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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 775 records · Page 43
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

l-asparaginase induces intrinsic mitochondrial-mediated apoptosis in human gastric adenocarcinoma cells and impedes tumor progression

Highlights: • We first confirmed that l-asparagine is essential for the growth and proliferation of AGS cells. • We further clarified that l-asparagine deprivation by l-asparaginase promotes anti-proliferation and apoptosis of AGS cells. • We demonstrated that action of l-asparaginase alters mitochondrial membrane permeability and activates intrinsic apoptosis. • We also showed that l-asparaginase impedes tumor progression. l-asparagine essentially regulates growth and proliferation of cancer cells. l-asparaginase is an anti-cancer enzyme that deprives the cancer cells of l-asparagine. The purpose of this study was to explore the mechanism of a novel l-asparaginase from Pseudomonas fluorescens on l-asparagine deprivation mediated anti-proliferation, apoptosis in human gastric adenocarcinoma cells and to evaluate inhibition of angiogenesis. We observed that, the presence of extracellular l-asparagine was essential for the growth of AGS cells. l-asparagine deprivation by l-asparaginase induced metabolic stress, cytotoxicity and apoptosis by G0 phase cell-cycle arrest, modulated the mitochondrial membrane integrity, accelerated caspase-3 activation and instigated DNA damage. The RT-PCR analysis of pro-apoptosis genes: bak1, bax, bbc3, bik, pmaip1, bnip3l, apaf1, casp3, casp7 and casp9 were significantly higher (P xiap, bid, mcl1, and death receptor genes tnf and tradd were significantly down-regulated (P l-asparaginase alters mitochondrial membrane permeability and auxiliary activates intrinsic apoptosis. Therefore, this mechanistic approach might be considered as a targeted enzymotherapy against gastric adenocarcinoma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Circular RNA HIPK3 exerts oncogenic properties through suppression of miR-124 in lung cancer

Highlights: • CircHIPK3 is upregulated in human lung cancer cells. • CircHIPK3 siRNA inhibits lung cancer cell survival and proliferation. • CircHIPK3 overexpression promotes lung cancer cell survival and proliferation. • CircHIPK3 regulates expression miR-124 and its targets in lung cancer cells. • CircHIPK3 upregulation correlates with miR-124 downregulation in human lung cancer tissues. The current study tested the expression and potential functions of circular RNA HIPK3 (circHIPK3) in human lung cancer. Our results show that circHIPK3 expression is upregulated in established (A549 line) and primary human lung cancer cells, when compared to its low level in the lung epithelial cells. siRNA-mediated silencing of circHIPK3 potently inhibited survival and proliferation of lung cancer cells, but inducing significant apoptosis activation. Contrarily, forced overexpression of circHIPK3 by a lentiviral construct promoted lung cancer cell survival and proliferation. CircHIPK3 acted as a microRNA-124 (miR-124) sponger and regulated the expression of miR-124 mRNA targets, including SphK1, CDK4 and STAT3, in lung cancer cells. Transfection of miR-124 inhibitor significantly inhibited circHIPK3 siRNA-induced lung cancer cell death and apoptosis. At last, we show that circHIPK3 levels are upregulated in human lung cancer tissues, correlated with miR-124 downregulation. The miR-124 targets (SphK1, STAT3 and CDK4) are upregulated in lung cancer tissues. Together, we propose that circHIPK3 promotes lung cancer cell progression possibly by sponging miR-124. These observations indicate a possible novel therapeutic strategy involving circHIPK3-miR-124 pathway against lung cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

AURKA contributes to the progression of oral squamous cell carcinoma (OSCC) through modulating epithelial-to-mesenchymal transition (EMT) and apoptosis via the regulation of ROS

Highlights: • AURKA knockdown inhibited the proliferation and ETM in OSCC cell lines. • Silencing AURKA induced apoptosis and ROS in OSCC cell lines. • AURKA knockdown inhibited tumor growth in vivo. Oral squamous cell carcinoma (OSCC) is known as one of the most common cancer influencing the head and neck region. However, the molecular mechanisms revealing OSCC progression is largely unclear. Aurora kinase A (AURKA) is a serine-threonine kinase that functions in mitotic spindle formation and chromosome segregation, and is associated with the progression of human cancers. But its role in regulating OSCC development has not yet been investigated. In the study, we found that AURKA expression was up-regulated in OSCC cell lines and tumor specimens from patients. OSCC patients with high expression of AURKA exhibited a significant decreased overall survival rate. In vitro, AURKA knockdown markedly reduced the proliferation, migration and invasion of OSCC cells using cell counting kit-8 (CCK-8), EdU, colony formation and transwell analysis. EMT was suppressed by AURKA silence, as evidenced by the up-regulated expression of E-cadherin and down-regulated Vimentin in OSCC cells. In addition, apoptosis was markedly induced by AURKA inhibition through promoting the expression of cleaved Caspase-3 and poly (ADP)-ribose polymerase (PARP). Reactive oxygen species (ROS) production was also markedly enhanced in AURKA-knockdown OSCC cells. Importantly, we found that repressing ROS generation using its scavenger of n-acetylcysteine (NAC) significantly abolished AURKA silence-induced apoptosis, accompanied with restored proliferation and EMT. In vivo, AURKA knockdown notably inhibited tumor growth. Therefore, knockdown of AURKA suppressed cell proliferation, migration and invasion, and also induced apoptosis and ROS generation in OSCC possibly via the production of ROS, demonstrating that AURKA inhibition might represent a novel therapeutic target for the prevention of OSCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Filters from taxis air conditioning system: A tool to characterize driver's occupational exposure to bioburden?

Highlights: • Filters from air conditioning system are a suitable method to characterize bioburden in vehicles. • Fungi and bacteria occur widely in taxis and personal vehicles. • The genera Aspergillus, Cladosporium and Penicillium were often detected. • Filters should be more frequently replaced to avoid bioburden proliferation and reaerosolization. • Culture based and molecular methods used in parallel enabled an improved risk characterization. Bioburden proliferation in filters from air conditioning systems of taxis represents a possible source of occupational exposure. The aim of this study was to determine the occurrence of fungi and bacteria in filters from the air conditioning system of taxis used for patient transportation and to assess the exposure of drivers to bioburden. Filters from the air conditioning systems of 19 taxis and 28 personal vehicles (used as controls) operating in three Portuguese cities including the capital Lisbon, were collected during the winter season. The occurrence and significance of bioburden detected in the different vehicles are reported and discussed in terms of colony-forming units (CFU) per 1 m{sup 2} of filter area and by the identification of the most frequently detected fungal isolates based on morphology. Azole-resistant mycobiota, fungal biomass, and molecular detection of Aspergillus species/strains were also determined. Bacterial growth was more prevalent in taxis (63.2%) than in personal vehicles (26.3%), whereas fungal growth was more prevalent in personal vehicles (53.6%) than in taxis (21.1–31.6%). Seven different azole-resistant species were identified in this study in 42.1% taxi filters. Levels of fungal biomass were above the detection limit in 63% taxi filters and in 75% personal vehicle filters. No toxigenic species were detected by molecular analysis in the assessed filters. The results obtained show that bioburden proliferation occurs widely in filters from the air conditioning systems of taxis, including the proliferation of azole-resistant fungal species, suggesting that filters should be replaced more frequently. The use of culture based-methods and molecular tools combined enabled an improved risk characterization in this setting.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

Effects of polychlorinated biphenyls (PCB) on California sea lion (Zalophus californianus) lymphocyte functions upon in vitro exposure

Highlights: • PCBs induce immunomodulation of California sea lion lymphocytes. • Non dioxin-like PCBs stimulate sea lion lymphocyte proliferation at low concentrations. • Sea lion NK activity can increase under high levels of some non-dioxin PCB congeners. • PCB-induced modulation of sea lion lymphocytes can influence tumor progression. • Frozen lymph node mononuclear cells are viable for ecotoxicological analyses. Polychorinated biphenyl (PCB) congeners are a cause for concern due to their persistence in the environment, their lipophilic properties that cause them to bio-accumulate in top predators, and their adverse effects on mammalian health. For example, the common urogenital carcinoma reported in California sea lions (Zalophus californianus) (CSL) is associated with high tissue levels of PCBs, but the mechanisms responsible for this association are unknown. This study investigated the effect of exposure to six PCB congeners and a congener mix at low and environmentally relevant concentrations on NK cell-like and T cell activity using in vitro assays on cryopreserved lymph node mononuclear cells isolated from dead CSL. Non dioxin-like congeners 153 and 180 increased lymphocyte proliferation at 5 and 10 ppm, while congener 138 decreased proliferation by up to 43% at 15 ppm. Dioxin-like PCBs 118 and 169 did not affect lymphocyte proliferation, while the effects of congener 105 depended on the mitogen concentration; these did not correlate with their predicted toxic equivalent factors. NK cell-like activity was affected only by the highest concentration of PCBs tested; it was increased by non-dioxin-like congeners 138 and 153, and decreased by dioxin-like congener 169. The PCB congener mix suggested that the effects of PCB congeners were not simply additive. Our results concur with effects of PCBs reported for other pinniped's lymphocytes and add further experimental support to the observation that dioxin-like PCBs are not the most toxic congeners for marine mammals, contrary to effects in other species. This is the first evidence of in vitro suppression of NK cell-like cytotoxicity by a dioxin-like congener in a pinniped. More importantly, the observed results suggest that PCBs can modulate the CSL immune system, increasing exposed individuals’ susceptibility to viral and oncogenic challenges.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/β-catenin signaling in an Alzheimer's disease model

Neurogenesis is the process by which neural stem cells (NSCs) proliferate and differentiate into neurons. This is diminished in several neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by the deposition of amyloid (A)β peptides and neuronal loss. Stimulating NSCs to replace lost neurons is therefore a promising approach for AD treatment. Our previous study demonstrated that osthole modulates NSC proliferation and differentiation, and may reduce Aβ protein expression in nerve cells. Here we investigated the mechanism underlying the effects of osthole on NSCs. We found that osthole enhances NSC proliferation and neuronal differentiation while suppressing apoptosis, effects that were exerted via activation of Wnt/β-catenin signaling. These results provide evidence that osthole can potentially be used as a therapeutic agent in the treatment of AD and other neurodegenerative disorders. - Highlights: • An Alzheimer's disease model was successfully established by transfecting APP gene into neural stem cells in vitro. • Roles of osthole in experimental AD cells were studied. • Osthole promotes proliferation and differentiation into neurons and inhibits accumulation of Aβ{sub 1–42} peptide and apoptosis. • Osthole exerts protection via Wnt/β-catenin signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Clozapine-induced agranulocytosis: Evidence for an immune-mediated mechanism from a patient-specific in-vitro approach

Use of the atypical antipsychotic clozapine (CZP) is compromised by the risk of potentially fatal agranulocytosis/granulocytopenia (CIAG). To address this, we have established a simple, personalized cell culture-based strategy to identify CIAG-susceptible patients, hypothesizing that an immunogenic and possibly haptene-based mechanism underlies CIAG pathophysiology. To detect a putative haptene-induced response to CZP in vitro exposure, a traditional lymphocyte stimulation assay was adapted and applied to patient-specific peripheral blood-derived mononuclear cells (PBMC). 6 patients with a history of CIAG, 6 patients under CZP treatment (without CIAG) and 12 matched healthy controls were studied. In vitro CZP exposure, even at strikingly low levels, resulted in significantly increased proliferation rates only in CIAG patients' PBMC. Other parameters including cell viability and mitogen-induced proliferation were also affected by in vitro CZP exposure, yet there was no significant difference between the groups. This personalized approach is a starting point for further investigations into a putative haptene-based mechanism underlying CIAG development, and may facilitate the future development of predictive testing. - Highlights: • Clozapine induces proliferation in PBMCs from patients with a history of CIAG. • Simple, PBMC-based assay results in robust effects of physiological clozapine levels. • Haptene-based mechanisms discussed to underlie clozapine-induced proliferation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Up-regulated miR-548k promotes esophageal squamous cell carcinoma progression via targeting long noncoding RNA-LET

Highlights: • miR-548k is significantly upregulated in ESCC and indicates poor prognosis. • miR-548k promotes the proliferation and migration of ESCC cells. • miR-548k directly targets and represses long noncoding RNA-LET (lncRNA-LET). • lncRNA-LET inhibits the proliferation and migration of ESCC cells. • The roles of miR-548k on ESCC are dependent on the negative regulation of lncRNA-LET. Dysregulated noncoding RNAs have been observed in diverse cancers. MIR458K is frequently amplified in esophageal squamous cell carcinoma (ESCC). However, the expression, clinical significances, and action mechanisms of miR-548k in ESCC are still unclear. In this study, we found that miR-548k is significantly up-regulated in ESCC tissues and cell lines. Up-regulated miR-548k expression is significantly correlated with advanced invasion depth, lymph node metastasis, advanced TNM stage, and poor overall survival. Gain-of- and loss-of-function assays demonstrated that miR-548k promotes the proliferation and migration of ESCC cells in vitro and tumor growth in vivo. Mechanistically, we found that miR-548k directly targets and represses the expression of long noncoding RNA-LET (lncRNA-LET), and further down-regulates p53 and up-regulates NF90. In addition, we found that lncRNA-LET is down-regulated and inversely correlated with miR-548k in ESCC. Down-regulated lncRNA-LET also indicated poor overall survival of ESCC patients. Functional assays demonstrated that lncRNA-LET inhibits the proliferation and migration of ESCC cells, and the effects of miR-548k on ESCC are dependent on the negative regulation of lncRNA-LET. In summary, our data revealed the critical roles of miR-548k-lncRNA-LET regulation axis in ESCC and suggested that the miR-548k-lncRNA-LET regulation axis may be promising prognostic biomarkers and therapeutic targets for ESCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma

Highlights: • MSC exosomes promote Tregs proliferation by upregulating IL-10 and TGF-β1 in asthma. • MSC exosomes enhance immunosuppression capacity of Tregs from asthmatic patient. • The effect of MSC exosomes on Tregs may be mediated by APCs. Mesenchymal stem cells (MSCs) and regulatory T cells (Tregs) are both potent immune-modulators. The aberrant proliferation and function of Tregs plays an important role in the development of asthma. Our previous studies have demonstrated the role of MSCs in promoting proliferation and immune-modulating of Tregs, as well as alleviating airway inflammation of asthmatic mice. In the present study, we isolated exosomes secreted by MSCs and investigated their immunomodulation effect on peripheral blood mononuclear cells (PBMCs) of asthmatic patient. We found that MSC exosomes upregulated IL-10 and TGF-β1 from PBMCs, thus promoting proliferation and immune-suppression capacity of Tregs. Furthermore, antigen presenting cells (APCs) but not CD4+ T cells-dependent pathway was shown to be possible mechanism involved in MSC exosome-mediated regulation. Our data elucidated the key role of exosomes in immune-modulation of MSCs, and suggested the therapeutic potential of MSC exosomes for asthma.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Matrix stiffness regulates the differentiation of tendon-derived stem cells through FAK-ERK1/2 activation

Highlights: • TDSC proliferation was enhanced with the increasing matrix stiffness. • More F-actin stress fibers formed in TDSCs while matrix stiffness increased. • Higher matrix stiffness inhibited the differentiation of TDSCs. • FAK or ERK1/2 activation was involved in the regulatory effect. Tendon derived stem cells (TDSCs) were vital in tendon homeostasis. Nevertheless, the regulation of TDSCs differentiation in tendinopathy is unclear. Matrix stiffness modulated stem cells differentiation, and matrix stiffness of tendinopathic tissues decreased significantly. In order to clarify the role of matrix stiffness in TDSCs differentiation, they were cultured on the gelatin hydrogels with the stiffness from 2.34 ± 1.48 kPa to 24.09 ± 14.03 kPa. The effect of matrix stiffness on TDSCs proliferation and differentiation were investigated with CCK8 assay, immunofluorescences, real time PCR and western blot. It was found the proliferation of TDSCs increased and more stress fibers formed with increasing matrix stiffness. The differentiation of TDSCs into tenogenic, chondrogenic, and osteogenic lineages were inhibited on stiff hydrogel evidenced by reduced expression of tenocyte markers THBS4, TNMD, SCX, chondrocyte marker COL2, and osteocyte markers Runx2, Osterix, and ALP. Furthermore, the phosphorylation of FAK and ERK1/2 were enhanced when TDSCs grew on stiff hydrogel. After FAK or ERK1/2 was inhibited, the effect of matrix stiffness on differentiation of TDSCs was inhibited as well. The above results indicated matrix stiffness modulated the proliferation and differentiation of TDSCs, and the regulation effect could correlate to the activation of FAK or ERK1/2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

YAP via interacting with STAT3 regulates VEGF-induced angiogenesis in human retinal microvascular endothelial cells

Endothelial dysfunction is a main feature of retinal neovascular diseases which are the leading cause of blindness in developed countries. Yes-associated protein (YAP) and signal transducer and activator of transcription factor 3 (STAT3) participate in angiogenesis via vascular endothelial growth factor (VEGF) signaling. Additionally, YAP can bind STAT3 in endothelial cells. In the study, dimethyloxalylglycine (DMOG) stimulated human retinal microvascular endothelial cells (HRMECs) was used as retinal endothelial hypoxia model. The proliferation of HRMECs, as well as t-YAP, p-STAT3 (Tyr705) increased, while p-YAP (Ser127), p-YAP (Ser397) decreased following hypoxia. Meanwhile, YAP and STAT3 translocated to the nucleus. YAP knockdown inhibited the proliferation, migration and tube formation of HRMECs. YAP overexpression up-regulated phosphorylation of STAT3. The YAP overexpression-induced HRMECs proliferation, migration and tube formation were reversed by S3I-201, a selective STAT3 inhibitor. YAP interacted with STAT3 to promote STAT3 nuclear translocation. Additionally, YAP and STAT3 promoted the transcription of VEGF synergistically. Finally, inhibition of YAP alleviated retinal pathological neovascularization in mouse oxygen-induced retinopathy (OIR) model. In summary, activated YAP interacted with STAT3 to promote the activation and nuclear translocation of STAT3, hence boosted the proliferation, migration and tube formation of HRMECs via VEGF signaling following hypoxia. The data will further elucidate the mechanisms of retinal neovascular diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Identification and characterization of distinct cell cycle stages in cardiomyocytes using the FUCCI transgenic system

Understanding the regulatory mechanism by which cardiomyocyte proliferation transitions to endoreplication and cell cycle arrest during the neonatal period is crucial for identifying proproliferative factors and developing regenerative therapies. }We used a transgenic mouse model based on the fluorescent ubiquitination-based cell cycle indicator (FUCCI) system to isolate and characterize cycling cardiomyocytes at different cell cycle stages at a single-cell resolution. Single-cell transcriptome analysis of cycling and noncycling cardiomyocytes was performed at postnatal days 0 (P0) and 7 (P7). }The FUCCI system proved to be efficient for the identification of cycling cardiomyocytes with the highest mitotic activity at birth, followed by a gradual decline in the number of cycling and mitotic cardiomyocytes during the neonatal period. Cardiomyocytes showed premature cell cycle exit at G1/S shortly after birth and delayed G1/S progression during endoreplication at P7. Single-cell RNA-seq confirmed previously described signaling pathways involved in cardiomyocyte proliferation (Erbb2 and Hippo/YAP), and maturation-related transcriptional changes during postnatal development, including the metabolic switch from glycolysis to fatty acid oxidation in cardiomyocytes. Importantly, we generated transcriptional profiles specific to cell division and endoreplication in cardiomyocytes at different developmental stages that may facilitate the identification of genes important for adult cardiomyocyte proliferation and heart regeneration. }In conclusion, the FUCCI mouse provides a valuable system to study cardiomyocyte cell cycle activity at single cell resolution that can help to decipher the switch from cardiomyocyte proliferation to endoreplication, and to revert this process to facilitate endogenous repair.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Calibration of Multi-Parameter Models of Avascular Tumor Growth Using Time Resolved Microscopy Data

Abstract Two of the central challenges of using mathematical models for predicting the spatiotemporal development of tumors is the lack of appropriate data to calibrate the parameters of the model, and quantitative characterization of the uncertainties in both the experimental data and the modeling process itself. We present a sequence of experiments, with increasing complexity, designed to systematically calibrate the rates of apoptosis, proliferation, and necrosis, as well as mobility, within a phase-field tumor growth model. The in vitro experiments characterize the proliferation and death of human liver carcinoma cells under different initial cell concentrations, nutrient availabilities, and treatment conditions. A Bayesian framework is employed to quantify the uncertainties in model parameters. The average difference between the calibration and the data, across all time points is between 11.54% and 14.04% for the apoptosis experiments, 7.33% and 23.30% for the proliferation experiments, and 8.12% and 31.55% for the necrosis experiments. The results indicate the proposed experiment-computational approach is generalizable and appropriate for step-by-step calibration of multi-parameter models, yielding accurate estimations of model parameters related to rates of proliferation, apoptosis, and necrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Twist1-positive epithelial cells retain adhesive and proliferative capacity throughout dissemination

Dissemination is the process by which cells detach and migrate away from a multicellular tissue. The epithelial-to-mesenchymal transition (EMT) conceptualizes dissemination in a stepwise fashion, with downregulation of E-cadherin leading to loss of intercellular junctions, induction of motility, and then escape from the epithelium. This gain of migratory activity is proposed to be mutually exclusive with proliferation. We previously developed a dissemination assay based on inducible expression of the transcription factor Twist1 and here utilize it to characterize the timing and dynamics of intercellular adhesion, proliferation and migration during dissemination. Surprisingly, Twist1+ epithelium displayed extensive intercellular junctions, and Twist1– luminal epithelial cells could still adhere to disseminating Twist1+ cells. Although proteolysis and proliferation were both observed throughout dissemination, neither was absolutely required. Finally, Twist1+ cells exhibited a hybrid migration mode; their morphology and nuclear deformation were characteristic of amoeboid cells, whereas their dynamic protrusive activity, pericellular proteolysis and migration speeds were more typical of mesenchymal cells. Our data reveal that epithelial cells can disseminate while retaining competence to adhere and proliferate.

Life Sciences & Biomedicine - Other Topics↗
DOE OSTI2024

Creation Synthetic Data to Train a Digital Twin to Predict Reactor Operations

Understanding techniques to strengthen the nuclear safeguards regime is crucial in preventing nuclear proliferation due to recent advancements in the nuclear energy industry such as Generation IV reactors and microreactors. Prior to the construction of a nuclear power plant, it is necessary to understand the proliferation potential of the plant's reactor. Digital twins serve as a unique solution to recognizing reactor behavior indicative of nuclear proliferation. A digital twin is defined as a virtual model that works in unison to represent a physical asset, with a transference of data between the virtual and physical assets [1]. This work serves as validation for training a digital twin on synthetic data fabricated via means of Serpent reactor physics and point kinetics equations simulations. In this case this work is based on parameters of Idaho State University's AGN-201 reactor. The synthetic data can then be utilized to train machine learning models in the future to further investigate the utility of these methods. The accuracy of the predicted data is measured against real operational data to verify the reliability of the synthetic data creation methods and decide whether these methods should be used in the future to inform inspectors of a reactor's proliferation potential.

98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL P↗
DOE OSTI2024

An Autonomous Critical Data Extrapolator for the AGN-201m

Nuclear nonproliferation serves as a key goal, being undertaken by the International Atomic Energy Agency (IAEA). To recognize proliferation there are two pathways that states, who intend to use nuclear material for malicious purposes can take, diversion can misuse. Diversion is when fissile nuclear material is declared to the IAEA for non-weapon purposes, but then covertly removed. If the source of nuclear material, that is not declared and not fissionable, is placed inside the reactor core to create fissile material used to create weapons then the state is using the second pathway of proliferation, misuse. With the emerging development in areas of simulation and machine learning the creation of virtual models of reactor systems, digital twins, serve as a potential method to identify proliferation through detecting anomalous behavior in the reactor. A digital twin for a physical nuclear reactor has never been developed, as digital twins serve as an emerging technology. To investigate the process for development and use of a digital twin for a nuclear reactor Idaho State University’s AGN-201m serves as the nuclear reactor used for development of this digital twin. A data acquisition system has been installed to the reactor system allowing for the transfer of collected data from a reactor operation to Idaho National Laboratory’s Deeplynx data warehouse. When utilizing data to train reactor physics and machine learning models, a significant challenge encountered is the initial state of the data. Nuclear proliferation will have the capacity to be detected when the reactor immediately starts up, nor will it occur after the reactor shuts down. Generally, it will be detected when the reactor is operating at some desired power over a sufficient period for that specific reactor design. For the AGN-201m this will be when the reactor is critical (generally 1 mW or above) for a timespan that is within or less than the range of a regular business day. Datasets sent to Deeplynx have had to be manually cut to when the reactor is critical based on plots of power levels. This method is inefficient and laborious, especially when using multiple datasets at once to train a model. To provide a more streamlined approach an automated critical data extrapolator is developed, with capabilities of recognizing when the reactor operation first reaches criticality, and when the reactor undergoes a SCRAM and is shutdown.

99 GENERAL AND MISCELLANEOUS↗
NASA NTRS2002

Inhibition of caspases prevents ototoxic and ongoing hair cell death

Sensory hair cells die after acoustic trauma or ototoxic insults, but the signal transduction pathways that mediate hair cell death are not known. Here we identify several important signaling events that regulate the death of vestibular hair cells. Chick utricles were cultured in media supplemented with the ototoxic antibiotic neomycin and selected pharmacological agents that influence signaling molecules in cell death pathways. Hair cells that were treated with neomycin exhibited classically defined apoptotic morphologies such as condensed nuclei and fragmented DNA. Inhibition of protein synthesis (via treatment with cycloheximide) increased hair cell survival after treatment with neomycin, suggesting that hair cell death requires de novo protein synthesis. Finally, the inhibition of caspases promoted hair cell survival after neomycin treatment. Sensory hair cells in avian vestibular organs also undergo continual cell death and replacement throughout mature life. It is unclear whether the loss of hair cells stimulates the proliferation of supporting cells or whether the production of new cells triggers the death of hair cells. We examined the effects of caspase inhibition on spontaneous hair cell death in the chick utricle. Caspase inhibitors reduced the amount of ongoing hair cell death and ongoing supporting cell proliferation in a dose-dependent manner. In isolated sensory epithelia, however, caspase inhibitors did not affect supporting cell proliferation directly. Our data indicate that ongoing hair cell death stimulates supporting cell proliferation in the mature utricle.

Non-NASA Center↗
NASA NTRS2001

TGF-beta1 release from biodegradable polymer microparticles: its effects on marrow stromal osteoblast function

BACKGROUND: Controlled release of transforming growth factor-beta1 (TGF-beta1) to a bone defect may be beneficial for the induction of a bone regeneration cascade. The objectives of this work were to assess the feasibility of using biodegradable polymer microparticles as carriers for controlled TGF-beta1 delivery and the effects of released TGF-beta1 on the proliferation and differentiation of marrow stromal cells in vitro. METHODS: Recombinant human TGF-beta1 was incorporated into microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG). Fluorescein isothiocynate-labeled bovine serum albumin (FITC-BSA) was co-encapsulated as a porogen. The effects of PEG content (0, 1, or 5% by weight [wt%]) and buffer pH (3, 5, or 7.4) on the protein release kinetics and the degradation of PLGA were determined in vitro for as long as 28 days. Rat marrow stromal cells were seeded on a biodegradable poly(propylene fumarate) (PPF) substrate. The dose response and biological activity of released TGF-beta1 was determined after 3 days in culture. The effects of TGF-beta1 released from PLGA/PEG microparticles on marrow stromal cell proliferation and osteoblastic differentiation were assessed during a 21-day period. RESULTS: TGF-beta1 was encapsulated along with FITC-BSA into PLGA/PEG blend microparticles and released in a multiphasic fashion including an initial burst for as long as 28 days in vitro. Increasing the initial PEG content resulted in a decreased cumulative mass of released proteins. Aggregation of FITC-BSA occurred at lower buffer pH, which led to decreased release rates of both proteins. The degradation of PLGA was increased at higher PEG content and significantly accelerated at acidic pH conditions. Rat marrow stromal cells cultured on PPF substrates showed a dose response to TGF-beta1 released from the microparticles similar to that of added TGF-beta1, indicating that the activity of TGF-beta1 was retained during microparticle fabrication and after growth factor release. At an optimal TGF-beta1 dosage of 1.0 ng/ml after 3 days, the released TGF-beta1 enhanced the proliferation and osteoblastic differentiation of marrow stromal cells over 21 days of culture, with increased total cell number, alkaline phosphatase activity, and osteocalcin production. CONCLUSIONS: PLGA/PEG blend microparticles can serve as delivery vehicles for controlled release of TGF-beta1, and the released growth factor enhances marrow stromal cell proliferation and osteoblastic differentiation in vitro. CLINICAL RELEVANCE: Controlled release of TGF-beta1 from PLGA/PEG microparticles is representative of emerging tissue engineering technologies that may modulate cellular responses to encourage bone regeneration at a skeletal defect site.

Non-NASA Center↗