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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 685 records · Page 38
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Isolation and characterization of neural stem cells from dystrophic mdx mouse

The blood-brain barrier (BBB) is altered in mdx mouse, an animal model to study Duchenne muscular dystrophy (DMD). Our previous work demonstrated that perivascular glial endfeet control the selective exchanges between blood and neuropil as well as the BBB development and integrity; the alterations of dystrophin and dystrophin-associated protein complex (DAPs) in the glial cells of mdx mouse, parallel damages of the BBB and increase in vascular permeability. The aim of this study was to improve our knowledge about brain cellular components in the mdx mouse through the isolation, for the first time, of the adult neural stem cells (ANSCs). We characterized them by FACS, electron microscopy, confocal immunofluorescence microscopy, Real Time-PCR and western blotting, and we studied the expression of the DAPs aquaporin-4 (AQP4), potassium channel Kir4.1, α- and β-dystroglycan (αDG, βDG), α-syntrophin (αSyn), and short dystrophin isoform Dp71 proteins. The results showed that the mdx ANSCs expressed CD133 and Nestin receptor as the control ones, but showed a reduction in Notch receptor and altered cell proliferation with an increment in the apoptotic nuclei. Ultrastructurally, they appeared 50% size reduced compared to control ones, with a few cytoplasmic organelles. Moreover, the mdx ANSCs are devoid in full length dystrophin 427, and they expressed post-transcriptional reduction in the Dp71 in parallel with the ubiquitin proteasome activation, and decrement of DAPs proteins which appeared diffused in the cytoplasm and not polarized on the stem cells plasmamembrane, as prevalently observed in the controls. Overall, these results indicate that structural and molecular alterations affect the neural stem cells in the dystrophic brain, whose increased apoptosis and reduced Dp71 and DAPs proteins expression, together with loss in Dp427 dystrophin, could be responsible of the altered mdx glial maintenance and differentiation and consequent failure in the vessels barrier control occurring in the adult dystrophic brain.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Neuron-specific knockdown of Drosophila PDHB induces reduction of lifespan, deficient locomotive ability, abnormal morphology of motor neuron terminals and photoreceptor axon targeting

Highlights: • Drosophila CG11876 (dPDHB) is a homolog of human pyruvate dehydrogenase beta, PDHB. • Neuron-specific knockdown of dPDHB causes locomotive defects and reduced life span. • Neuron-specific knockdown of dPDHB causes structural defects in NMJ. • Neuron-specific knockdown of dPDHB induces mitochondrial fragmentation in brain. • Knockdown of dPDHB induces a rough eye and aberrant photoreceptor axon targeting. Pyruvate dehydrogenase complex deficiency (PDCD) is a common primary cause of defects in mitochondrial function and also can lead to peripheral neuropathy. Pyruvate dehydrogenase E1 component subunit beta (PDHB) is a subunit of pyruvate dehydrogenase E1, which is a well-known component of PDC. In Drosophila melanogaster, the CG11876 (dPDHB) gene is a homolog of human PDHB. In this study, we established a Drosophila model with neuron-specific knockdown of dPDHB to investigate its role in neuropathy pathogenesis. Knockdown of dPDHB in pan-neurons induced locomotor defects in both larval and adult stages, which were consistent with abnormal morphology of the motor neuron terminals at neuromuscular junctions and mitochondrial fragmentation in brains. Moreover, neuron-specific knockdown of dPDHB also shortened the lifespan of adult flies. In addition, flies with knockdown of dPDHB manifested a rough eye phenotype and aberrant photoreceptor axon targeting. These results with the Drosophila model suggest the involvement of PDHB in peripheral neuropathy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

FoxJ1 regulates spinal cord development and is required for the maintenance of spinal cord stem cell potential

Development of the spinal cord requires dynamic and tightly controlled expression of numerous transcription factors. Forkhead Box protein J1 (FoxJ1) is a transcription factor involved in ciliogenesis and is specifically expressed in ependymal cells (ECs) in the adult central nervous system. However, using FoxJ1 fate-mapping mouse lines, we observed that FoxJ1 is also transiently expressed by the progenitors of other neural subtypes during development. Moreover, using a knock-in mouse line, we discovered that FoxJ1 is essential for embryonic progenitors to follow a normal developmental trajectory. FoxJ1 loss perturbed embryonic progenitor proliferation and cell fate determination, and resulted in formation of adult ECs having impaired stem cell potential and an inability to respond to spinal cord injury in both male and female animals. Thus, our study uncovers unexpected developmental functions of FoxJ1 in cell fate determination of subsets of neural cells and suggests that FoxJ1 is critical for maintaining the stem cell potential of ECs into adulthood.

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 OSTI2024

Activity-Based Protein Profiling to Probe Relationships between Cytochrome P450 Enzymes and Early-Age Metabolism of Two Polycyclic Aromatic Hydrocarbons (PAHs): Phenanthrene and Retene

A growing body of literature has linked early life exposures to polycyclic aromatic hydrocarbons (PAH) with adverse neurodevelopmental effects. Once in the body, metabolism serves as a powerful mediator of PAH toxicity by bioactivating and detoxifying PAH metabolites. Since enzyme expression and activity varies considerably throughout human development, we evaluated infant metabolism of PAHs as a potential contributing factor to PAH susceptibility. Here, we measured and compared rates of phenanthrene and retene (two primary PAH constituents of woodsmoke) metabolism in human hepatic microsomes from individuals ≤21 months of age to a pooled sample (n = 200) consisting primarily of adults. We used activity-based protein profiling (ABPP) to characterize cytochrome P450 enzymes (CYPs) in the same hepatic microsome samples. Once incubated in microsomes, phenanthrene demonstrated rapid depletion. Best fit models for phenanthrene metabolism demonstrated either 1 or 2 phases, depending on the sample, indicating that multiple enzymes could metabolize phenanthrene. We observed no statistically significant differences in phenanthrene metabolism as a function of age, although samples from the youngest individuals had the slowest phenanthrene metabolism rates. We observed slower rates of retene metabolism compared to phenanthrene also in multiple phases. Rates of retene metabolism increased in an age-dependent manner until adult (pooled) levels were achieved at ~12 mo. ABPP identified 28 unique CYPs among all samples, and we observed lower amounts of active CYPs in individuals ≤21 months of age compared to the pooled sample. Phenanthrene metabolism correlated to CYPs 1A1, 1A2, 2C8, 4A22, 3A4, and 3A43 and activities and retene metabolism correlated to CYPs 1A1, 1A2, and 2C8 activities measured by ABPP and vendor-supplied substrate marker activities. These results will aid efforts to determine human health risk and susceptibility to PAHs exposures during early life.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase by (1 S ,3 S )-3-Amino-4-difluoromethylene-1-cyclopentanoic Acid (CPP-115)

gamma-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment of infantile spasms and refractory adult epilepsy. Recently, CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylene group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5'-phosphate (PMP). The partition ratio for CPP-115 with GABA-AT is about 2000, releasing cyclopentanone-2,4-dicarboxylate (22) and two other precursors of this compound (20 and 21). Time-dependent inactivation occurs by a conformational change induced by the formation of the aldimine of 4-aminocyclopentane-1,3-dicarboxylic acid and PMP (20), which disrupts an electrostatic interaction between Glu270 and Arg445 to form an electrostatic interaction between Arg445 and the newly formed carboxylate produced by hydrolysis of the difluoromethylene group in CPP-115, resulting in a noncovalent, tightly bound complex. This represents a novel mechanism for inactivation of GABA-AT and a new approach for the design of mechanism-based inactivators in general.

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

ExpoKids: An R-based tool for characterizing aggregate chemical exposure during childhood

Background: Aggregate exposure, the combined exposures to a single chemical from all pathways, is a critical children’s health issue. Objective: The primary objective is to develop a tool to illustrate potential differences in aggregate exposure at various childhood lifestages and the adult lifestage. Methods: We developed ExpoKids (an R-based tool) using oral exposure estimates across lifestages generated by US EPA’s Exposure Factors Interactive Resource for Scenarios Tool (ExpoFIRST). Results: ExpoKids is applied to illustrate aggregate oral exposure, for ten media, as average daily doses (ADD) and lifetime average daily doses (LADD) in five graphs organized across seven postnatal childhood lifestages and the adult lifestage. This data visualization tool conveys ExpoFIRST findings, from available exposure data, to highlight the relative contributions of media and lifestages to chemical exposure. To evaluate the effectiveness of ExpoKids, three chemical case examples (di[2-ethylhexyl] phthalate [DEHP], manganese, and endosulfan) were explored. Data available from the published literature and databases for each case example were used to explore research questions regarding media and lifestage contributions to aggregate exposure. Significance: These illustrative case examples demonstrate ExpoKids’ versatile application to explore a diverse set of children’s health risk assessment and management questions by visually depicting specific media and lifestage contributions to aggregate exposure.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Reactivation of a developmentally silenced embryonic globin gene

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

A single-cell atlas of the bobtail squid visual and nervous system highlights molecular principles of convergent evolution

Abstract The cephalopod and vertebrate visual systems are a textbook example of convergent evolution with unknown molecular underpinnings. Here we characterize 98,537 single-cell transcriptomes in the bobtail squidEuprymna berryito understand how the cephalopod retina and optic lobes relate to the vertebrate retina. We confirm the overall relative simplicity of the cephalopod retina but identify two related photoreceptor cell subtypes expressing distinct r-opsins. By contrast, the adult optic lobe contains a diverse repertoire of neuronal and glial cell types, with a predominance of dopaminergic neurons. We show that cephalopod-specific gene duplicates probably contributed to this cell type diversification. Comparing neuronal cell population in the optic lobes of hatchlings and adults, we reveal a switch towards dopaminergic neurotransmitter usage with age, indicative of a maturation process. We further identify an FMRF-amide-based retrograde signal from the optic lobe towards the retina that supports the functional analogy of the cephalopod optic lobe cortex and the vertebrate inner retina in visual signal processing from a molecular standpoint. Finally, comparative analyses with vertebrate and arthropod cells suggest a scenario in which two photoreceptor types and two neuronal populations may have already been present in the eye of the bilaterian ancestor.

Environmental Sciences & Ecology↗
DOE OSTI2024

Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues

While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets from the same tissues revealed a strong correlation between the chromatin contacts and chromatin state at distal enhancers, as well as gene expression patterns at predicted target genes. We predicted target genes of 15,098 candidate enhancers and used them to annotate target genes of homologous candidate enhancers in the human genome that harbor risk variants of human diseases. We present evidence that schizophrenia and other adult disease risk variants are frequently found in fetal enhancers, providing support for the hypothesis of fetal origins of adult diseases.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins

Acute lung injury (ALI) leads to progressive loss of breathing capacity and hypoxemia, as well as pulmonary surfactant dysfunction. ALI’s pathogenesis and management are complex, and it is a significant cause of morbidity and mortality worldwide. Exogenous surfactant therapy, even for research purposes, is impractical for adults because of the high cost of current surfactant preparations. Prior in vitro work has shown that poly-N-substituted glycines (peptoids), in a biomimetic lipid mixture, emulate key biophysical activities of lung surfactant proteins B and C at the air-water interface. Here we report good in vivo efficacy of a peptoid-based surfactant, compared with extracted animal surfactant and a synthetic lipid formulation, in a rat model of lavage-induced ALI. Adult rats were subjected to whole-lung lavage followed by administration of surfactant formulations and monitoring of outcomes. Treatment with a surfactant protein C mimic formulation improved blood oxygenation, blood pH, shunt fraction, and peak inspiratory pressure to a greater degree than surfactant protein B mimic or combined formulations. All peptoid-enhanced treatment groups showed improved outcomes compared to synthetic lipids alone, and some formulations improved outcomes to a similar extent as animal-derived surfactant. Robust biophysical mimics of natural surfactant proteins may enable new medical research in ALI treatment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Reconstruction of larval origins based on genetic relatedness and biophysical modeling

The assessment of the mechanisms and patterns of larval connectivity between geographically separated populations leads to a better understanding of benthic marine population dynamics, especially in commercially valuable species. This study investigated for the first time the fine-scale temporal genetic variability of new settlers and their origins in a benthic marine organism with one of the longest pelagic larval phases, the Caribbean spiny lobster (Panulirus argus). We genotyped newly settled postlarvae in the Florida Keys and adults of spiny lobster from the Florida Keys and throughout the Caribbean Sea. We identified strong larval connectivity between Dominican Republic, Belize, Nicaragua, the Florida Keys, and West-Florida. the larval dispersal modeling suggests that Florida’s lobster population could receive recruits from within and from other areas outside its state and national maritime boundaries. The genetic analyses refine the oceanographic model indicating that the connectivity patterns described could also result from unknown parental populations sourcing adults and postlarvae in different spawning seasons to the Florida Keys. We discuss the importance of small temporal scales to identify patterns in larval export. Our findings are significant on two levels. From the larval dispersal perspective, genetic results and biophysical modeling identify patterns of gene flow enhancing persistence of local populations. From an economic and fishery perspective, P. argus is the most important commercial species in the Caribbean and our results inform how considering larval source and sink dynamics across international boundaries could improve management plans at local, national, and regional levels.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Mycorrhizal feedbacks influence global forest structure and diversity

One mechanism proposed to explain high species diversity in tropical systems is strong negative conspecific density dependence (CDD), which reduces recruitment of juveniles in proximity to conspecific adult plants. Although evidence shows that plant-specific soil pathogens can drive negative CDD, trees also form key mutualisms with mycorrhizal fungi, which may counteract these effects. Across 43 large-scale forest plots worldwide, we tested whether ectomycorrhizal tree species exhibit weaker negative CDD than arbuscular mycorrhizal tree species. We further tested for conmycorrhizal density dependence (CMDD) to test for benefit from shared mutualists. We found that the strength of CDD varies systematically with mycorrhizal type, with ectomycorrhizal tree species exhibiting higher sapling densities with increasing adult densities than arbuscular mycorrhizal tree species. Moreover, we found evidence of positive CMDD for tree species of both mycorrhizal types. Collectively, these findings indicate that mycorrhizal interactions likely play a foundational role in global forest diversity patterns and structure.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Global divergence in urban demographic change and migration patterns

Cities are central to economic development, climate adaptation and social stability, yet globally consistent evidence on how city populations are changing remains limited. Here we analyze annual age- and sex-structured population estimates for more than 10,000 cities worldwide from 2000 to 2020 and show that urban demographic change was highly uneven. Globally, the ratio of children and older adults to working-age adults declined from 0.87 to 0.59, but smaller cities remained consistently younger than larger cities, especially in Africa. We also find pronounced spatial variation in urban sex ratios, including strong male surpluses in parts of the Middle East and North Africa, consistent with patterns of labor migration. Finally, we estimate that 45% of urban population growth was attributable to net migration and 55% to natural increase. These results show that national averages can obscure substantial differences between cities, and highlight the value of globally consistent city-level demographic estimates for understanding regional demographic change and informing locally tailored urban planning.

development studies↗
DOE OSTI2015

Measurement of natural radionuclides in Malaysian bottled mineral water and consequent health risk estimation

The radionuclides of {sup 226}Ra, {sup 232}Th and {sup 40}K were measured in ten mineral water samples, of which from the radioactivity obtained, the ingestion doses for infants, children and adults were calculated and the cancer risk for the adult was estimated. Results showed that the calculated ingestion doses for the three age categories are much lower than the average worldwide ingestion exposure of 0.29 mSv/y and the estimated cancer risk is much lower than the cancer risk of 8.40 × 10{sup −3} (estimated from the total natural radiation dose of 2.40 mSv/y). The present study concludes that the bottled mineral water produced in Malaysia is safe for daily human consumption.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2020

Relationship of estrogen synthesis capacity in the brain with obesity and self-control in men and women

Significance Obesity is a major public health problem in a growing proportion of children and adults in the developed world. Estrogen influences body weight and behavioral responses to appetitive stimuli. Estrogen biosynthesis is catalyzed by the enzyme aromatase in all organs measured, including the brain. Using the aromatase radiotracer [ 11 C]vorozole, we measured aromatase availability in the amygdala in healthy-weight to obese adults. Obesity was associated with lower aromatase availability and less constraint independent of sex and age. Variability in brain estrogen synthesis may contribute to obesity by directly regulating feeding and broadly by affecting self-control. These findings suggest that brain aromatase imaging offers a method for characterizing the role of brain estrogen in obesity and other impairments in self-regulation.

Biegon, Anat↗
DOE OSTI2014

Monitoring Stock-Specific Abundance, Run Timing, and Straying of Chinook Salmon in the Columbia River Using Genetic Stock Identification (GSI)

Abstract Genetic stock identification (GSI) provides a method of characterizing stock-specific abundance, run timing, and straying as they pertain to the population demographics and behavior of both hatchery and wild fish and thus assists with fisheries management. In this study, tissues were collected and genotyped at 13 microsatellite loci from adult Chinook Salmon Oncorhynchus tshawytscha that passed Bonneville Dam during four consecutive migration years (2004–2007). GSI methods were used to estimate the proportions of stocks in a broad genetic baseline, with high-density coverage of Chinook Salmon across the eastern Pacific Rim. The estimates of abundance for interior Columbia River stocks showed widespread decline consistent with a shift to poor ocean conditions during the years when the fish in this study were at sea, but divergent stock- and age-specific patterns were also observed. For example, the upper Columbia River spring-run stock experienced a unique net gain in abundance during this period, and the interior Columbia River summer–fall-run stock experienced a delayed decline of 4-year-olds. Stocks with early run timing shifted to later migrations. However, run timing distributions did not shift unidirectionally for all stocks across years, and stock membership in three major run timing categories was maintained. Of 9,215 total adults sampled, 27 (0.3%) were out-of-basin strays and a quarter of the strays were putatively of wild origin. The general concordance of GSI results with those based on more traditional methods supports the effectiveness of GSI as a tool for fisheries management. Received May 5, 2013; accepted October 23, 2013 Published online February 10, 2014

Hess, Jon E.↗
DOE OSTI2015

Stock Differences in Growth, Smolting, and Early Male Maturation in Hatchery Spring Chinook Salmon: a Common-Garden Experiment

Abstract Hatchery spring Chinook Salmon Oncorhynchus tshawytscha from Parkdale Hatchery on the Hood River, Oregon, and Carson National Fish Hatchery (CNFH) on the Wind River, Washington, were reared under a common-garden experimental regime at CNFH over three consecutive brood years (2008–2010) to assess the effects of stock on smoltification and early male maturation. Rearing groups were monitored for size, percent solid (a surrogate for whole-body lipid), gill Na+,K+-ATPase activity, and rate of precocious maturation in males (i.e., age-2 minijack rate). Despite rearing of the stocks under identical conditions, the out-of-basin Hood River stock was significantly smaller throughout the study and at release as smolts, had lower whole-body lipid at release, and had lower gill Na+,K+-ATPase activity at release than the Carson stock; furthermore, the Hood River stock exhibited much higher mean minijack rates than the Carson stock (45% versus 23% of males). Using logistic regression, we demonstrated that the threshold size for initiation of early male maturation was significantly lower for the Hood River stock than for the Carson stock, suggesting a genetic basis for this life history difference. The present study highlights the importance of understanding how specific genotypes may respond differently to the unique environmental conditions in a given hatchery environment. These differences may in turn influence physiological and life history pathways that affect smolt-to-adult return rates and the demography of returning adults.

Spangenberg, Dina K.↗