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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 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Products and methods for organ protection with noble nanoparticles

Products and methods for redirecting the pathological biochemical process of accumulation of reduced pyridine nucleotides under deleterious hypoxia conditions toward the reduction of the precursor salt and the biosynthesis of biologically compatible, antioxidant noble metal nanoparticles and the simultaneous restoring of the tissue redox state are provided. The products and methods have application in the treatment of hypoxia and hypoxia-related diseases and disorders. Such products and methods are also useful in organ transplantation and recovery, in screening of anti-hypoxia agents, and in detecting elevated levels of the reducing equivalents of the redox state, for example, NADH, NADPH, GSH, and TrxSH 2 , in cells, tissues, or organs.

Rozhkova, Elena A.↗
DOE OSTI2023

Single-cell, whole-embryo phenotyping of mammalian developmental disorders

Mouse models are a critical tool for studying human diseases, particularly developmental disorders. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be ‘decomposable’ through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

The key role of the ferroptosis mechanism in neurological diseases and prospects for targeted therapy

Neurological disorders represent a major global health concern owing to their intricate pathological processes. Ferroptosis, defined as a form of cell death that is reliant on iron, has been closely linked to various neurological conditions. The fundamental process underlying ferroptosis is defined by the excessive buildup of iron ions, which initiates lipid peroxidation processes leading to cellular demise. Neurons, as highly metabolically active cells, are susceptible to oxidative stress, and imbalances in iron metabolism can directly initiate the ferroptosis process. In neurodegenerative disorders like Alzheimer’s disease and Parkinson’s disease, ferroptosis driven by iron accumulation represents a fundamental pathological connection. Although the connection between ferroptosis and neurological diseases is clear, clinical application still faces challenges, such as precise regulation of iron metabolism, development of specific drugs, and assessment of efficacy. The limited comprehension of the ferroptosis mechanism hinders the development of personalized treatment approaches. Consequently, subsequent investigations must tackle these obstacles to facilitate the clinical application of ferroptosis-associated therapies in neurological disorders. This article provides a comprehensive overview of the most recent advancements regarding the underlying mechanisms of ferroptosis. Subsequently, the study investigates the mechanistic contributions of ferroptosis within the nervous system. In conclusion, we evaluate and deliberate on targeted therapeutic strategies associated with ferroptosis and neurological disorders.

Xie, Chenyu↗
DOE OSTI2021

Modulation of Neuroinflammation by Low-Dose Radiation Therapy in an Animal Model of Alzheimer's Disease

Recently, several studies have reported that low-dose radiation therapy (RT) suppresses the release of proinflammatory cytokines in inflammatory-degenerative disorders, including Alzheimer disease (AD). AD is the most common cause of dementia, and neuroinflammation is one of the major contributing factors in AD pathogenesis. Therefore, low-dose RT may be used clinically for treating AD. However, the appropriate doses, effects, and underlying mechanisms of RT in AD have not been determined. In this study, we aimed to determine the appropriate RT dose and schedule for AD treatment and to investigate the therapeutic effects and mechanisms of low-dose RT in AD.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2019

Synthesis and in silico and in vitro evaluation of trimethoxy-benzamides designed as anti-prion derivatives

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are neurodegenerative disorders which affect mammals, including the human species, and arise after the conversion of the monomeric cellular prion protein (PrP{sup C}) into the aggregated scrapie form (PrP{sup Sc}). There is no therapy to treat TSEs and the identification of compounds that bind PrP{sup C}, preventing its conversion into PrP{sup Sc}, is a viable therapeutic strategy. We designed and synthesized six novel trimethoxy-benzamide compounds as anti-prion drug candidates. Molecular docking analyses predicted that all the derivatives bind to a hotspot region located in the PrP globular domain with very similar spatial orientation and interaction mode. Although none of the analogs inhibited in vitro-aggregation of recombinant PrP (rPrP) in a cell-free conversion assay, the RT-QuIC, compound 8a accelerated rPrP conversion into PrP{sup Sc}-like species. STD-NMR and ITC analyses indicated that both 8a and 8b bind to rPrP{sup 90–231}. These analogs were toxic to PrP{sup Sc}-infected cell lines, hence we could not assess their anti-prion activity by using this cellular approach, although this toxicity was cell line-dependent. These results point out that the 4-amino-quinoline trimethoxy-benzamide scaffold described herein represents a novel chemical pattern useful as a starting point for future structural optimization in the design of PrP ligands with improved affinity and safety profiles.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Single-atom materials boosting wearable orthogonal uric acid detection

Abstract Uric acid (UA) is a vital biomarker for the diagnosis and management of various health conditions, including cardiovascular diseases, gout, kidney disorders, metabolic syndrome, and wound healing. Despite significant advances in wearable sensor technology, challenges persist in developing wearable sensors that are capable of maintaining high sensitivity, selectivity, and stability. In this study, we present an epidermal sensing platform enhanced with single-atom materials (SAMs) designed for flexible and orthogonal electrochemical detection of UA. We designed and synthesized an SAM with Fe-N 5 active sites to boost the electrochemical sensing signals, integrating it with laser-engraved graphene (LEG) to fabricate a wearable SAM-based UA patch sensor. This design provides superior UA detection performance compared to sensors based on conventional nanomaterials. In addition, we enhanced the detection accuracy and range by using an orthogonal approach that combines direct oxidation through differential pulse voltammetry (DPV) along with parallel biocatalytic amperometric detection. The resulting SAM-based UA orthogonal sensor patch demonstrated exceptional performance in wearable applications through tests measuring sweat UA levels in subjects before and after consuming a purine-rich diet. Graphical Abstract

Ding, Shichao↗
DOE OSTI2026

Ultra-low field 13 C MRI of hyperpolarized pyruvate

Medicine is evolving beyond therapy largely predicated on anatomical information and towards incorporating patient-specific molecular biomarkers of disease for more accurate diagnosis and effective treatment. The complementary combination of hyperpolarization by spin-lock induced crossing signal amplification by reversible exchange (SLIC SABRE) and low field magnetic resonance imaging (MRI) can enable accessible metabolic imaging to advance personalized medicine. Hyperpolarized 13 C-enriched pyruvate has demonstrated promise for imaging metabolism in cancer, heart disease and neurodegenerative disorders; however, broader clinical adoption awaits validated clinical indications, and is further constrained by the cost and limited availability of current hyperpolarization technology. Parahydrogen-based polarization techniques, paired with low-cost high-performance MRI at millitesla fields, offer a means of broadening the reach of metabolic imaging. Here we show results demonstrating in situ hyperpolarization of pyruvate at 6.5 mT by SLIC SABRE, followed by immediate readout without field cycling or sample shuttling. We achieve 13 C signal enhancements several million times above thermal equilibrium at 6.5 mT, corresponding to polarization levels of approximately 3%. Leveraging this enhancement, we perform 13 C MRI and acquire NMR spectra with resolution sufficient to distinguish chemical shifts between pyruvate isotopomers. These results show a viable pathway towards accessible metabolic imaging with hyperpolarized 13 C MRI at ultra-low field.

Medical and clinical diagnostics↗
DOE OSTI2020

Mechanistic insights explain the transforming potential of the T507K substitution in the protein-tyrosine phosphatase SHP2

The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, in this work we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Simulated Night- Shift Schedule Disrupts the Plasma Lipidome and Reveals Early Markers of Cardiovascular Disease Risk

Introduction: The circadian system coordinates daily rhythms in lipid metabolism, storage and utilization. Disruptions of internal circadian rhythms due to altered sleep/wake schedules, such as in night-shift work, have been implicated in increased risk of cardiovascular disease and metabolic disorders. To determine the impact of a night-shift schedule on the human blood plasma lipidome, an in-laboratory simulated shift work study was conducted. Methods: Fourteen healthy young adults were assigned to 3 days of either a simulated day or night-shift schedule, followed by a 24-h constant routine protocol with fixed environmental conditions, hourly isocaloric snacks, and constant wakefulness to investigate endogenous circadian rhythms. Blood plasma samples collected at 3-h intervals were subjected to untargeted lipidomics analysis. Results: More than 400 lipids were identified and quantified across 21 subclasses. Focusing on lipids with low between-subject variation per shift condition, alterations in the circulating plasma lipidome revealed generally increased mean triglyceride levels and decreased mean phospholipid levels after night-shift relative to day-shift. The circadian rhythms of triglycerides containing odd chain fatty acids peaked earlier during constant routine after night-shift. Regardless of shift condition, triglycerides tended to either peak or be depleted at 16:30 h, with chain-specific differences associated with the direction of change. Discussion: The simulated night-shift schedule was associated with altered temporal patterns in the lipidome. This may be premorbid to the elevated cardiovascular risk that has been found epidemiologically in night-shift workers.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Metagenomic Alterations in Gut Microbiota Precede and Predict Onset of Colitis in the IL10 Gene-Deficient Murine Model

SUMMARY. Currently, predictive markers for the development andcourse of inflammatory bowel diseases (IBD) are not available. This study supports the notion that gut microbiome metagenomic profiles could be developed into a useful tool to assess risk and manage human IBD. BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are chronic inflammatory disorders where predictive bio-markers for the disease development and clinical course are sorely needed for development of prevention and early intervention strategies that can be implemented to improve clinical outcomes. Since gut microbiome alterations can reflect and/or contribute to impending host health changes, we examined whether gut microbiota metagenomic profiles would provide more robust measures for predicting disease outcomes in colitis-prone hosts. METHODS: Using the interleukin (IL) 10 gene-deficient (IL10KO) murine model where early life dysbiosis from antibiotic (cefoperozone [CPZ]) treated dams vertically transferred to pups increases risk for colitis later in life, we investigated temporal metagenomic profiles in the gut microbiota of post-weaning offspring and determined their relationship to even-tual clinical outcomes. RESULTS: Compared to controls, offspring acquiring maternalCPZ-induced dysbiosis exhibited a restructuring of intestinal microbial membership in both bacteriome and mycobiome that was associated with alterations in specific functional subsystems. Furthermore, among IL10 KO offspring fromCPZ-treated dams, several functional subsystems, particularly nitrogen metabolism, diverged between mice that developed spontaneous colitis (CPZ-colitis) versus those that did not (CPZ-no-colitis) at a time point prior to eventual clinical outcome. CONCLUSIONS: Our findings provide support that functional metagenomic profiling of gut microbes has potential and promise meriting further study for development of tools to assess risk and manage human IBD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Effects of Site and Magnetic Disorder on the Oxygen Vacancy Formation and Electronic and Optical Properties of La x Sr 1– x CoO 3–δ and SrFe y Co 1– y O 3–δ [plus supplemental information]

Disorder is an inevitable issue in practical applications of perovskites with the A-site occupied by La/Sr and the B-site occupied by Co/Fe. We performed density functional theory calculations to reveal the site and magnetic disorder effect on the oxygen vacancy formation and the electronic and optical properties of La x Sr 1–x CoO 3–δ and SrFe y Co 1–y O 3–δ systems. Generally, site disorder has little influence on the physical properties we studied, while magnetic disorder has a property-dependent effect for La A-site and Fe B-site doping of SrCoO 3 . Compared to ordered ferromagnetic (FM) calculations, disordered paramagnetic (PM) results can better describe the high-temperature behavior of lattice expansion and the multiple spin states of Co ions in La x Sr 1–x CoO 3 . The oxygen vacancy formation energy results show that the magnetic disorder has a more remarkable effect on SrFe y Co 1–y O 3–δ systems with a robust magnetic order than that on the La x Sr 1–x CoO 3–δ systems with a fragile magnetic order. The electronic structures in the PM phase have less spin polarization and broadened bands, by which the optical absorptions from the single spin channel transition in the FM phase have an obvious change in the magnitude and/or the trend. Furthermore, our work provides guidance for where and why to consider the disorder.

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

Regulation of Iron Homeostasis through Parkin-Mediated Lactoferrin Ubiquitylation

Somatic mutations that perturb Parkin ubiquitin ligase activity and the misregulation of iron homeostasis have both been linked to Parkinson’s disease. Lactotransferrin (LTF) is a member of the family of transferrin iron binding proteins that regulate iron homeostasis, and increased levels of LTF and its receptor have been observed in neurodegenerative disorders like Parkinson’s disease. Here, we report that Parkin binds to LTF and ubiquitylates LTF to influence iron homeostasis. Parkin-dependent ubiquitylation of LTF occurred most often on lysines (K) 182 and 649. Substitution of K182 or K649 with alanine (K182A or K649A, respectively) led to a decrease in the level of LTF ubiquitylation, and substitution at both sites led to a major decrease in the level of LTF ubiquitylation. Importantly, Parkin-mediated ubiquitylation of LTF was critical for regulating intracellular iron levels as overexpression of LTF ubiquitylation site point mutants (K649A or K182A/K649A) led to an increase in intracellular iron levels measured by ICP-MS/MS. Consistently, RNAi-mediated depletion of Parkin led to an increase in intracellular iron levels in contrast to overexpression of Parkin that led to a decrease in intracellular iron levels. Together, these results indicate that Parkin binds to and ubiquitylates LTF to regulate intracellular iron levels. These results expand our understanding of the cellular processes that are perturbed when Parkin activity is disrupted and more broadly the mechanisms that contribute to Parkinson’s disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Suppression of Disorder in Benzamide and Thiobenzamide Crystals by Fluorine Substitution

Disorder is a common feature of molecular crystals that complicates determination of structures and can potentially affect electric and mechanical properties. Suppression of disorder is observed in otherwise severely disordered benzamide and thiobenzamide crystals by substituting hydrogen with fluorine in the ortho-position of the phenyl ring. Fluorine occupancies of 20–30% are sufficient to suppress disorder without changing the packing motif. Crystal structure prediction calculations reveal a much denser lattice energy landscape for benzamide compared to 2-fluorobenzamide, suggesting that fluorine substitution makes disorder less likely.

36 MATERIALS SCIENCE↗