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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 1,351 records · Page 75
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

A revisited concept: Contact inhibition of growth. From cell biology to malignancy

In cell biology, contact inhibition refers to two different but closely related phenomena, contact inhibition of locomotion and contact inhibition of proliferation, exhibited by fibroblasts when in contact with one another. Normal fibroblasts migrate across the surface of a culture dish until they make contact with a neighboring cell. Further cell migration is then inhibited, and normal cells adhere to each other, forming an orderly array of cells on the culture dish surface. Tumor cells, in contrast, continue moving after contact with their neighbors, migrating over adjacent cells, and growing in disordered, multilayered patterns. Not only the movement but also the proliferation of many normal cells is inhibited by cell-cell contact, and cancer cells are characteristically insensitive to such contact inhibition. - Highlights: • Contact inhibition refers to contact inhibition of locomotion and of proliferation. • Normal fibroblasts migrate across a culture dish until they make contact with a neighboring cell. • Tumor cells, in contrast, continue moving after contact with their neighbors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Pancreatic stellate cell activation is regulated by fatty acids and ER stress

Introduction: Pancreatic pathologies are characterized by a progressive fibrosis process. Pancreatic stellate cells (PSC) play a crucial role in pancreatic fibrogenesis. Endoplasmic reticulum (ER) stress emerges as an important determinant of fibrotic remodeling. Overload of fatty acids (FA), typical to obesity, may lead to lipotoxic state and cellular stress. Aim: To study the effect of different lipolytic challenges on pancreatic ER stress and PSC activation. Methods: Primary PSCs were exposed to different FAs, palmitate (pal) and oleate (ole), at pathophysiological concentrations typical to obese state, and in acute caerulein-induced stress (cer). PSC activation and differentiation were analyzed by measuring fat accumulation (oil-red staining and quantitation), proliferation (cells count) and migration (wound- healing assay). PSC differentiation markers (α-sma, fibronectin, tgf-β and collagen secretion), ER stress unfolded protein response and immune indicators (Xbp1, CHOP, TNF-α, IL-6) were analyzed at the transcript and protein expression levels (quantitative RT-PCR and western blotting). Results: PSC exposure to pal and ole FAs (500 µM) increased significantly fat accumulation. Proliferation and migration analysis demonstrated that ole FA retained PSC activation, while exposure to pal FA significantly halted proliferation rate and delayed migration. Cer significantly augmented PSC differentiation markers α- sma, fibronectin and collagen, and ER stress and inflammation markers including Xbp1, CHOP, TNF-α and IL-6. The ole FA treatment significantly elevated PSC differentiation markers α-sma, fibronectin and collagen secretion. PSC ER stress was demonstrated following pal treatment with significant elevation of Xbp1 splicing and CHOP levels. Conclusion: Exposure to pal FA halted PSC activation and differentiation and elevated ER stress markers, while cer and ole exposure significantly induced activation, differentiation and fibrosis. Thus, dietary FA composition should be considered and optimized to regulate PSC activation and differentiation in pancreatic pathologies. - Highlights: • Pancreatic stellate cells (PSC) play a crucial role in pancreatic fibrogenesis. • Endoplasmic reticulum (ER) stress is an important determinant of fibrotic remodeling. • Overload of fatty acids, typical to obesity, may lead to lipotoxicity and cellular stress. • Exposure to pal FA halts PSC activation, differentiation and elevated ER stress. • Cer and ole exposure significantly induced activation, differentiation and fibrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Study on the role of Hsa-miR-31-5p in hypertrophic scar formation and the mechanism

Highlights: • The level of miR31-5p in HS was higher than in NS. • MiR31-5p plays a central role for hypoxia induced ECM synthesis and contraction. • Blocking miR31-5p inhibits HIF-1a activation in hypoxic via upregulating FIH. Hypertrophic scar (HS) formation is associated with the fibrosis of fibrocytes caused by excessive extracellular matrix (ECM) synthesis and deposition, the initial event of HS formation. Our high throughput screen of miRNA expression profiles identified hsa-miR31-5p, whose transcription level was most differentially in normal skin fibroblasts (NS) and HS among other miRNAs. The level of hsa-miR31-5p in HS was significantly higher than in NS. In-vitro functional experiments showed hsa-miR31-5p knockdown remarkably suppressed the proliferation of hypertrophic scar fibroblasts (HSFBs) under hypoxia, promoted cell invasion, and inhibited the expression of Collagen I and III and Fibronectin (FN), suggesting that hsa-miR31-5p knockdown effectively reduces HS formation caused by excessive ECM synthesis and deposition in HSFBs under hypoxia. Mechanism study showed that the regulation of HS formation by hsa-miR31-5p was mediated by its target gene, factor-inhibiting HIF-1 (FIH): under hypoxia, hsa-miR31-5p down-regulated FIH and thus increased the level of hypoxia inducible factor-1α (HIF-1α), which subsequently activated the HIF-1α fibrosis regulation pathway in HSFBs, and stimulated the proliferation and ECM synthesis in HSFBs, eventually resulting in fibrosis and scar formation. The data also show that knockdown of hsa-miR31-5p in HSFBs impaired the trend of increased proliferation, reduced invasion and excessive ECM synthesis and deposition caused by HIF-1a activation under hypoxia through upregulating FIH, indicating that knockdown of hsa-miR31-5p effectively inhibits the formation of HS. In conclusion, hsa-miR31 -5p plays an important role in HS formation by inhibiting FIH and regulating the HIF-1α pathway. Therefore, hsa-miR31 -5p may be a novel therapeutic target for HS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

cxcl12 gene engineered endothelial progenitor cells further improve the functions of oligodendrocyte precursor cells

Highlights: • cxcl12 gene engineering of EPCs promoted VEGF and IGF expression by EPCs. • Conditioned media from CXCL12-EPCs further promoted the functions of OPCs. • CXCL12-EPCs conditioned media affected the expression of trophic factors by OPCs. • CXCR4 knockdown suppressed the proliferation and migration of OPCs and reduced PDGFR-α and bFGF expression. • CXCR7 knockdown inhibited the expression of MBP by OPCs and caused slower differentiation. Oligodendrocyte precursor cells (OPCs) are needed for white matter repair after various brain injury. Means that promote OPC functions could benefit white matter recovery after injury. Chemokine CXCL12 and endothelial progenitor cells (EPCs) both have been shown to promote remyelination. We hypothesize that the beneficial effects of EPCs and CXCL12 can be harnessed by genetically modifying EPCs with cxcl12 to synergistically improve the functions of OPCs. In this work, CXCL12-EPC was generated using virus-mediated gene transfer. OPCs were cultured with CXCL12-EPC conditioned media (CM) to analyze its impact on the proliferation, migration, differentiation and survival properties of OPCs. We blocked or knocked-down the receptors of CXCL12, namely CXCR4 and CXCR7, respectively to investigate their functions in regulating OPCs properties. Results revealed that CXCL12-EPC CM further promoted OPCs behavioral properties and upregulated the expression of PDGFR-α, bFGF, CXCR4 and CXCR7 in OPCs, albeit following different time course. Blocking CXCR4 diminished the beneficial effects of CXCL12 on OPCs proliferation and migration, while knocking down CXCR7 inhibited OPCs differentiation. Our results supported that cxcl12 gene modification of EPCs further promoted EPCs’ ability in augmenting the remyelination properties of OPCs, suggesting that CXCL12-EPC hold great potential in white matter repair.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

MicroRNA-21a-5p promotes fibrosis in spinal fibroblasts after mechanical trauma

Highlights: • Established a new spinal fibroblast scratch damage model. • MiR-21a-5p regulates the differentiation, proliferation, and apoptosis of spinal fibroblasts in scratch damage model. • MicroRNA-21 promotes the activation of Smads signaling in scratch damage model. Traumatic spinal cord injury (SCI) causes permanent disability to at least 180,000 people per year worldwide. Early regulation of spinal fibroblast proliferation may inhibit fibrotic scar formation, allowing the creation of a favorable environment for neuronal regeneration and thereby enhancing recovery from traumatic SCIs. In this study, we aimed to identify the role of microRNA-21a–5p (miR-21a-5p) in regulating spinal fibroblasts after mechanical trauma and to investigate the dysregulation of miR-21a-5p in the pathological process of spinal SCI. We investigated the differential expression of microRNAs in primary spinal fibroblasts after mechanical trauma and found that the expression of miR-21a-5p was higher in spinal fibroblasts after scratch damage (SD). In addition, mouse spinal fibroblasts were transfected with miR-21a-5p mimics/inhibitor, and the role of miR-21a-5p in spinal fibrogenic activation was analyzed. These experiments demonstrated that miR-21a-5p overexpression promoted fibrogenic activity in spinal fibroblasts after mechanical trauma, as well as enhancing proliferation and attenuating apoptosis in spinal fibroblasts. Finally, the potential role of miR-21a-5p in regulating the Smad signaling pathway was examined. MiR-21a-5p activated the Smad signaling pathway by enhancing Smad2/3 phosphorylation. These results suggest that miR-21a-5p promotes spinal fibrosis after mechanical trauma. Based on these findings, we propose a close relationship between miR-21a-5p and spinal fibrosis, providing a new potential therapeutic target for SCI.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Drosophila intestinal homeostasis requires CTP synthase

CTP synthase (CTPS) senses all four nucleotides and forms filamentous structures termed cytoophidia in all three domains of life. How CTPS and cytoophidia function in a developmental context, however, remains underexplored. We report that CTPS forms cytoophidia in a subset of cells in the Drosophila midgut. We found that cytoophidia exist in intestinal stem cells (ISC) and enteroblasts in similar proportions. Both refeeding after starvation and feeding with dextran sulfate sodium (DSS) induce ISC proliferation and elongate cytoophidia. Knockdown of CTPS inhibits ISC proliferation. Remarkably, disruption of CTPS cytoophidia inhibits DSS-induced ISC proliferation. Taken together, these data suggest that both the expression level and the filament-form property of CTPS are crucial for intestinal homeostasis in Drosophila.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

An oscillatory network controlling self-renewal of skeletal muscle stem cells

The balance between proliferation and differentiation of muscle stem cells is tightly controlled, ensuring the maintenance of a cellular pool needed for muscle growth and repair. Muscle stem cells can proliferate, they can generate differentiating cells, or they self-renew to produce new stem cells. Notch signaling plays a crucial role in this process. Recent studies revealed that expression of the Notch effector HES1 oscillates in activated muscle stem cells. The oscillatory expression of HES1 periodically represses transcription from the genes encoding the myogenic transcription factor MYOD and the Notch ligand DLL1, thereby driving MYOD and DLL1 oscillations. This oscillatory network allows muscle progenitor cells and activated muscle stem cells to remain in a proliferative and ‘undecided’ state, in which they can either differentiate or self-renew. When HES1 is downregulated, MYOD oscillations become unstable and are replaced by sustained expression, which drives the cells into terminal differentiation. During development and regeneration, proliferating stem cells contact each other and the stability of the oscillatory expression depends on regular DLL1 inputs provided by neighboring cells. In such communities of cells that receive and provide Notch signals, the appropriate timing of DLL1 inputs is important, as sustained DLL1 cannot replace oscillatory DLL1. Thus, in cell communities, DLL1 oscillations ensure the appropriate balance between self-renewal and differentiation. In summary, oscillations in myogenic cells are an important example of dynamic gene expression determining cell fate.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Regulation of T cell expansion by antigen presentation dynamics

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher-affinity clones can suppress the proliferation of lower-affinity clones, thereby promoting the specificity of the response. Using the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Investigation of Relevant Distribution System Representation With DG for Voltage Stability Margin Assessment

This paper emphasizes the importance of including unbalanced distribution systems for voltage stability studies in power systems. The paper aims to: discuss the various simulation methods for power system analysis; highlight the need for modeling unbalanced distribution system for accurate load margin assessment; demonstrate the influence of net-load unbalance (NLU) on voltage stability margin (VSM). We also share a T&D co-simulation interface with commercial power system solvers. The distribution system is evolving rapidly with high proliferation of distributed energy resources (DERs); these are not guaranteed to proliferate in a balanced manner and uncertainty resulting due to these DERs is well acknowledged. These uncertainties cannot be captured or visualized without representing the distribution system in detail along with the transmission system. We show the impact of proliferation of DERs in various 3-phase proportions on voltage stability margin through T&D co-simulation. We also study the impact of volt/VAR control on voltage stability margin. This analysis is only possible by representing the distribution system in detail through T&D co-simulation. In conclusion, higher percentage of net-load unbalance (NLU) in distribution system aggravates the voltage stability margin of the distribution system, which can further negatively influence the overall voltage stability margin of the system.

24 POWER TRANSMISSION AND DISTRIBUTION↗
DOE OSTI2015

SU-E-T-751: Three-Component Kinetic Model of Tumor Growth and Radiation Response for Stereotactic Radiosurgery

Purpose: To develop and study a kinetic model of tumor growth and its response to stereotactic radiosurgery (SRS) by assuming that the cells in irradiated tumor volume were made of three types. Methods: A set of ordinary differential equations (ODEs) were derived for three types of cells and a tumor growth rate. It is assumed that the cells were composed of actively proliferating cells, lethally damaged-dividing cells, and non-dividing cells. We modeled the tumor volume growth with a time-dependent growth rate to simulate the saturation of growth. After SRS, the proliferating cells were permanently damaged and converted to the lethally damaged cells. The amount of damaged cells were estimated by the LQ-model. The damaged cells gradually stopped dividing/proliferating and died with a constant rate. The dead cells were cleared from their original location with a constant rate. The total tumor volume was the sum of the three components. The ODEs were numerically solved with appropriate initial conditions for a given dosage. The proposed model was used to model an animal experiment, for which the temporal change of a rhabdomyosarcoma tumor volume grown in a rat was measured with time resolution sufficient to test the model. Results: To fit the model to the experimental data, the following characteristics were needed with the model parameters. The α-value in the LQ-model was smaller than the commonly used value; furthermore, it decreased with increasing dose. At the same time, the tumor growth rate after SRS had to increase. Conclusions: The new 3-component model of tumor could simulate the experimental data very well. The current study suggested that the radiation sensitivity and the growth rate of the proliferating tumor cells may change after irradiation and it depended on the dosage used for SRS. These preliminary observations must be confirmed by future animal experiments.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Genomic analysis and identification of a novel superantigen, SargEY, in Staphylococcus argenteus isolated from atopic dermatitis lesions

During surveillance of Staphylococcus aureus in lesions from patients with atopic dermatitis (AD), we isolated Staphylococcus argenteus, a species registered in 2011 as a new member of the genus Staphylococcus and previously considered a lineage of S. aureus. Genome sequence comparisons between S. argenteus isolates and representative S. aureus clinical isolates from various origins revealed that the S. argenteus genome from AD patients closely resembles that of S. aureus causing skin infections. We previously reported that 17%–22% of S. aureus isolated from skin infections produce staphylococcal enterotoxin Y (SEY), which predominantly induces T-cell proliferation via the T-cell receptor (TCR) Vα pathway. Complete genome sequencing of S. argenteus isolates revealed a gene encoding a protein similar to superantigen SEY, designated as SargEY, on its chromosome. Population structure analysis of S. argenteus revealed that these isolates are ST2250 lineage, which was the only lineage positive for the SEY-like gene among S. argenteus. Recombinant SargEY demonstrated immunological cross-reactivity with anti-SEY serum. SargEY could induce proliferation of human CD4 + and CD8 + T cells, as well as production of TNF-α and IFN-γ. SargEY showed emetic activity in a marmoset monkey model. S arg EY and SET (a phylogenetically close but uncharacterized SE) revealed their dependency on TCR Vα in inducing human T-cell proliferation. Additionally, TCR sequencing revealed other previously undescribed Vα repertoires induced by SEH. S arg EY and SEY may play roles in exacerbating the respective toxin-producing strains in AD.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Effects of Escherichia coli Nissle 1917 and Ciprofloxacin on small intestinal epithelial cell mRNA expression in the neonatal piglet model of human rotavirus infection

We evaluated the effects of the probiotic Escherichia coli Nissle 1917 (EcN) and the antibiotic Ciprofloxacin (Cipro) on mRNA expression of intestinal epithelial cells (IEC) in gnotobiotic (Gn) piglets colonized with a defined commensal microflora (DMF) and inoculated with human rotavirus (HRV) that infects IECs. We analyzed mRNA levels of IEC genes for enteroendocrine cells [chromogranin A (CgA)], goblet cells [mucin 2 (MUC2)], transient amplifying progenitor cell [proliferating cell nuclear antigen (PCNA)], intestinal epithelial stem cell (SOX9) and enterocytes (villin). Cipro treatment enhanced HRV diarrhea and decreased the mRNA levels of MUC 2 and villin but increased PCNA. These results suggest that Cipro alters the epithelial barrier, potentially decreasing the numbers of mature enterocytes (villin) and goblet cells secreting protective mucin (MUC 2 ). These alterations may induce increased IEC proliferation (PCNA expression) to restore the integrity of the epithelial layer. Coincidental with decreased diarrhea severity in EcN treated groups, the expression of CgA and villin was increased, while SOX9 expression was decreased representing higher epithelial integrity indicative of inhibition of cellular proliferation. Thus, EcN protects the intestinal epithelium from damage by increasing the gene expression of enterocytes and enteroendocrine cells, maintaining the absorptive function and, consequently, decreasing the severity of diarrhea in HRV infection.

Gastroenterology & Hepatology↗
DOE OSTI2013

Hexavalent Chromium Reduction under Fermentative Conditions with Lactate Stimulated Native Microbial Communities

Microbial reduction of toxic hexavalent chromium (Cr(VI)) in-situ is a plausible bioremediation strategy in electron-acceptor limited environments. However, higher [Cr(VI)] may impose stress on syntrophic communities and impact community structure and function. The study objectives were to understand the impacts of Cr(VI) concentrations on community structure and on the Cr(VI)-reduction potential of groundwater communities at Hanford, WA. Steady state continuous flow bioreactors were used to grow native communities enriched with lactate (30 mM) and continuously amended with Cr(VI) at 0.0 (No-Cr), 0.1 (Low-Cr) and 3.0 (High-Cr) mg/L. Microbial growth, metabolites, Cr(VI), 16S rRNA gene sequences and GeoChip based functional gene composition were monitored for 15 weeks. Temporal trends and differences in growth, metabolite profiles, and community composition were observed, largely between Low-Cr and High-Cr bioreactors. In both High-Cr and Low-Cr bioreactors, Cr(VI) levels were below detection from week 1 until week 15. With lactate enrichment, native bacterial diversity substantially decreased as Pelosinus spp., and Sporotalea spp., became the dominant groups, but did not significantly differ between Cr concentrations. The Archaea diversity also substantially decreased after lactate enrichment from Methanosaeta (35%), Methanosarcina (17%) and others, to mostly Methanosarcina spp. (95%). Methane production was lower in High-Cr reactors suggesting some inhibition of methanogens. Several key functional genes were distinct in Low-Cr bioreactors compared to High-Cr. Among the Cr resistant microbes, Burkholderia vietnamiensis, Comamonas testosterone and Ralstonia pickettii proliferated in Cr amended bioreactors. In-situ fermentative conditions facilitated Cr(VI) reduction, and as a result 3.0 mg/L Cr(VI) did not impact the overall bacterial community structure.

Somenahally, Anil C↗
DOE OSTI2014

Impaired osteoblast differentiation in Annexin A2- and -A5-deficient cells

Annexins are a class of calcium-binding proteins with diverse functions in the regulation of lipid rafts inflammation,fibrinolysis, transcriptional programming and ion transport. Within bone, they are well-characterized as components of mineralizing matrix vesicles, although little else is known as to their function during osteogenesis. We generated annexin A2 (AnxA2)- or annexin A5 (AnxA5)-knockdown pre-osteoblasts, and asked whether proliferation or osteogenic differentiation was altered in knockdown cells, compared to vector controls. We report that DNA content, a marker of proliferation, was significantly reduced in both AnxA2 and AnxA5 knockdown cells. Alkaline phosphatase expression and staining activity were also suppressed in AnxA2- or AnxA5-knockdown after 14 days of culture. The pattern of osteogenic gene expression was altered in knockdown cells, with Col1a1 expressed more rapidly in knock-down cells, compared to controls. In contrast, Runx2, Ibsp, and Bglap all revealed decreased expression after 14 days of culture. Using a murine fracture model, we demonstrate that AnxA2 and AnxA5 are rapidly expressed within the fracture callus. These data demonstrate that AnxA2 and AnxA5 can influence bone formation via regulation of osteoprogenitor proliferation and differentiation in addition to their well-studied function in matrix vesicles.

annexin, bone, gene expression↗
DOE OSTI2017

Structural basis of divergent cyclin-dependent kinase activation by Spy1/RINGO proteins

Cyclin-dependent kinases (Cdks) are principal drivers of cell division and are an important therapeutic target to inhibit aberrant proliferation. Cdk enzymatic activity is tightly controlled through cyclin interactions, posttranslational modifications, and binding of inhibitors such as the p27 tumor suppressor protein. Spy1/RINGO (Spy1) proteins bind and activate Cdk but are resistant to canonical regulatory mechanisms that establish cell-cycle checkpoints. Cancer cells exploit Spy1 to stimulate proliferation through inappropriate activation of Cdks, yet the mechanism is unknown. We have determined crystal structures of the Cdk2-Spy1 and p27-Cdk2-Spy1 complexes that reveal how Spy1 activates Cdk. We find that Spy1 confers structural changes to Cdk2 that obviate the requirement of Cdk activation loop phosphorylation. Spy1 lacks the cyclin-binding site that mediates p27 and substrate affinity, explaining why Cdk-Spy1 is poorly inhibited by p27 and lacks specificity for substrates with cyclin-docking sites. We identify mutations in Spy1 that ablate its ability to activate Cdk2 and to proliferate cells. Our structural description of Spy1 provides important mechanistic insights that may be utilized for targeting upregulated Spy1 in cancer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Predictive features of ligand-specific signaling through the estrogen receptor

Some estrogen receptor-α (ERα)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ERα ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERα activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called activation function-2 (AF-2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single inter-atomic distance in the ligand-binding domain predicted their proliferative effects. In contrast, the N-terminal coactivator-binding site, activation function-1 (AF-1), determined cell-specific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ERα.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Multilateral Spent Fuel Management Efforts: Nonproliferation and Energy Implications in the Asia Pacific

Management of spent nuclear fuel in the Asia Pacific will be a growing challenge in coming decades as the region continues its rapid economic and nuclear energy expansion. Accompanying this growth has been skyrocketing energy demand. The capacity of nuclear energy in the Asia Pacific is expected to increase by approximately 50% by 2035. In fact, of the 66 reactors under construction worldwide, 47 are being built in the Asia Pacific region alone. In a sense, the area is experiencing the so-called ‘Nuclear Renaissance’, which could simultaneously increase proliferation risks while fueling economic growth and political stability. And because ‘Asia Pacific’ includes North America, Oceania, East Asia, Southeast Asia and, by some definitions, South and Central Asia as well as the Middle East, the demand for nuclear energy in particular is expected to continue. Consequently, the Asia Pacific region will soon face important decisions about how to support and implement the necessary infrastructure for nuclear energy expansion and deal with the waste, while also meeting all nonproliferation obligations under the Treaty on the Non-Proliferation of Nuclear Weapons (NPT). One option for dealing with spent nuclear fuel that should be considered is multilateral spent fuel management. Such an effort could help reduce risks associated with safety, proliferation and security of nuclear energy. While the original idea of multilateral spent nuclear fuel management is a decades-old concept, no official plan has been developed because of challenges related to cost, liability, transportation, export controls, international commerce, and nonproliferation, to name a few. Nonetheless, as more and more newcomer countries decide to develop nuclear energy, but do not yet have a strategic plan or the financial means to deal with the waste, the international community may need to take a more proactive approach in developing a multilateral effort, particularly with respect to geological repositories and interim dry storage. Risks and benefits will need to be analyzed, while the role of such an effort in the revival of the Nuclear Renaissance will need to be evaluated. This paper provides an overview of spent nuclear fuel management efforts in the Asia Pacific region and attempts to analyze the possible benefits and feasibility of a multilateral approach.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2018

Regulation of T cell expansion by antigen presentation dynamics

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher affinity clones can suppress the proliferation of lower affinity clones, thereby promoting the specificity of the response. Employing the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.

60 APPLIED LIFE SCIENCES↗