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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 55 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Nebulized delivery of a broadly neutralizing SARS-CoV-2 RBD-specific nanobody prevents clinical, virological, and pathological disease in a Syrian hamster model of COVID-19

There remains an unmet need for globally deployable, low-cost therapeutics for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Previously, we reported on the isolation and in vitro characterization of a potent single-domain nanobody, NIH-CoVnb-112, specific for the receptor-binding domain (RBD) of SARS-CoV-2. Here, we report on the molecular basis for the observed broad in vitro neutralization capability of NIH-CoVnb-112 against variant SARS-CoV-2 pseudoviruses. The structure of NIH-CoVnb-112 bound to SARS-CoV-2 RBD reveals a large contact surface area overlapping the angiotensin converting enzyme 2 (ACE2) binding site, which is largely unencumbered by the common RBD mutations. In an in vivo pilot study, we demonstrate effective reductions in weight loss, viral burden, and lung pathology in a Syrian hamster model of COVID-19 following nebulized delivery of NIH-CoVnb-112. These findings support the further development of NIH-CoVnb-112 as a potential adjunct preventative therapeutic for the treatment of SARS-CoV-2 infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

PYK-SubstitutionOME: an integrated database containing allosteric coupling, ligand affinity and mutational, structural, pathological, bioinformatic and computational information about pyruvate kinase isozymes

Interpreting changes in patient genomes, understanding how viruses evolve and engineering novel protein function all depend on accurately predicting the functional outcomes that arise from amino acid substitutions. To that end, the development of first-generation prediction algorithms was guided by historic experimental datasets. However, these datasets were heavily biased toward substitutions at positions that have not changed much throughout evolution (i.e. conserved). Although newer datasets include substitutions at positions that span a range of evolutionary conservation scores, these data are largely derived from assays that agglomerate multiple aspects of function. To facilitate predictions from the foundational chemical properties of proteins, large substitution databases with biochemical characterizations of function are needed. We report here a database derived from mutational, biochemical, bioinformatic, structural, pathological and computational studies of a highly studied protein family—pyruvate kinase (PYK). A centerpiece of this database is the biochemical characterization—including quantitative evaluation of allosteric regulation—of the changes that accompany substitutions at positions that sample the full conservation range observed in the PYK family. We have used these data to facilitate critical advances in the foundational studies of allosteric regulation and protein evolution and as rigorous benchmarks for testing protein predictions. We trust that the collected dataset will be useful for the broader scientific community in the further development of prediction algorithms.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Irradiation of the kidneys causes pathologic remodeling in the nontargeted heart: A role for the immune system

Cardiac disease is a frequent and significant adverse event associated with radiotherapy for cancer. Identifying the underlying mechanism responsible for radiation injury to the heart will allow interventions to be developed. In the present study, we tested if local kidney irradiation results in remodeling of the shielded, nontargeted heart. One kidney, two kidneys, or the total body of male WAG and Dahl SS rats were irradiated with 10 Gy of X-rays. Local kidney irradiation resulted in systemic hypertension, increased BUN, infiltration of T lymphocytes, natural killer cells, and macrophages into the renal cortex and medulla, and renal fibrosis. Local irradiation of kidneys in WAG rats resulted in remodeling in the nontargeted heart after 120 days, manifested by perivascular fibrosis and increased interventricular septal thickness, but was not seen in Dahl SS rats due to a high baseline level of fibrosis in the sham-irradiated animals. Genetic depletion of T cells mitigated the nephropathy after local kidney irradiation, indicating a role for the immune system in mediating this outcome. Local kidney irradiation resulted in a cascade of pro-inflammatory cytokines and low-molecular weight metabolites into the circulation associated with transmission of signals resulting in pathologic remodeling in the nontargeted heart. A new model is proposed whereby radiation-induced cardiac remodeling in susceptible animals is indirect, with lower hemi body organs such as the kidney exporting factors into the circulation that cause remodeling outside of the irradiated field in the shielded, nontargeted heart. This nontargeted effect appears to be mediated, in part, by the immune system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Global Explainability of A Deep Abstaining Classifier for Cancer Pathology Reports

We present a global explainability method to characterize sources of errors in a real-world multitask deep abstaining classifier (DAC), in the context of cancer histology prediction. Our multitask classifier, currently deployed for automated annotation of cancer pathology reports from NCI-SEER registries, was trained and evaluated on 1.04 million hand-annotated samples and makes simultaneous predictions of cancer site, subsite, histology, laterality, and behavior for each report. The DAC framework enables the model to abstain on ambiguous reports and confusing classes to achieve the target accuracy on the retained (non-abstained) samples, but at the cost of decreased coverage. Requiring 97% accuracy on the histology task caused our model to retain only 22% of all samples, mostly the less ambiguous and common classes. Local explainability with the GradInp technique provided a computationally efficient way of obtaining contextual reasoning for hundreds of thousands of individual predictions. Our method, involving dimensionality reduction of approximately 13000 aggregated local explanations (ALE), offers a tractable path to true global explainability. It enabled identification of sources of errors in histology classification, globally, as hierarchical complexity among classes, label noise, insufficient information, and conflicting evidence. This suggests several strategies for iterative improvement of our DAC, including well-designed exclusion criteria, focused annotation, and reduced penalties for errors involving hierarchically related classes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Age, vascular disease, and Alzheimer’s disease pathologies in amyloid negative elderly adults

Background: We recently reported that CSF phosphorylated tau (p-Tau 181 ) relative to Aβ 40 (CSF p-Tau/Aβ 40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau 181 alone. While elevations of CSF p-Tau/Aβ 40 can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity. Methods: We examined relationships between CSF p-Tau/Aβ 40 , and CSF Aβ 42 /Aβ 40 , Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer’s disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had 18 F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ 40 associations with these measures as well. Results: Elevated CSF p-Tau/Aβ 40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ 42 /Aβ 40 , higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ 40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ 40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements. Conclusions: These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

T Cells Contribute to Pathological Responses in the Non-Targeted Rat Heart following Irradiation of the Kidneys

Heart disease is a significant adverse event caused by radiotherapy for some cancers. Identifying the origins of radiogenic heart disease will allow therapies to be developed. Previous studies showed non-targeted effects manifest as fibrosis in the non-irradiated heart after 120 days following targeted X-irradiation of the kidneys with 10 Gy in WAG/RijCmcr rats. To demonstrate the involvement of T cells in driving pathophysiological responses in the out-of-field heart, and to characterize the timing of immune cell engagement, we created and validated a T cell knock downrat on the WAG genetic backgrou nd. Irradiation of the kidneys with 10 Gy of X-rays in wild-type rats resulted in infiltration of T cells, natural killer cells, and macrophages after 120 days, and none of these after 40 days, suggesting immune cell engagement is a late response. The radiation nephropathy and cardiac fibrosis that resulted in these animals after 120 days was significantly decreased in irradiated T cell depleted rats. We conclude that T cells function as an effector cell in communicating signals from the irradiated kidneys which cause pathologic remodeling of non-targeted heart.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Benefits and pathologies associated with the inflammatory response

Adult skeletal muscle regenerates completely after a damage, thanks to the satellite cells, or muscle stem cells (MuSCs), that implement the adult myogenic program. This program is sustained by both robust intrinsic mechanisms and extrinsic cues coming from the close neighborhood of MuSCs during muscle regeneration. Among the various cell types present in the regenerating muscle, immune cells, and particularly macrophages, exert numerous functions and provide sequential transient niches to support the myogenic program. The adequate orchestration of the delivery of these cues ensures efficient muscle regeneration and full functional recovery. The situation is very different in muscular dystrophies where asynchronous and permanent microinjuries occur, triggering contradictory regenerating cues at the same time in a specific area, that lead to chronic inflammation and fibrogenesis. Here we review the beneficial effects that leukocytes, and particularly macrophages, exert on their neighboring cells during skeletal muscle regeneration after an acute injury. Then, the more complicated (and less beneficial) roles of leukocytes during muscular dystrophies are presented. Finally, we discuss how the inflammatory compartment may be a target to improve muscle regeneration in both acute muscle injury and muscle diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Tissue replication and mucosal swab detection of Sosuga virus in Syrian hamsters in the absence of overt tissue pathology and clinical disease

Human infection with Sosuga virus (SOSV), a recently discovered pathogenic paramyxovirus, has been reported in one individual to date. No animal models of disease are currently available for SOSV. Here, we describe initial characterization of experimental infection in Syrian hamsters, including kinetics of virus dissemination and replication, and the corresponding clinical parameters, immunological responses, and histopathology. Here, we demonstrate susceptibility of hamsters to infection in the absence of clinical signs or significant histopathologic findings in tissues.

60 APPLIED LIFE SCIENCES↗