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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 757 records · Page 42
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Lead optimization and efficacy evaluation of quinazoline-based BET family inhibitors for potential treatment of cancer and inflammatory diseases

Extensive optimization of quinazoline-based lead 8 is described. The structure-activity relationship studies indicate the S-configuration is preferred for the phenylmorpholine substitution. Together with incorporation of a (2-hydroxyl-2-methylpropyl)pyrazole moiety at the 2-position leads to analogs with comparable potency and marked improvement in the pharmacokinetic profile over our previously reported lead compounds. Further in vivo efficacy studies in Kasumi-1 xenograft mouse model demonstrates that the selected inhibitors are well tolerated and highly efficacious in the inhibition of tumor growth. Additionally, the representative analog 19 also demonstrated significant improvement of arthritis severity in a collagen-induced arthritis (CIA) mouse model. These results indicate potential use of these quinazoline-based BET inhibitors for treatment of cancer and inflammatory diseases. Finally, a brief discussion of the co-crystallized structure of 19 with BRD4 (BD1) is also highlighted.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

cindr, the Drosophila Homolog of the CD2AP Alzheimer's Disease Risk Gene, Is Required for Synaptic Transmission and Proteostasis

The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (CD2AP), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the Drosophila ortholog cindr enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that Cindr is expressed in neurons and present at synaptic terminals. cindr mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3?, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of cindr elevates PMCA levels and reduces cytosolic calcium. Studies of Cd2ap null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.

Alzheimer's disease, risk gene, cindr, Drosophila,↗
DOE OSTI2015

Chlorophyll derivatives for pest and disease control: Are they safe?

Chlorophyll derivatives are getting widespread acceptance among the researchers as natural photosensitizers for photodynamic control of pests and disease vectors; however, rare attention has been given to evaluation of their toxicity to non-target organisms in the environment. This perspective article highlights that chlorophyll derivatives may not be as safe as believed and can possibly pose risk to non-target organisms in the environment. We invite the attention of environmental biologists, particularly ecotoxicologists, to contribute their role in making the application of chlorophyll derivatives more environmentally friendly and publicly acceptable.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Prefrontal white matter pathology in air pollution exposed Mexico City young urbanites and their potential impact on neurovascular unit dysfunction and the development of Alzheimer's disease

Millions of urban children are chronically exposed to high concentrations of air pollutants, i.e., fine particulate matter (PM{sub 2.5}) and ozone, associated with increased risk for Alzheimer's disease. Compared with children living with clear air those in Mexico City (MC) exhibit systemic, brain and intrathecal inflammation, low CSF Aβ{sub 42,} breakdown of the BBB, attention and short-term memory deficits, prefrontal white matter hyperintensities, damage to epithelial and endothelial barriers, tight junction and neural autoantibodies, and Alzheimer and Parkinson's hallmarks. The prefrontal white matter is a target of air pollution. We examined by light and electron microscopy the prefrontal white matter of MC dogs (n: 15, age 3.17±0.74 years), children and teens (n: 34, age: 12.64±4.2 years) versus controls. Major findings in MC residents included leaking capillaries and small arterioles with extravascular lipids and erythrocytes, lipofuscin in pericytes, smooth muscle and endothelial cells (EC), thickening of cerebrovascular basement membranes with small deposits of amyloid, patchy absence of the perivascular glial sheet, enlarged Virchow–Robin spaces and nanosize particles (20–48 nm) in EC, basement membranes, axons and dendrites. Tight junctions, a key component of the neurovascular unit (NVU) were abnormal in MC versus control dogs (χ{sup 2}<0.0001), and white matter perivascular damage was significantly worse in MC dogs (p=0.002). The integrity of the NVU, an interactive network of vascular, glial and neuronal cells is compromised in MC young residents. Characterizing the early NVU damage and identifying biomarkers of neurovascular dysfunction may provide a fresh insight into Alzheimer pathogenesis and open opportunities for pediatric neuroprotection. - Highlights: • The prefrontal white matter is a target of air pollution. • Tight junctions, key neurovascular unit elements, are abnormal in young urbanites. • Identifying neurovascular dysfunction biomarkers is key for pediatric neuroprotection. • Early characterization of NVU damage may provide a fresh insight into AD pathogenesis.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Projection of temperature-related mortality due to cardiovascular disease in beijing under different climate change, population, and adaptation scenarios

Highlights: • The population change can bring 5 times growth to temperature-related CVD deaths. • Increase of heat-related CVD deaths is higher than decrease of cold-related ones. • The adaptation to climate change may cause more temperature-related CVD deaths. Human health faces unprecedented challenges caused by climate change. Thus, studies of the effect of temperature change on total mortality have been conducted in numerous countries. However, few of those studies focused on temperature-related mortality due to cardiovascular disease (CVD) or considered future population changes and adaptation to climate change. We present herein a projection of temperature-related mortality due to CVD under different climate change, population, and adaptation scenarios in Beijing, a megacity in China. To this end, 19 global circulation models (GCMs), 3 representative concentration pathways (RCPs), 3 socioeconomic pathways, together with generalized linear models and distributed lag non-linear models, were used to project future temperature-related CVD mortality during periods centered around the years 2050 and 2070. The number of temperature-related CVD deaths in Beijing is projected to increase by 3.5–10.2% under different RCP scenarios compared with that during the baseline period. Using the same GCM, the future daily maximum temperatures projected using the RCP2.6, RCP4.5, and RCP8.5 scenarios showed a gradually increasing trend. When population change is considered, the annual rate of increase in temperature-related CVD deaths was up to fivefold greater than that under no-population-change scenarios. The decrease in the number of cold-related deaths did not compensate for the increase in that of heat-related deaths, leading to a general increase in the number of temperature-related deaths due to CVD in Beijing. In addition, adaptation to climate change may enhance rather than ameliorate the effect of climate change, as the increase in cold-related CVD mortality greater than the decrease in heat-related CVD mortality in the adaptation scenarios will result in an increase in the total number of temperature-related CVD mortalities.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Whole blood mercury and the risk of cardiovascular disease among the Greenlandic population

Highlights: • The Greenlandic Inuit have very high levels of whole blood mercury. • Whole blood mercury was not associated with incident CVD in Greenland. • CVD was associated with traditional risk factors such as HbA{sub 1c} and physical activity. Studies have found mercury to be associated with cardiovascular disease (CVD), however, primarily in populations with low exposure. The highest levels, and variations in the levels, of whole blood mercury (WBM) worldwide have been found in Greenland. We prospectively assessed the association between WBM and the risk of developing CVD in the Greenlandic population.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Renal Function and exposure to Bisphenol A and phthalates in children with Chronic Kidney Disease

Highlights: • Exposure to bisphenol A and phthalates is lower in children with CKD than healthy controls. • Exposure to bisphenol A has no effect on kidney function in children with CKD. • Exposure to select phthalates is associated with increased GFR in children with CKD. • The long-term impact of these environmental chemicals requires further study. Exposure to Bisphenol A (BPA) and phthalates is ubiquitous among adults and children in the United States. Among children and adolescents, those with chronic kidney disease (CKD) are potentially at greater risk of adverse effects from BPA and phthalate exposure. The objective of this study was to evaluate BPA and phthalate exposure among children with CKD and evaluate associations with three measures of kidney function.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2025

Verifying infectious disease scenario planning for geographically diverse populations

In the face of the COVID-19 pandemic, the literature saw a spike in publications for epidemic models, and a renewed interest in capturing contact networks and geographic movement of populations. There remains a general lack of consensus in the modeling community around best practices for spatiotemporal epi-modeling, specifically as it pertains to the infection rate formulation and the underlying contact or mixing model. We mathematically verify several common modeling assumptions in the literature, to prove when certain choices can provide consistent results across different geographic resolutions, population densities and patterns, and mixing assumptions. The most common infection rate formulation, a computationally low cost per capita infection rate assumption, fails the consistency tests for heterogeneous populations and gravity-weighting assumptions. Future modeling efforts in spatiotemporal disease modeling should be wary of this limitation, particularly when working with more heterogeneous or sparse populations. Our results provide guidance for testing that a model preserves desirable properties even when model inputs mask potential problems due to symmetry or homogeneity. We also provide a recipe for performing this type of verification, strengthening decision support tools.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2014

Metal-sulfide mineral ores, Fenton chemistry and disease. Particle induced inflammatory stress response in lung cells

The inhalation of mineral particulates and other earth materials, such as coal, can initiate or enhance disease in humans. Workers in occupations with high particulate exposure, such as mining, are particularly at risk. The ability of a material to generate an inflammatory stress response (ISR), a measure of particle toxicity, is a useful tool in evaluating said exposure risk. ISR is defined as the upregulation of cellular reactive oxygen species (ROS) normalized to cell viability. This study compares the ISR of A549 human lung epithelial cells after exposure to well-characterized common metal-sulfide ore mineral separates. The evaluation of the deleterious nature of ore minerals is based on a range of particle loadings (serial dilutions of 0.002 m 2 /mL stock) and exposure periods (beginning at 30 min and measured systematically for up to 24 h). There is a wide range in ISR values generated by the ore minerals. The ISR values produced by the sphalerite samples are within the range of inert materials. Arsenopyrite generated a small ISR that was largely driven by cell death. Galena showed a similar, but more pronounced response. Copper-bearing ore minerals generated the greatest ISR, both by upregulating cellular ROS and generating substantial and sustained cell death. Chalcopyrite and bornite, both containing ferrous iron, generated the greatest ISR overall. Particles containing Fenton metals as major constituents produce the highest ISR, while other heavy metals mainly generate cell death. Furthermore, this study highlights the importance of evaluating the chemistry, oxidation states and structure of a material when assessing risk management.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2013

CXC Receptor 1 and 2 and Neutrophil Elastase Inhibitors Alter Radiation-induced Lung Disease in the Mouse

Purpose: We previously reported increased numbers of neutrophils to be associated with the development of the radiation-induced lung responses of alveolitis (pneumonitis) and fibrosis in mice. In the present study we investigated whether CXC receptor 1 and 2 antagonism with DF2156A, a small molecule inhibitor of neutrophil chemotaxis, or the neutrophil elastase inhibitor sivelestat decreases the lung response to irradiation. Methods and Materials: KK/HIJ mice received 14 Gy whole-thorax irradiation, and a subset of them received drug treatment 3 times per week from the day of irradiation until they were killed because of respiratory distress symptoms. Results: Irradiated mice receiving sivelestat survived 18% longer than did mice receiving radiation alone (73 vs 60 days for female mice, 91 vs 79 days for male mice), whereas postirradiation survival times did not differ between the group of mice receiving DF2156A and the radiation-only group. The numbers of neutrophils in lung tissue and in bronchoalveolar lavage fluid did not differ among groups of irradiated mice, but they significantly exceeded the levels in unirradiated control mice. The extent of alveolitis, assessed histologically, did not differ between irradiated mice treated with either drug and those receiving radiation alone, when assessed at the end of the experiment, but it was significantly reduced, as were the neutrophil measures, in sivelestat-treated mice at the common kill time of 60 days after irradiation. Mice treated with radiation and DF2156A developed significantly less fibrosis than did mice receiving radiation alone, and this difference was associated with decreased expression of interleukin-13 in lung tissue. Conclusions: We conclude that neutrophil elastase inhibition affects alveolitis and prolongs survival, whereas CXCR1/2 antagonism reduces radiation-induced fibrotic lung disease in mice without affecting the onset of distress.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
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 OSTI2021

Radiation Toxicity in Patients With Collagen Vascular Disease: A Meta-Analysis of Case-Control Studies

Several retrospective series have reported that patients with collagen vascular disease (CVD) are at increased risk of radiation (RT) toxicity. However, the evidence is mixed, and many series lack control groups. We performed a meta-analysis including only case-cohort or randomized studies that examined the risk of RT toxicity for patients with CVD compared with controls.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2025

Lipid and lipoprotein metabolism in microglia: Alzheimer’s disease mechanisms and interventions

Alzheimer's disease (AD) presents a significant challenge owing to its widespread prevalence and complex neuropathogenesis, affecting millions worldwide. Current therapeutic strategies that predominantly target amyloid-beta accumulation are insufficient, particularly for ApoE4 carriers. Alterations in lipid composition are well documented in AD, characterized by reductions in phospholipids and sulfatides, along with increases in cholesterol, cholesteryl esters, and triglycerides (TGs). Microglia, the brain's resident immune cells, link dysfunctional lipid processing to AD neuropathogenesis. For example, genetic studies have pointed to microglial lipid and lipoprotein processing gene variants as some of the strongest risk factors for AD. In addition, microglial dysfunction, characterized by lipid droplet accumulation, increased cholesterol and TG levels, and altered lipid transport, may exacerbate the pathological hallmarks of AD, such as amyloid-beta and tau accumulation. Conversely, emerging studies have shown that strategies aimed at inhibiting lipid droplet accumulation in microglia, reducing TG synthesis, and promoting the activity of lipoprotein receptors expressed by microglia can improve cell functions and markers of AD pathology. This review dissects the interplay between microglial lipid metabolism and AD, highlighting the significance of lipid transport and trafficking within the CNS. Given the intrinsic link between microglial metabolism and AD progression, emerging and potential therapeutic strategies aimed at restoring lipid handling and improving microglial function are explored. This review provides a comprehensive examination of the emerging literature, detailing the current state of knowledge on microglial lipid metabolism, its genetic underpinnings, and the potential for novel interventions targeting these mechanisms to ameliorate AD pathology.

Alzheimer's disease↗
DOE OSTI2025

Discovery of Proteoforms Associated With Alzheimer's Disease Through Quantitative Top-Down Proteomics

The complex nature of Alzheimer's disease (AD) and its heterogenous clinical presentation has prompted numerous large-scale - omic analyses aimed at providing a global understanding of the pathophysiological processes involved. AD involves isoforms, proteolytic products, and posttranslationally modified proteins such as amyloid beta (Aβ) and microtubule-associated protein tau. Top-down proteomics directly measures these species and thus, offers a comprehensive view of pathologically relevant proteoforms that are difficult to analyze using traditional proteomic techniques. Here, we broadly explored associations between proteoforms and clinicopathological traits of AD by deploying a quantitative top-down proteomics approach across frontal cortex of 103 subjects selected from the ROS and MAP cohorts. The approach identified 1213 proteins and 11,782 proteoforms, of which 154 proteoforms had at least one significant association with a clinicopathological phenotype. One important finding included identifying Aβ C-terminal truncation state as the key property for differential association between amyloid plaques and cerebral amyloid angiopathy. Furthermore, various N-terminally truncated forms of Aβ had noticeably stronger association with amyloid plaques and global cognitive function. Additionally, we discovered six VGF neuropeptides that were positively associated with cognitive function independent of pathological burden. The database of brain cortex proteoforms provides a valuable context for functional characterization of the proteins involved in AD and other late-onset brain pathologies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease

The relationships between β-amyloid (Aβ), tau and neurodegeneration within Alzheimer's Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Aβ PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 Aβ PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB (Aβ) PET and 18FAV1451 (tau) PET. Multimodal correlation analyses were run at both voxel- and region-of-interest levels. 11C-PiB retention in AD showed the most diffuse uptake pattern throughout association neocortex, whereas 18F-AV1451 and gray matter volume reduction (GMR) showed a progressive predilection for posterior cortices (p < 0.05 Family-Wise Error-[FWE]-corrected). Voxel-level analysis identified negative correlations between 18F-AV1451 and gray matter peaking in medial and infero-occipital regions (p < 0.01 False Discovery Rate-[FDR]-corrected). 18F-AV1451 and 11C-PiB were positively correlated in right parietal and medial/inferior occipital regions (p < 0.001 uncorrected). 11C-PiB did not correlate with GMR at the voxel-level. Regionally, 18F-AV1451 was largely associated with local/adjacent GMR whereas frontal 11C-PiB correlated with GMR in posterior regions. These findings suggest that, in mild AD, tau aggregation drives local neurodegeneration, whereas the relationships between Aβ and neurodegeneration are not region specific and may be mediated by the interaction between Aβ and tau.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model

Huntington's disease (HD) is a currently incurable and, ultimately, fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion within exon 1 of the huntingtin (HTT) gene, which results in the production of a mutant protein that forms inclusions and selectively destroys neurons in the striatum and other adjacent structures. The RNA-guided Cas9 endonuclease from CRISPR-Cas9 systems is a versatile technology for inducing DNA double-strand breaks that can stimulate the introduction of frameshift-inducing mutations and permanently disable mutant gene function. Here, we show that the Cas9 nuclease from Staphylococcus aureus, a small Cas9 ortholog that can be packaged alongside a single guide RNA into a single adeno-associated virus (AAV) vector, can be used to disrupt the expression of the mutant HTT gene in the R6/2 mouse model of HD following its in vivo delivery to the striatum. Specifically, we found that CRISPR-Cas9-mediated disruption of the mutant HTT gene resulted in a ~50% decrease in neuronal inclusions and significantly improved lifespan and certain motor deficits. These results thus illustrate the potential for CRISPR-Cas9 technology to treat HD and other autosomal dominant neurodegenerative disorders caused by a trinucleotide repeat expansion via in vivo genome editing.

59 BASIC BIOLOGICAL SCIENCES↗