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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 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin 1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Rethinking the Susceptibility-Based Strategy for Marine Cloud Brightening Climate Intervention: Experiment With CESM2 and Its Implications

Previous modeling studies indicate that even though marine cloud brightening under a susceptibility-based strategy is effective in reducing the global average surface temperature, it triggers a La Niña-like sea-surface temperature response with cooling mostly confined within lower latitudes. Here we explore a different cloud seeding strategy involving seeding of regions with low susceptibility, primarily over the ocean in midlatitudes during the winter. Simulations with the Community Earth System Model, version 2 reveal that because the regional forcing is weaker and more widespread, cooling is more evenly distributed over the globe. This new strategy also does not result in the La Niña-like state seen in the other strategies.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Heracles: Predictive Tools for Opioid Crisis Intervention - m/q Initiative Project Report

The opioid crisis in the United States is being fueled primarily by fentanyl and its molecular analogs, which can be anywhere from 50 to 1,000 times more potent than morphine. Fentanyl itself is straightforward to synthesize; furthermore, the structure is such that fentanyl’s flexible, rotatable side chains are easy to modify to create new analogs. Reference-free computational techniques to predict and identify new fentanyls have the potential to provide a desperately needed preemptive advantage to regulatory stakeholders and toxicologists. The computational pipeline Heracles was developed with this preemptive advantage in mind. Heracles has two primary components: 1) the creation of an in silico library of putative fentanyl analogs, and 2) a downselection pipeline to prioritize generated fentanyl analogs predicted to be potent and easy to synthesize. Experimental observables were also predicted for prioritized analogs, with validation of the observables begun. Heracles has demonstrated potential to aid in the advancement of reference-free paradigms while providing new tools to first responders and other stakeholders attempting to mitigate the opioid crisis.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Regulatory interventions improve the biosynthesis of limiting amino acids from methanol carbon to improve synthetic methylotrophy in Escherichia coli

Synthetic methylotrophy aims to engineer methane and methanol utilization pathways in platform hosts like Escherichia coli for industrial bioprocessing of natural gas and biogas. While recent attempts to engineer synthetic methylotrophs have proved successful, autonomous methylotrophy, that is, the ability to utilize methane or methanol as sole carbon and energy substrates, has not yet been realized. Here, we address an important limitation of autonomous methylotrophy in E. coli: the inability of the organism to synthesize several amino acids when grown on methanol. We targeted global and local amino acid regulatory networks. Those include removal of amino acid allosteric feedback inhibition (argA H15Y , ilvA L447F , hisG E271K , leuA G462D , proB D107N , thrA S345F, trpE S40F ), knockouts of transcriptional repressors (ihfA, metJ); and overexpression of amino acid biosynthetic operons (hisGDCBHAFI, leuABCD, thrABC, trpEDCBA) and transcriptional regulators (crp, purR). Compared to the parent methylotrophic E. coli strain that was unable to synthesize these amino acids from methanol carbon, these strategies resulted in improved biosynthesis of limiting proteinogenic amino acids (histidine, leucine, lysine, methionine, phenylalanine, threonine, tyrosine) from methanol carbon. In several cases, improved amino acid biosynthesis from methanol carbon led to improvements in methylotrophic growth in methanol minimal medium supplemented with a small amount of yeast extract. Here, this study addresses a key limitation currently preventing autonomous methylotrophy in E. coli and possibly other synthetic methylotrophs and provides insight as to how this limitation can be alleviated via global and local regulatory modifications.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention

Type 1 diabetes results from the progressive loss of beta cells, a process propagated by pro-inflammatory cytokine signaling that disrupts the balance between the expression of pro- and anti-apoptotic proteins. To identify such proteins, we performed comprehensive proteomics of human pancreatic islets treated with interleukin-1ß and interferon-?, leading to the identification of 11,325 proteins, of which 387 were significantly regulated by treatment. We then tested the function of growth/differentiation factor 15 (GDF15), which was repressed by the cytokine treatment. We found that GDF15 translation was blocked during inflammation, while the addition of exogenous GDF15 inhibited interleukin-1ß/interferon-?-induced apoptosis of human islets and a human beta-cell line. Furthermore, administration of GDF15 significantly decreased insulitis in NOD mice. Our approach provides a unique resource for the identification of the human islet proteins regulated by cytokines and was effective in discovering a potential target for type 1 diabetes therapy.

Nakayasu, Ernesto S.↗