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At least 1,099 records · Page 61

All sources NASA NTRS DOE OSTI

DOE OSTI2014

Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors

Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

HAM-5 functions as a MAP kinase scaffold during cell fusion in Neurospora crassa

Cell fusion in genetically identical Neurospora crassa germlings and in hyphae is a highly regulated process involving the activation of a conserved MAP kinase cascade that includes NRC1, MEK2 and MAK2. During chemotrophic growth in germlings, the MAP kinase cascade members localize to conidial anastomosis tube (CAT) tips every 4 minutes, perfectly out of phase with another protein that is recruited to the tip: SOFT, a protein of unknown biochemical function. How this oscillation process is initiated, maintained and what proteins regulate the MAP kinase cascade is currently unclear. A global phosphoproteomics approach using an allele of mak-2 (mak-2Q100G) that can be specifically inhibited by the ATP analog 1NM-PP1 was utilized to identify MAK2 kinase targets in germlings that were potentially involved in this process. One such putative target was HAM5, a protein of unknown biochemical function. Previously, Δham-5 mutants were shown to be deficient for hyphal fusion. Here we show that HAM5-GFP co-localized with NRC1, MEK2 and MAK2 and oscillated with identical dynamics from the cytoplasm to CAT tips during chemotropic interactions. In the Δmak-2 strain, HAM5-GFP localized to punctate complexes that did not oscillate, but still localized to the germling tip, suggesting that MAK2 activity influences HAM5 function/localization. However, MAK2-GFP showed only cytoplasmic and nuclear localization in a Δham-5 strain and did not localize to puncta, as observed in wild type germlings. Via co-immunoprecipitation experiments, HAM5 was shown to physically interact with MAK2, MEK2 and NRC1, suggesting that it functions as a scaffold/transport hub for the MAP kinase cascade members during oscillation and chemotropic interactions during both germling and hyphal fusion in N. crassa. The identification of HAM5 as a scaffold-like protein will help to link the activation of MAK2 to upstream factors and other proteins involved in this intriguing process of fungal communication.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

High-Throughput RNA FISH Analysis by Imaging Flow Cytometry Reveals That Pioneer Factor Foxa1 Reduces Transcriptional Stochasticity

Genes are regulated at the single-cell level. Here, we performed RNA FISH of thousands of cells by flow cytometry (flow-RNA FISH) to gain insight into transcriptional variability between individual cells. These experiments utilized the murine adenocarcinoma 3134 cell line with 200 copies of the MMTV-Ras reporter integrated at a single genomic locus. The MMTV array contains approximately 800–1200 binding sites for the glucocorticoid receptor (GR) and 600 binding sites for the pioneer factor Foxa1. Hormone activation of endogenous GR by dexamethasone treatment resulted in highly variable changes in the RNA FISH intensity (25–300 pixel intensity units) and size (1.25–15 mm), indicative of probabilistic or stochastic mechanisms governing GR and cofactor activation of the MMTV promoter. Exogenous expression of the pioneer factor Foxa1 increased the FISH signal intensity and size as expected for a chromatin remodeler that enhances transcriptional competence through increased chromatin accessibility. In addition, specific analysis of Foxa1-enriched cell sub-populations showed that low and high Foxa1 levels substantially lowered the cell-to-cell variability in the FISH intensity as determined by a noise calculation termed the % coefficient of variation. These results suggest that an additional function of the pioneer factor Foxa1 may be to decrease transcriptional noise.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2025

Project Presentation: Hardware-Based Demonstration of Temperature Control Functions for Reactor Systems

Autonomous thermal regulation in nuclear reactors remains crucial for maintaining stable operation and ensuring the integrity of fuel. To alleviate public skepticism of the safety of nuclear reactors, demonstrating control over this key factor is pivotal. Utilizing electric heat pads to simulate the heat released in a reactor core, thermocouples for temperature monitoring, and an Arduino micro programmable logic controller (PLC) with an embedded proportional-integral-derivative (PID) algorithm for control, a hardware-based demonstration of a reactor heating system will validate the efficacy of reactor control over this key parameter. This report covers internship project presentation as well as relevant experience with nuclear and proposal for project upgrade.

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗

DOE OSTI2026

National Laboratory of the Rockies: Pennsylvania Public Utility Commission/ Technical Utility Services Bureau Distribution System Resilience Deep Dive 2025

The following is a summary of the National Laboratory of the Rockies (NLR) - Pennsylvania PUC/ Technical Utility Services Bureau (TUS) Distribution System Resiliency Deep-Dive project. This is work that NLR performed to provide the support that the TUS requested under the Resources and Support for State Energy Offices & Regulators (RASOR) program.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗

DOE OSTI2021

Developing Practical Models of Complex Salts for Molten Salt Reactors

Molten salt reactors (MSRs) utilize salts as coolant or as the fuel and coolant together with fissile isotopes dissolved in the salt. It is necessary to therefore understand the behavior of the salts to effectively design, operate, and regulate such reactors, and thus there is a need for thermodynamic models for the salt systems. Molten salts, however, are difficult to represent as they exhibit short-range order that is dependent on both composition and temperature. A widely useful approach is the modified quasichemical model in the quadruplet approximation that provides for consideration of first- and second-nearest-neighbor coordination and interactions. Its use in the CALPHAD approach to system modeling requires fitting parameters using standard thermodynamic data such as phase equilibria, heat capacity, and others. A shortcoming of the model is its inability to directly vary coordination numbers with composition or temperature. Another issue is the difficulty in fitting model parameters using regression methods without already having very good initial values. The proposed paper will discuss these issues and note some practical methods for the effective generation of useful models.

Besmann, Theodore M. (ORCID:0000000155980550)↗

NASA NTRS1975

Power processing system for a 200 watt communication satellite transmitter

A power processing system (PPS) for a communication satellite, high power (200W RF) multi-stage depressed collector, 12 GHz, traveling wave tube, is described. The PPS converts spacecraft bus power at a nominal voltage of 76 Vdc to the levels necessary for operating a ten-collector coupled cavity TWT requiring approximately 500 watts of input power. Regulated voltages of up to -11.3K Vdc are provided along with command, protection and telemetry signal conditioning circuits. Power processor interface requirements are set forth and a block diagram illustrating the basic approach utilized is presented. Overall performance, design characteristics and unique features are discussed. Thermal and mechanical interface requirements impacting on PPS design are described as well as the thermal control technique utilized for the overall PPS/TWT assembly.

Farber, B. F.↗

NASA NTRS2023

Automated Fluidics Device for Extraction and Quantification of miRNA Biomarkers From Blood

Radiation Assessment DuRing Exposure And long-Duration Spaceflight (RADREADS) demonstrates space-compatible point-of-care technology for quantitative biological monitoring of blood miRNA biomarkers in response to long-term low dose radiation exposure. This individualized monitoring approach will inform targeted treatment strategies to maximize medical resource utilization by accounting for individual susceptibility to radiation-related illnesses. As human spaceflight progresses beyond Earth’s magnetic shielding, radiation exposure poses a significant risk to astronaut health and safety. Extended operation in this environment comes with an increased risk of radiation exposure, leading to higher risks of radiation sickness, cancer, central nervous system effects, and degenerative diseases. While conventional physical dosimetry techniques capture radiation dose, individualistic susceptibility to radiation damage is varied. Multiple characteristics, including age, body weight, sex, genetics, and immune status, have been found to influence radiosensitivity (Liu et al. 2011, and Bouffler 2016). This differential response necessitates individualized monitoring and targeted treatment strategies to maximize medical resource utilization; however, a practical diagnostic platform for quantifying long-term, low dose radiation-induced tissue damage does not currently exist. MicroRNAs (miRNAs) are a class of small, non-coding RNAs that regulate gene expression by mediating the degradation of messenger RNA. The levels of particular miRNAs are influenced by biological processes such as inflammation and serve as biomarkers for a variety of conditions including cancer (Singh et al. 2017). MicroRNAs are found in various bodily fluids and are amenable to collection via liquid biopsies, providing a minimally invasive and easily quantifiable readout for a variety of radiosensitive reporters. A preliminary signature of 15 spaceflight sensitive miRNA has been identified in rodent and human studies, including miR-21-5p, miR-24-3p, miR-92a-3p, miR-17-5p, miR-16a-3p, miR-34a-3p, and miR-223-3p. These targets generally increased expression with radiation dose and linear energy transfer, though variation between individuals is not yet described. Current gaps in the field include a lack of understanding of longitudinal biological responses to long-term, low dose radiation exposure and the absence of space-compatible point-of-care technology for quantitative biological monitoring. In this body of work, we aim to develop an automated bleed-to-read system to process whole blood for the detection of miRNA biomarkers in order to monitor individualistic responses to radiation exposure. This will be achieved via separating serum (or plasma) from whole blood, followed by extraction, amplification, and quantification of the miRNA using a RT-qPCR reaction. Previously, the WetLab-2 hardware enabled execution of a RT-qPCR reaction aboard ISS; however, it is a manual system that requires crew manipulation and bulky components (Parra et al. 2017). To address these issues, automated fluid handling hardware was developed for each stage of sample preparation. Extraction of total RNA is achieved by sequentially pumping reagents through an off-the-shelf nucleic acid binding column (miRNeasy Serum/Plasma Advanced Kit, Qiagen). This approach eliminates several manual pipetting and centrifuging steps and limits the use of toxic chemicals commonly found in other sample processing techniques. The resulting elution will then be automatically dispensed for RT-qPCR analysis using a compact rotary qPCR (Mic qPCR Cycler, Bio Molecular Systems) that will improve spaceflight compatibility by removing bubbles from the detection region, another challenge highlighted by WetLab-2 (Parra et al. 2017). Efforts are also being made to simplify the RT-qPCR reaction to a 1-step air-dryable mix to improve long-term reagent stability at room temperature and reduce system complexity. By automating the RT-qPCR processes via microfluidic manipulation, RADREADS will reduce crewmember hands-on time and enable the personalized detection of radiation-induced tissue damage during long duration missions. Minimally invasive, longitudinal monitoring of individual’s response to radiation exposure will inform how the physiological system responds to long-term low dose space radiation and enables development of targeted countermeasures by the medical team. Ultimately, this portable technology will require minimal technical expertise and can also be used to monitor miRNA biomarkers associated with other diseases.

Tristen Head↗

DOE OSTI2025

Poster: Hardware-Based Demonstration of Temperature Control Functions for Reactor Systems

21 - SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLAN↗

DOE OSTI2017

Regulation of Nitrogen Metabolism by GATA Zinc Finger Transcription Factors in Yarrowia lipolytica

Nitrogen source is commonly used to control lipid production in industrial fungi. Here we identified regulators of nitrogen catabolite repression in the oleaginous yeast Y. lipolytica to determine how the nitrogen source regulates lipid metabolism. We show that disruption of both activators and repressors of nitrogen catabolite repression leads to increased lipid accumulation via activation of carbon catabolite repression through an as yet uncharacterized method.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Performance-Based Evaluation of Courtyard Design in China’s Cold-Winter Hot-Summer Climate Regions

A courtyard is a traditional and popular construction feature found in China’s urban buildings. This case study evaluates the performance of the traditional courtyard design of the Jiangnan Museum, located in Jiangsu Province. In the evaluation, the spatial layout of courtyards is adjusted, the aspect ratio is changed, and an ecological buffer space is created. To model and evaluate the performance of the courtyard design, this study applied the Computational fluid dynamics (CFD) software, Parabolic Hyperbolic Or Elliptic Numerical Integration Code Series (PHOENICS), for wind environment simulation, and the EnergyPlus-based software, DesignBuilder, for energy simulation. Results show that a good combination of courtyard layout and aspect ratio can improve the use of natural ventilation by increasing free cooling during hot summers and reducing cold wind in winters. The results also show that ecological buffer areas of a courtyard can reduce cooling loads in summer by approximately 19.6% and heating loads in winter by approximately 22.3%. The study provides insights into the optimal design of a courtyard to maximize its benefit in regulating the microclimate during both winter and summer.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗

DOE OSTI2016

Ammonia Generation and Utilization in a Passive SCR (TWC+SCR) System on Lean Gasoline Engine

Lean gasoline engines offer greater fuel economy than the common stoichiometric gasoline engine, but the current three-way catalyst (TWC) on stoichiometric engines is unable to control nitrogen oxide (NOX) emissions in the oxygen-rich exhaust. Thus, lean NOX emission control is required to meet existing Tier 2 and upcoming Tier 3 emission regulations set by the U.S. Environmental Protection Agency (EPA). While urea-based selective catalytic reduction (SCR) has proven effective in controlling NOX from diesel engines, the urea storage and delivery components can add significant size and cost. As such, onboard NH3 production via a passive SCR approach is of interest. In a passive SCR system, NH3 is generated over a close-coupled TWC during periodic slightly rich engine operation and subsequently stored on an underfloor SCR catalyst. Upon switching to lean operation, NOX passes through the TWC and is reduced by the stored NH3 on the SCR catalyst. In this work, a passive SCR system was evaluated on a 2.0-liter BMW lean burn gasoline direct injection engine to assess NH3 generation over a Pd-only TWC and utilization over a Cu-based SCR catalyst. System NOX reduction efficiency and fuel efficiency improvement compared to stoichiometric engine operation were measured. A feedback control strategy based on cumulative NH3 produced by the TWC during rich operation and NOX emissions during lean operation was implemented on the engine to control lean/rich cycle timing. 15% excess NH3 production over a 1:1 NH3:NOX ratio was required (via longer rich cycle timing) to achieve 99.7% NOX conversion at an SCR average inlet temperature of 350 C. Increasing NH3 generation further resulted in even higher NOX conversion; however, tailpipe NH3 emissions resulted. At higher temperatures, NH3 oxidation becomes important and limits NH3 availability for NOX reduction. At the engine conditions studied here, greater than 99% NOX conversion was achieved with passive SCR while delivering fuel efficiency benefits ranging between 6-11% compared with stoichiometric operation.

Prikhodko, Vitaly Y↗

DOE OSTI2016

Ammonia Generation and Utilization in a Passive SCR (TWC+SCR) System on Lean Gasoline Engine

Lean gasoline engines offer greater fuel economy than the common stoichiometric gasoline engine, but the current three way catalyst (TWC) on stoichiometric engines is unable to control nitrogen oxide (NOX) emissions in oxidizing exhaust. For these lean gasoline engines, lean NOX emission control is required to meet existing Tier 2 and upcoming Tier 3 emission regulations set by the U.S. Environmental Protection Agency (EPA). While urea-based selective catalytic reduction (SCR) has proven effective in controlling NOX from diesel engines, the urea storage and delivery components can add significant size and cost. As such, onboard NH 3 production via a passive SCR approach is of interest. In a passive SCR system, NH 3 is generated over a close-coupled TWC during periodic slightly rich engine operation and subsequently stored on an underfloor SCR catalyst. Upon switching to lean operation, NOX passes through the TWC and is reduced by the stored NH 3 on the SCR catalyst. In this work, a passive SCR system was evaluated on a 2.0-liter BMW lean burn gasoline direct injection engine to assess NH 3 generation over a Pd-only TWC and utilization over a Cu-based SCR catalyst. System NOX reduction efficiency and fuel efficiency improvement compared to stoichiometric engine operation were measured. A feedback control strategy based on cumulative NH 3 produced by the TWC during rich operation and NOX emissions during lean operation was implemented on the engine to control lean/rich cycle timing. At an SCR average inlet temperature of 350 °C, an NH 3 :NOX ratio of 1.15:1 (achieved through longer rich cycle timing) resulted in 99.7 % NOX conversion. Increasing NH 3 generation further resulted in even higher NOX conversion; however, tailpipe NH 3 emissions resulted. At higher underfloor temperatures, NH 3 oxidation over the SCR limited NH 3 availability for NOX reduction. At the engine conditions studied, greater than 99 % NOX conversion was achieved with passive SCR while delivering fuel efficiency benefits ranging between 6-11 % compared with stoichiometric operation.

33 ADVANCED PROPULSION SYSTEMS↗

DOE OSTI2016

Discovery of novel selenium derivatives as Pin1 inhibitors by high-throughput screening

Peptidyl prolyl cis/trans isomerization by Pin1 regulates various oncogenic signals during cancer progression, and its inhibition through multiple approaches has established Pin1 as a therapeutic target. However, lack of simplified screening systems has limited the discovery of potent Pin1 inhibitors. We utilized phosphorylation-dependent binding of Pin1 to its specific substrate to develop a screening system for Pin1 inhibitors. Using this system, we screened a chemical library, and identified a novel selenium derivative as Pin1 inhibitor. Based on structure-activity guided chemical synthesis, we developed more potent Pin1 inhibitors that inhibited cancer cell proliferation. -- Highlights: •Novel screening for Pin1 inhibitors based on Pin1 binding is developed. •A novel selenium compound is discovered as Pin1 inhibitor. •Activity guided chemical synthesis of selenium derivatives resulted potent Pin1 inhibitors.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

Bisphenol A differentially activates protein kinase C isoforms in murine placental tissue

Bisphenol A is utilized to make polycarbonate plastics and is an environmental pollutant. Recent research has indicated that it is an endocrine disruptor and may interfere with reproductive processes. Our lab has previously shown that bisphenol A could regulate corticotrophin releasing hormone and aromatase in cultured placental cells. In the present study, the effect of bisphenol A on these two genes in the placenta was investigated in mice. Pregnant ICR mice were gavaged with bisphenol A at 2, 20 and 200 mg/kg body weight/day from E13 to E16 and were euthanized at E17. Compared to the control mice, increased plasma estrogen and corticotrophin releasing hormone were observed in bisphenol A-treated mice. Messenger RNA quantification indicated that placental crh but not cyp19 was induced in mice treated with bisphenol A. Tracking the related signaling pathway, we found that protein kinase C ζ/λ and δ were activated in the placentas of bisphenol A-treated mice. As the gene promoter of crh contains CRE and the half site of ERE, either phospho-PKC or estrogen could stimulate the gene transactivation. These results indicate that bisphenol A might increase plasma concentrations of estradiol, testosterone, corticotrophin releasing hormone and placental phospho-PKC ζ/λ and δ in mice. Ultimately, the incidence of premature birth in these mice could increase. - Highlights: • The pollutant bisphenol A differentially activated PKC isoforms in the placenta. • CRE-binding activity in the nuclear protein of placenta was increased. • Bisphenol A induces CRH mRNA expression in mice.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2015

The utility of protein and mRNA correlation

Not Available

Payne, Samuel H.↗

DOE OSTI2021

The combined application of the anti- RAS1 and anti- RIM101 2'- O MethylRNA oligomers enhances Candida albicans filamentation control

Abstract Although antisense oligomers (ASOs) have been successfully utilized to control gene expression, they have been little exploited to control Candida albicans virulence's determinants. Filamentation is an important virulence factor of C. albicans, and RAS1 and RIM101 genes are involved in its regulation. Thus, the main goal of this work was to project ASOs, based on 2'-OMethyl chemical modification, to target RAS1 and RIM101 mRNA and to validate its application either alone or in combination, to reduce Candida filamentation in different human body fluids. It was verified that both, anti-RAS1 2'OMe and anti-RIM101 2'OMe oligomers, were able to reduce the levels of RAS1 and RIM101 genes’ expression and to significantly reduce C. albicans filamentation. Furthermore, the combined application of anti-RAS1 2'OMe oligomer and anti-RIM101 2'OMe oligomer enhances the control of C. albicans filamentation in artificial saliva and urine. Our work confirms that ASOs are useful tools for research and therapeutic development on the control of candidiasis.

Barbosa, Ana↗

DOE OSTI2015

c-Myc alters substrate utilization and O-GlcNAc protein posttranslational modifications without altering cardiac function during early aortic constriction

Pressure overload cardiac hypertrophy alters substrate metabolism. Prior work showed that myocardial inactivation of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we hypothesize that Myc regulates substrate preferences for the citric acid cycle during pressure overload hypertrophy from transverse aortic constriction (TAC) and that these metabolic changes impact cardiac function and growth. To test this hypothesis, we subjected mice with cardiac specific, inducible Myc inactivation (MycKO-TAC) and non-transgenic littermates (Cont-TAC) to transverse aortic constriction (TAC; n=7/group). A separate group underwent sham surgery (Sham, n=5). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. Compared to Sham, Cont-TAC had increased free fatty acid fractional contribution with a concurrent decrease in unlabeled (predominately glucose) contribution. The changes in free fatty acid and unlabeled fractional contributions were abrogated by Myc inactivation during TAC (MycKO-TAC). Additionally, protein posttranslational modification by O-GlcNAc was significantly greater in Cont-TAC versus both Sham and MycKO-TAC. Lastly, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy.

59 BASIC BIOLOGICAL SCIENCES↗