two-domain structure comprising a glutathione binding G-domain and a hydrophobic ligand H domain. A water molecule was hydrogen-bonded to residues Thr9 and Ser 11, as reported for the yeast Gtt2, suggesting a primary role in the reaction. Molecular docking showed that GSH could bind at the G-site in the vicinity of Ser11. G-site mutationsT9A and S11A were analyzed. S11A retained 30% activity, while T9A/S11A showed no detectable activity. VpGSTT2 was the first bacterial Gtt2 characterized, in which residues Ser11 and Thr9 coordinated a water molecule as part of a catalytic mechanism that was characteristic of yeast GTT2. The GTT2 family has been shown to provide protection against metal toxicity; in some cases, excess heavy metals appear in shrimp ponds presenting AHPND/EMS. Further studies may address whether GTT2 in V. parahaemolyticus pathogenic strains may provide a competitive advantage as a novel detoxification mechanism.

59 BASIC BIOLOGICAL SCIENCES↗