Science.gov

Sample records for ras design simulation

  1. Design, synthesis and biological evaluation of sugar-derived Ras inhibitors.

    PubMed

    Peri, Francesco; Airoldi, Cristina; Colombo, Sonia; Martegani, Enzo; van Neuren, Anske Stephanie; Stein, Matthias; Marinzi, Chiara; Nicotra, Francesco

    2005-10-01

    The design and synthesis of novel Ras inhibitors with a bicyclic scaffold derived from the natural sugar D-arabinose are presented. Molecular modelling showed that these ligands can bind Ras by accommodating the aromatic moieties and the phenylhydroxylamino group in a cavity near the Switch II region of the protein. All the synthetic compounds were active in inhibiting nucleotide exchange on p21 human Ras in vitro, and two of them selectively inhibited Ras-dependent cell growth in vivo.

  2. Design and Performance of McRas in SCMs and GEOS I/II GCMs

    NASA Technical Reports Server (NTRS)

    Sud, Yogesh C.; Einaudi, Franco (Technical Monitor)

    2000-01-01

    The design of a prognostic cloud scheme named McRAS (Microphysics of clouds with Relaxed Arakawa-Schubert Scheme) for general circulation models (GCMs) will be discussed. McRAS distinguishes three types of clouds: (1) convective, (2) stratiform, and (3) boundary-layer types. The convective clouds transform and merge into stratiform clouds on an hourly time-scale, while the boundary-layer clouds merge into the stratiform clouds instantly. The cloud condensate converts into precipitation following the auto-conversion equations of Sundqvist that contain a parametric adaptation for the Bergeron-Findeisen process of ice crystal growth and collection of cloud condensate by precipitation. All clouds convect, advect, as well as diffuse both horizontally and vertically with a fully interactive cloud-microphysics throughout the life-cycle of the cloud, while the optical properties of clouds are derived from the statistical distribution of hydrometeors and idealized cloud geometry. An evaluation of McRAS in a single column model (SCM) with the GATE Phase III and 5-ARN CART datasets has shown that together with the rest of the model physics, McRAS can simulate the observed temperature, humidity, and precipitation without many systematic errors. The time history and time mean incloud water and ice distribution, fractional cloudiness, cloud optical thickness, origin of precipitation in the convective anvil and towers, and the convective updraft and downdraft velocities and mass fluxes all show a realistic behavior. Performance of McRAS in GEOS 11 GCM shows several satisfactory features but some of the remaining deficiencies suggest need for additional research involving convective triggers and inhibitors, provision for continuously detraining updraft, a realistic scheme for cumulus gravity wave drag, and refinements to physical conditions for ascertaining cloud detrainment level.

  3. Rational design of small molecule inhibitors targeting the Ras GEF, SOS1

    PubMed Central

    Evelyn, Chris R.; Duan, Xin; Biesiada, Jacek; Seibel, William L.; Meller, Jaroslaw; Zheng, Yi

    2014-01-01

    Summary Ras GTPases regulate intracellular signaling involved in cell proliferation. Elevated Ras signaling activity has been associated with human cancers. Ras activation is catalyzed by guanine-nucleotide exchange factors (GEFs), of which SOS1 is a major member that transduces receptor tyrosine kinase signaling to Ras. We have developed a rational approach coupling virtual screening with experimental screening in identifying small-molecule inhibitors targeting the catalytic site of SOS1 and SOS1-regulated Ras activity. A lead inhibitor, NSC-658497, is found to bind to SOS1, competitively suppresses SOS1-Ras interaction, and dose-dependently inhibits SOS1 GEF activity. Mutagenesis and structure-activity relationship studies map the NSC-658497 site of action to the SOS1 catalytic site, and define the chemical moieties in the inhibitor essential for the activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation. These studies establish a proof of principle for rational design of small-molecule inhibitors targeting Ras GEF enzymatic activity. PMID:25455859

  4. Rational design of small molecule inhibitors targeting the Ras GEF, SOS1.

    PubMed

    Evelyn, Chris R; Duan, Xin; Biesiada, Jacek; Seibel, William L; Meller, Jaroslaw; Zheng, Yi

    2014-12-18

    Ras GTPases regulate intracellular signaling involved in cell proliferation. Elevated Ras signaling activity has been associated with human cancers. Ras activation is catalyzed by guanine nucleotide exchange factors (GEFs), of which SOS1 is a major member that transduces receptor tyrosine kinase signaling to Ras. We have developed a rational approach coupling virtual screening with experimental screening in identifying small-molecule inhibitors targeting the catalytic site of SOS1 and SOS1-regulated Ras activity. A lead inhibitor, NSC-658497, was found to bind to SOS1, competitively suppress SOS1-Ras interaction, and dose-dependently inhibit SOS1 GEF activity. Mutagenesis and structure-activity relationship studies map the NSC-658497 site of action to the SOS1 catalytic site, and define the chemical moieties in the inhibitor essential for the activity. NSC-658497 showed dose-dependent efficacy in inhibiting Ras, downstream signaling activities, and associated cell proliferation. These studies establish a proof of principle for rational design of small-molecule inhibitors targeting Ras GEF enzymatic activity.

  5. An innovative modeling approach using Qual2K and HEC-RAS integration to assess the impact of tidal effect on River Water quality simulation.

    PubMed

    Fan, Chihhao; Ko, Chun-Han; Wang, Wei-Shen

    2009-04-01

    Water quality modeling has been shown to be a useful tool in strategic water quality management. The present study combines the Qual2K model with the HEC-RAS model to assess the water quality of a tidal river in northern Taiwan. The contaminant loadings of biochemical oxygen demand (BOD), ammonia nitrogen (NH(3)-N), total phosphorus (TP), and sediment oxygen demand (SOD) are utilized in the Qual2K simulation. The HEC-RAS model is used to: (i) estimate the hydraulic constants for atmospheric re-aeration constant calculation; and (ii) calculate the water level profile variation to account for concentration changes as a result of tidal effect. The results show that HEC-RAS-assisted Qual2K simulations taking tidal effect into consideration produce water quality indices that, in general, agree with the monitoring data of the river. Comparisons of simulations with different combinations of contaminant loadings demonstrate that BOD is the most import contaminant. Streeter-Phelps simulation (in combination with HEC-RAS) is also performed for comparison, and the results show excellent agreement with the observed data. This paper is the first report of the innovative use of a combination of the HEC-RAS model and the Qual2K model (or Streeter-Phelps equation) to simulate water quality in a tidal river. The combination is shown to provide an alternative for water quality simulation of a tidal river when available dynamic-monitoring data are insufficient to assess the tidal effect of the river.

  6. Ras history

    PubMed Central

    2010-01-01

    Although the roots of Ras sprouted from the rich history of retrovirus research, it was the discovery of mutationally activated RAS genes in human cancer in 1982 that stimulated an intensive research effort to understand Ras protein structure, biochemistry and biology. While the ultimate goal has been developing anti-Ras drugs for cancer treatment, discoveries from Ras have laid the foundation for three broad areas of science. First, they focused studies on the origins of cancer to the molecular level, with the subsequent discovery of genes mutated in cancer that now number in the thousands. Second, elucidation of the biochemical mechanisms by which Ras facilitates signal transduction established many of our fundamental concepts of how a normal cell orchestrates responses to extracellular cues. Third, Ras proteins are also founding members of a large superfamily of small GTPases that regulate all key cellular processes and established the versatile role of small GTP-binding proteins in biology. We highlight some of the key findings of the last 28 years. PMID:21686117

  7. Ras CAAX peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by inducing cytoplasmic accumulation of inactive Ras-Raf complexes.

    PubMed

    Lerner, E C; Qian, Y; Blaskovich, M A; Fossum, R D; Vogt, A; Sun, J; Cox, A D; Der, C J; Hamilton, A D; Sebti, S M

    1995-11-10

    Ras-induced malignant transformation requires Ras farnesylation, a lipid posttranslational modification catalyzed by farnesyltransferase (FTase). Inhibitors of this enzyme have been shown to block Ras-dependent transformation, but the mechanism by which this occurs remains largely unknown. We have designed FTI-276, a peptide mimetic of the COOH-terminal Cys-Val-Ile-Met of K-Ras4B that inhibited potently FTase in vitro (IC50 = 500 pM) and was highly selective for FTase over geranylgeranyltransferase I (GGTase I) (IC50 = 50 nM). FTI-277, the methyl ester derivative of FTI-276, was extremely potent (IC50 = 100 nM) at inhibiting H-Ras, but not the geranylgeranylated Rap1A processing in whole cells. Treatment of H-Ras oncogene-transformed NIH 3T3 cells with FTI-277 blocked recruitment to the plasma membrane and subsequent activation of the serine/threonine kinase c-Raf-1 in cells transformed by farnesylated Ras (H-RasF), but not geranylgeranylated, Ras (H-RasGG). FTI-277 induced accumulation of cytoplasmic non-farnesylated H-Ras that was able to bind Raf and form cytoplasmic Ras/Raf complexes in which Raf kinase was not activated. Furthermore, FTI-277 blocked constitutive activation of mitogen-activated protein kinase (MAPK) in H-RasF, but not H-RasGG, or Raf-transformed cells. FTI-277 also inhibited oncogenic K-Ras4B processing and constitutive activation of MAPK, but the concentrations required were 100-fold higher than those needed for H-Ras inhibition. The results demonstrate that FTI-277 blocks Ras oncogenic signaling by accumulating inactive Ras/Raf complexes in the cytoplasm, hence preventing constitutive activation of the MAPK cascade.

  8. Ras and GTPase-activating protein (GAP) drive GTP into a precatalytic state as revealed by combining FTIR and biomolecular simulations.

    PubMed

    Rudack, Till; Xia, Fei; Schlitter, Jürgen; Kötting, Carsten; Gerwert, Klaus

    2012-09-18

    Members of the Ras superfamily regulate many cellular processes. They are down-regulated by a GTPase reaction in which GTP is cleaved into GDP and P(i) by nucleophilic attack of a water molecule. Ras proteins accelerate GTP hydrolysis by a factor of 10(5) compared to GTP in water. GTPase-activating proteins (GAPs) accelerate hydrolysis by another factor of 10(5) compared to Ras alone. Oncogenic mutations in Ras and GAPs slow GTP hydrolysis and are a factor in many cancers. Here, we elucidate in detail how this remarkable catalysis is brought about. We refined the protein-bound GTP structure and protein-induced charge shifts within GTP beyond the current resolution of X-ray structural models by combining quantum mechanics and molecular mechanics simulations with time-resolved Fourier-transform infrared spectroscopy. The simulations were validated by comparing experimental and theoretical IR difference spectra. The reactant structure of GTP is destabilized by Ras via a conformational change from a staggered to an eclipsed position of the nonbridging oxygen atoms of the γ- relative to the β-phosphates and the further rotation of the nonbridging oxygen atoms of α- relative to the β- and γ-phosphates by GAP. Further, the γ-phosphate becomes more positive although two of its oxygen atoms remain negative. This facilitates the nucleophilic attack by the water oxygen at the phosphate and proton transfer to the oxygen. Detailed changes in geometry and charge distribution in the ligand below the resolution of X-ray structure analysis are important for catalysis. Such high resolution appears crucial for the understanding of enzyme catalysis.

  9. RAS Laboratory Groups

    Cancer.gov

    The RAS Initiative uses multiple technologies to attack RAS-driven cancers. The resources of the Frederick National Lab allocated to the RAS Hub are organized into seven laboratory groups, each contributing to the collaborative effort.

  10. The RAS Initiative

    Cancer.gov

    NCI established the RAS Initiative to explore innovative approaches for attacking the proteins encoded by mutant forms of RAS genes and to ultimately create effective, new therapies for RAS-related cancers.

  11. Design, Evaluation and GCM-Performance of a New Parameterization for Microphysics of Clouds with Relaxed Arakawa-Schubert Scheme (McRas)

    NASA Technical Reports Server (NTRS)

    Sud, Y. C.; Walker, G. K.

    1998-01-01

    A prognostic cloud scheme named McRAS (Microphysics of clouds with Relaxed Arakawa-Schubert Scheme) was developed with the aim of improving cloud-microphysics, and cloud-radiation interactions in GCMs. McRAS distinguishes convective, stratiform, and boundary-layer clouds. The convective clouds merge into stratiform clouds on an hourly time-scale, while the boundary-layer clouds do so instantly. The cloud condensate transforms into precipitation following the auto-conversion relations of Sundqvist that contain a parametric adaptation for the Bergeron-Findeisen process of ice crystal growth and collection of cloud condensate by precipitation. All clouds convect, advect, and diffuse both horizontally and vertically with a fully active cloud-microphysics throughout its life-cycle, while the optical properties of clouds are derived from the statistical distribution of hydrometeors and idealized cloud geometry. An evaluation of McRAS in a single column model (SCM) with the GATE Phase III data has shown that McRAS can simulate the observed temperature, humidity, and precipitation without discernible systematic errors. An evaluation with the ARM-CART SCM data in a cloud model intercomparison exercise shows reasonable but not an outstanding accurate simulation. Such a discrepancy is common to almost all models and is related, in part, to the input data quality. McRAS was implemented in the GEOS II GCM. A 50 month integration that was initialized with the ECMWF analysis of observations for January 1, 1987 and forced with the observed sea-surface temperatures and sea-ice distribution and vegetation properties (biomes, and soils), with prognostic soil moisture, snow-cover, and hydrology showed a very realistic simulation of cloud process, incloud water and ice, and cloud-radiative forcing (CRF). The simulated ITCZ showed a realistic time-mean structure and seasonal cycle, while the simulated CRF showed sensitivity to vertical distribution of cloud water which can be easily

  12. Combined rational design and a high throughput screening platform for identifying chemical inhibitors of a Ras-activating enzyme.

    PubMed

    Evelyn, Chris R; Biesiada, Jacek; Duan, Xin; Tang, Hong; Shang, Xun; Papoian, Ruben; Seibel, William L; Nelson, Sandra; Meller, Jaroslaw; Zheng, Yi

    2015-05-15

    The Ras family small GTPases regulate multiple cellular processes, including cell growth, survival, movement, and gene expression, and are intimately involved in cancer pathogenesis. Activation of these small GTPases is catalyzed by a special class of enzymes, termed guanine nucleotide exchange factors (GEFs). Herein, we developed a small molecule screening platform for identifying lead hits targeting a Ras GEF enzyme, SOS1. We employed an ensemble structure-based virtual screening approach in combination with a multiple tier high throughput experimental screen utilizing two complementary fluorescent guanine nucleotide exchange assays to identify small molecule inhibitors of GEF catalytic activity toward Ras. From a library of 350,000 compounds, we selected a set of 418 candidate compounds predicted to disrupt the GEF-Ras interaction, of which dual wavelength GDP dissociation and GTP-loading experimental screening identified two chemically distinct small molecule inhibitors. Subsequent biochemical validations indicate that they are capable of dose-dependently inhibiting GEF catalytic activity, binding to SOS1 with micromolar affinity, and disrupting GEF-Ras interaction. Mutagenesis studies in conjunction with structure-activity relationship studies mapped both compounds to different sites in the catalytic pocket, and both inhibited Ras signaling in cells. The unique screening platform established here for targeting Ras GEF enzymes could be broadly useful for identifying lead inhibitors for a variety of small GTPase-activating GEF reactions.

  13. Combined Rational Design and a High Throughput Screening Platform for Identifying Chemical Inhibitors of a Ras-activating Enzyme*

    PubMed Central

    Evelyn, Chris R.; Biesiada, Jacek; Duan, Xin; Tang, Hong; Shang, Xun; Papoian, Ruben; Seibel, William L.; Nelson, Sandra; Meller, Jaroslaw; Zheng, Yi

    2015-01-01

    The Ras family small GTPases regulate multiple cellular processes, including cell growth, survival, movement, and gene expression, and are intimately involved in cancer pathogenesis. Activation of these small GTPases is catalyzed by a special class of enzymes, termed guanine nucleotide exchange factors (GEFs). Herein, we developed a small molecule screening platform for identifying lead hits targeting a Ras GEF enzyme, SOS1. We employed an ensemble structure-based virtual screening approach in combination with a multiple tier high throughput experimental screen utilizing two complementary fluorescent guanine nucleotide exchange assays to identify small molecule inhibitors of GEF catalytic activity toward Ras. From a library of 350,000 compounds, we selected a set of 418 candidate compounds predicted to disrupt the GEF-Ras interaction, of which dual wavelength GDP dissociation and GTP-loading experimental screening identified two chemically distinct small molecule inhibitors. Subsequent biochemical validations indicate that they are capable of dose-dependently inhibiting GEF catalytic activity, binding to SOS1 with micromolar affinity, and disrupting GEF-Ras interaction. Mutagenesis studies in conjunction with structure-activity relationship studies mapped both compounds to different sites in the catalytic pocket, and both inhibited Ras signaling in cells. The unique screening platform established here for targeting Ras GEF enzymes could be broadly useful for identifying lead inhibitors for a variety of small GTPase-activating GEF reactions. PMID:25825487

  14. Hydro/Engineering Geophysical Parameters and Design Response Spectrum for Sustainable Development in Ras Muhammed National Park, Sinai

    NASA Astrophysics Data System (ADS)

    Khalil, Mohamed H.; Gamal, Mohamed A.

    2016-06-01

    The Egyptian government is preparing a sustainable development master plan for the Ras Muhammed National Park (RMNP), south Sinai. Noteworthy, the scarcity of the freshwater resources and close proximity to the active seismic zones of the Gulf of Aqaba implicate geophysical investigations for the fresh groundwater aquifers and construct a design response spectrum, respectively. Accordingly, 14 VESs, hydro/engineering geophysical analysis, pumping tests, downhole seismic test, a design response spectrum for buildings, and borehole data were carried out in the study area. The unconfined freshwater aquifer was effectively depicted with true resistivities, thickness, and EC ranged from 56 to 135 Ω m, 11 to 112 m, and 1.4 to 7.1 mS/m, respectively. The Northeastern part was characterized by higher aquifer potentiality, where coarser grains size, highest thickness (112 m), high true resistivity (135 Ω m), groundwater flow (0.074 m3/day), tortuosity (1.293-1.312), formation resistivity factor (4.1-4.6), and storativity (0.281-0.276). An increase in pumping rate was accompanied by an increase in well loss, increase in aquifer losses, decrease in well specific capacity, and decrease in well efficiency. Design response spectrum prognosticated the short buildings (<7 floors) in RMNP to be suffering from a high peak horizontal acceleration and shear forces for acceleration between 0.25 and 0.35 g. Therefore, appropriate detailing of shear reinforcement is indispensable to reduce the risk of structural damages at RMNP.

  15. Inhibitors of Ras-SOS Interactions.

    PubMed

    Lu, Shaoyong; Jang, Hyunbum; Zhang, Jian; Nussinov, Ruth

    2016-04-19

    Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still 'undruggable' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose "pathway drug cocktails", that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal.

  16. RAS - Screens & Assays

    Cancer.gov

    A primary goal of the RAS Initiative is to develop assays for RAS activity, localization, and signaling and adapt those assays so they can be used for finding new drug candidates. Explore the work leading to highly validated screening protocols.

  17. RAS Initiative - Community Outreach

    Cancer.gov

    Through community and technical collaborations, workshops and symposia, and the distribution of reference reagents, the RAS Initiative seeks to increase the sharing of knowledge and resources essential to defeating cancers caused by mutant RAS genes.

  18. RAS Initiative - Events

    Cancer.gov

    The NCI RAS Initiative has organized multiple events with outside experts to discuss how the latest scientific and technological breakthroughs can be applied to discover vulnerabilities in RAS-driven cancers.

  19. RAS - Target Identification - Informatics

    Cancer.gov

    The RAS Informatics lab group develops tools to track and analyze “big data” from the RAS Initiative, as well as analyzes data from external projects. By integrating internal and external data, this group helps improve understanding of RAS-driven cancers.

  20. Detailed structure of the H2PO4(-)-guanosine diphosphate intermediate in Ras-GAP decoded from FTIR experiments by biomolecular simulations.

    PubMed

    Xia, Fei; Rudack, Till; Cui, Qiang; Kötting, Carsten; Gerwert, Klaus

    2012-12-12

    Essential biochemical processes such as signal transduction, energy conversion, or substrate conversion depend on transient ligand binding. Thus, identifying the detailed structure and transient positioning of small ligands, and their stabilization by the surrounding protein, is of great importance. In this study, by decoding information from Fourier transform infrared (FTIR) spectra with biomolecular simulation methods, we identify the precise position and hydrogen network of a small compound, the guanosine diphosphate (GDP)-H(2)PO(4)(-) intermediate, in the surrounding protein-protein complex of Ras and its GTPase-activating protein, a central molecular switch in cellular signal transduction. We validate the simulated structure by comparing the calculated fingerprint vibrational modes of H(2)PO(4)(-) with those obtained from FTIR experiments. The new structural information, below the resolution of X-ray structural analysis, gives detailed insight into the catalytic mechanism.

  1. A channel simulator design study

    NASA Technical Reports Server (NTRS)

    Devito, D. M.; Goutmann, M. M.; Harper, R. C.

    1971-01-01

    A propagation path simulator was designed for the channel between a Tracking and Data Relay Satellite in geostationary orbit and a user spacecraft orbiting the earth at an altitude between 200 and 4000 kilometers. The simulator is required to duplicate the time varying parameters of the propagation channel.

  2. Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP.

    PubMed

    Garcia, Lia C; Donadío, Lucia Gandolfi; Mann, Ella; Kolusheva, Sofiya; Kedei, Noemi; Lewin, Nancy E; Hill, Colin S; Kelsey, Jessica S; Yang, Jing; Esch, Timothy E; Santos, Marina; Peach, Megan L; Kelley, James A; Blumberg, Peter M; Jelinek, Raz; Marquez, Victor E; Comin, Maria J

    2014-06-15

    The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2-5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.

  3. Process simulation and design '94

    SciTech Connect

    Not Available

    1994-06-01

    This first-of-a-kind report describes today's process simulation and design technology for specific applications. It includes process names, diagrams, applications, descriptions, objectives, economics, installations, licensors, and a complete list of process submissions. Processes include: alkylation, aromatics extraction, catalytic reforming, cogeneration, dehydration, delayed coking, distillation, energy integration, catalytic cracking, gas sweetening, glycol/methanol injection, hydrocracking, NGL recovery and stabilization, solvent dewaxing, visbreaking. Equipment simulations include: amine plant, ammonia plant, heat exchangers, cooling water network, crude preheat train, crude unit, ethylene furnace, nitrogen rejection unit, refinery, sulfur plant, and VCM furnace. By-product processes include: olefins, polyethylene terephthalate, and styrene.

  4. Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view.

    PubMed

    Lu, Shaoyong; Jang, Hyunbum; Gu, Shuo; Zhang, Jian; Nussinov, Ruth

    2016-09-21

    Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras-effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3Kα trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins.

  5. Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view.

    PubMed

    Lu, Shaoyong; Jang, Hyunbum; Gu, Shuo; Zhang, Jian; Nussinov, Ruth

    2016-09-21

    Ras proteins are small GTPases, cycling between inactive GDP-bound and active GTP-bound states. Through these switches they regulate signaling that controls cell growth and proliferation. Activating Ras mutations are associated with approximately 30% of human cancers, which are frequently resistant to standard therapies. Over the past few years, structural biology and in silico drug design, coupled with improved screening technology, led to a handful of promising inhibitors, raising the possibility of drugging Ras proteins. At the same time, the invariable emergence of drug resistance argues for the critical importance of additionally honing in on signaling pathways which are likely to be involved. Here we overview current advances in Ras structural knowledge, including the conformational dynamic of full-length Ras in solution and at the membrane, therapeutic inhibition of Ras activity by targeting its active site, allosteric sites, and Ras-effector protein-protein interfaces, Ras dimers, the K-Ras4B/calmodulin/PI3Kα trimer, and targeting Ras with siRNA. To mitigate drug resistance, we propose signaling pathways that can be co-targeted along with Ras and explain why. These include pathways leading to the expression (or activation) of YAP1 and c-Myc. We postulate that these and Ras signaling pathways, MAPK/ERK and PI3K/Akt/mTOR, act independently and in corresponding ways in cell cycle control. The structural data are instrumental in the discovery and development of Ras inhibitors for treating RAS-driven cancers. Together with the signaling blueprints through which drug resistance can evolve, this review provides a comprehensive and innovative master plan for tackling mutant Ras proteins. PMID:27396271

  6. Spinning Rocket Simulator Turntable Design

    NASA Technical Reports Server (NTRS)

    Miles, Robert W.

    2001-01-01

    Contained herein is the research and data acquired from the Turntable Design portion of the Spinning Rocket Simulator (SRS) project. The SRS Project studies and eliminates the effect of coning on thrust-propelled spacecraft. This design and construction of the turntable adds a structural support for the SRS model and two degrees of freedom. The two degrees of freedom, radial and circumferential, will help develop a simulated thrust force perpendicular to the plane of the spacecraft model while undergoing an unstable coning motion. The Turntable consists of a ten-foot linear track mounted to a sprocket and press-fit to a thrust bearing. A two-inch high column grounded by a Triangular Baseplate supports this bearing and houses the slip rings and pressurized, air-line swivel. The thrust bearing allows the entire system to rotate under the moment applied through the chain-driven sprocket producing a circumferential degree of freedom. The radial degree of freedom is given to the model through the helically threaded linear track. This track allows the Model Support and Counter Balance to simultaneously reposition according to the coning motion of the Model. Two design factors that hinder the linear track are bending and twist due to torsion. A Standard Aluminum "C" channel significantly reduces these two deflections. Safety considerations dictate the design of all the components involved in this project.

  7. Xyce parallel electronic simulator design.

    SciTech Connect

    Thornquist, Heidi K.; Rankin, Eric Lamont; Mei, Ting; Schiek, Richard Louis; Keiter, Eric Richard; Russo, Thomas V.

    2010-09-01

    This document is the Xyce Circuit Simulator developer guide. Xyce has been designed from the 'ground up' to be a SPICE-compatible, distributed memory parallel circuit simulator. While it is in many respects a research code, Xyce is intended to be a production simulator. As such, having software quality engineering (SQE) procedures in place to insure a high level of code quality and robustness are essential. Version control, issue tracking customer support, C++ style guildlines and the Xyce release process are all described. The Xyce Parallel Electronic Simulator has been under development at Sandia since 1999. Historically, Xyce has mostly been funded by ASC, the original focus of Xyce development has primarily been related to circuits for nuclear weapons. However, this has not been the only focus and it is expected that the project will diversify. Like many ASC projects, Xyce is a group development effort, which involves a number of researchers, engineers, scientists, mathmaticians and computer scientists. In addition to diversity of background, it is to be expected on long term projects for there to be a certain amount of staff turnover, as people move on to different projects. As a result, it is very important that the project maintain high software quality standards. The point of this document is to formally document a number of the software quality practices followed by the Xyce team in one place. Also, it is hoped that this document will be a good source of information for new developers.

  8. Simulation of a Wall-Bounded Flow using a Hybrid LES/RAS Approach with Turbulence Recycling

    NASA Technical Reports Server (NTRS)

    Quinlan, Jesse R.; Mcdaniel, James; Baurle, Robert A.

    2012-01-01

    Simulations of a supersonic recessed-cavity flow are performed using a hybrid large-eddy/ Reynolds-averaged simulation approach utilizing an inflow turbulence recycling procedure and hybridized inviscid flux scheme. Calorically perfect air enters the three-dimensional domain at a free stream Mach number of 2.92. Simulations are performed to assess grid sensitivity of the solution, efficacy of the turbulence recycling, and effect of the shock sensor used with the hybridized inviscid flux scheme. Analysis of the turbulent boundary layer upstream of the rearward-facing step for each case indicates excellent agreement with theoretical predictions. Mean velocity and pressure results are compared to Reynolds-averaged simulations and experimental data for each case, and these comparisons indicate good agreement on the finest grid. Simulations are repeated on a coarsened grid, and results indicate strong grid density sensitivity. The effect of turbulence recycling on the solution is illustrated by performing coarse grid simulations with and without inflow turbulence recycling. Two shock sensors, one of Ducros and one of Larsson, are assessed for use with the hybridized inviscid flux reconstruction scheme.

  9. The RAS Problem

    Cancer.gov

    More than 30% of all human cancers, including a high percentage of lung and colon cancers and 95% of pancreatic cancers are driven by mutations and possibly amplification (increased copies) of RAS genes.

  10. Sensitivity of Cirrus and Mixed-phase Clouds to the Ice Nuclei Spectra in McRAS-AC: Single Column Model Simulations

    NASA Technical Reports Server (NTRS)

    Betancourt, R. Morales; Lee, D.; Oreopoulos, L.; Sud, Y. C.; Barahona, D.; Nenes, A.

    2012-01-01

    The salient features of mixed-phase and ice clouds in a GCM cloud scheme are examined using the ice formation parameterizations of Liu and Penner (LP) and Barahona and Nenes (BN). The performance of LP and BN ice nucleation parameterizations were assessed in the GEOS-5 AGCM using the McRAS-AC cloud microphysics framework in single column mode. Four dimensional assimilated data from the intensive observation period of ARM TWP-ICE campaign was used to drive the fluxes and lateral forcing. Simulation experiments where established to test the impact of each parameterization in the resulting cloud fields. Three commonly used IN spectra were utilized in the BN parameterization to described the availability of IN for heterogeneous ice nucleation. The results show large similarities in the cirrus cloud regime between all the schemes tested, in which ice crystal concentrations were within a factor of 10 regardless of the parameterization used. In mixed-phase clouds there are some persistent differences in cloud particle number concentration and size, as well as in cloud fraction, ice water mixing ratio, and ice water path. Contact freezing in the simulated mixed-phase clouds contributed to transfer liquid to ice efficiently, so that on average, the clouds were fully glaciated at T approximately 260K, irrespective of the ice nucleation parameterization used. Comparison of simulated ice water path to available satellite derived observations were also performed, finding that all the schemes tested with the BN parameterization predicted 20 average values of IWP within plus or minus 15% of the observations.

  11. An orthosteric inhibitor of the RAS-SOS interaction.

    PubMed

    Nickerson, Seth; Joy, Stephen T; Arora, Paramjit S; Bar-Sagi, Dafna

    2013-01-01

    Rat sarcoma (RAS) proteins are signaling nodes that transduce extracellular cues into precise alterations in cellular physiology by engaging effector pathways. RAS signaling thus regulates diverse cell processes including proliferation, migration, differentiation, and survival. Owing to this central role in governing mitogenic signals, RAS pathway components are often dysregulated in human diseases. Targeted therapy of RAS pathways has generally not been successful, largely because of the robust biochemistry of the targets and their multifaceted network of molecular regulators. The rate-limiting step of RAS activation is Son of Sevenless (SOS)-mediated nucleotide exchange involving a single evolutionarily conserved catalytic helix from SOS. Structure function data of this mechanism provided a strong platform to design an SOS-derived, helically constrained peptide mimic as an inhibitor of the RAS-SOS interaction. In this chapter, we review RAS-SOS signaling dynamics and present evidence supporting the novel paradigm of inhibiting their interaction as a therapeutic strategy. We then describe a method of generating helically constrained peptide mimics of protein surfaces, which we have employed to inhibit the RAS-SOS active site interaction. The biochemical and functional properties of this SOS mimic support the premise that inhibition of RAS-nucleotide exchange can effectively block RAS activation and downstream signaling.

  12. Inhibition of Ras oncogenic activity by Ras protooncogenes.

    PubMed

    Diaz, Roberto; Lue, Jeffrey; Mathews, Jeremy; Yoon, Andrew; Ahn, Daniel; Garcia-España, Antonio; Leonardi, Peter; Vargas, Marcelo P; Pellicer, Angel

    2005-01-10

    Point mutations in ras genes have been found in a large number and wide variety of human tumors. These oncogenic Ras mutants are locked in an active GTP-bound state that leads to a constitutive and deregulated activation of Ras function. The dogma that ras oncogenes are dominant, whereby the mutation of a single allele in a cell will predispose the host cell to transformation regardless of the presence of the normal allele, is being challenged. We have seen that increasing amounts of Ras protooncogenes are able to inhibit the activity of the N-Ras oncogene in the activation of Elk in NIH 3T3 cells and in the formation of foci. We have been able to determine that the inhibitory effect is by competition between Ras protooncogenes and the N-Ras oncogene that occurs first at the effector level at the membranes, then at the processing level and lastly at the effector level in the cytosol. In addition, coexpression of the N-Ras protooncogene in thymic lymphomas induced by the N-Ras oncogene is associated with increased levels of p107, p130 and cyclin A and decreased levels of Rb. In the present report, we have shown that the N-Ras oncogene is not truly dominant over Ras protooncogenes and their competing activities might be depending on cellular context.

  13. RAS - Screens & Assays - Drug Discovery

    Cancer.gov

    The RAS Drug Discovery group aims to develop assays that will reveal aspects of RAS biology upon which cancer cells depend. Successful assay formats are made available for high-throughput screening programs to yield potentially effective drug compounds.

  14. Space shuttle visual simulation system design study

    NASA Technical Reports Server (NTRS)

    1973-01-01

    A recommendation and a specification for the visual simulation system design for the space shuttle mission simulator are presented. A recommended visual system is described which most nearly meets the visual design requirements. The cost analysis of the recommended system covering design, development, manufacturing, and installation is reported. Four alternate systems are analyzed.

  15. Engineering design and integration simulation utilization manual

    NASA Technical Reports Server (NTRS)

    Hirsch, G. N.

    1976-01-01

    A description of the Engineering Design Integration (EDIN) Simulation System as it exists at Johnson Space Center is provided. A discussion of the EDIN Simulation System capabilities and applications is presented.

  16. TC21 and Ras share indistinguishable transforming and differentiating activities.

    PubMed

    Graham, S M; Oldham, S M; Martin, C B; Drugan, J K; Zohn, I E; Campbell, S; Der, C J

    1999-03-25

    Constitutively activated mutants of the Ras-related protein TC21/R-Ras2 cause tumorigenic transformation of NIH3T3 cells. However, unlike Ras, TC21 fails to bind to and activate the Raf-1 serine-threonine kinase. Thus, whereas Ras transformation is critically dependent on Raf-1 TC21 activity is promoted by activation of Raf-independent signaling pathways. In the present study, we have further compared the functions of Ras and TC21. First we determined the basis for the inability of TC21 to activate Raf-1. Whereas Ras can interact with the two distinct Ras-binding sequences in NH2-terminus of Raf-1, designated RBS1 and Raf-Cys, TC21 could only bind Raf-Cys. Thus, the inability of TC21 to bind to RBS1 may prevent it from promoting the translocation of Raf-1 to the plasma membrane. Second, we found that TC21 is an activator of the JNK and p38, but not ERK, mitogen-activated protein kinase cascades and that TC21 transforming activity was dependent on Rac function. Thus, like Ras, TC21 may activate a Rac/JNK pathway. Third, we determined if TC21 could cause the same biological consequences as Ras in three distinct cell types. Like Ras, activated TC21 caused transformation of RIE-1 rat intestinal epithelial cells and terminal differentiation of PC12 pheochromocytoma cells. Finally, activated TC21 blocked serum starvation-induced differentiation of C2 myoblasts, whereas dominant negative TC21 greatly accelerated this differentiation process. Therefore, TC21 and Ras share indistinguishable biological activities in all cell types that we have evaluated. These results support the importance of Raf-independent pathways in mediating the actions of Ras and TC21.

  17. RasGRP Ras guanine nucleotide exchange factors in cancer

    PubMed Central

    Ksionda, Olga; Limnander, Andre

    2014-01-01

    Summary RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through −4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological-cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanism for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors. PMID:24744772

  18. Differential dynamics of RAS isoforms in GDP- and GTP-bound states.

    PubMed

    Kapoor, Abhijeet; Travesset, Alex

    2015-06-01

    RAS subfamily proteins regulates cell growth promoting signaling processes by cycling between active (GTP-bound) and inactive (GDP-bound) states. Different RAS isoforms, though structurally similar, exhibit functional specificity and are associated with different types of cancers and developmental disorders. Understanding the dynamical differences between the isoforms is crucial for the design of inhibitors that can selectively target a particular malfunctioning isoform. In this study, we provide a comprehensive comparison of the dynamics of all the three RAS isoforms (HRAS, KRAS, and NRAS) using extensive molecular dynamics simulations in both the GDP- (total of 3.06 μs) and GTP-bound (total of 2.4 μs) states. We observed significant differences in the dynamics of the isoforms, which rather interestingly, varied depending on the type of the nucleotide bound and the simulation temperature. Both SwitchI (Residues 25-40) and SwitchII (Residues 59-75) differ significantly in their flexibility in the three isoforms. Furthermore, Principal Component Analysis showed that there are differences in the conformational space sampled by the GTP-bound RAS isoforms. We also identified a previously unreported pocket, which opens transiently during MD simulations, and can be targeted to regulate nucleotide exchange reaction or possibly interfere with membrane localization. Further, we present the first simulation study showing GDP destabilization in the wild-type RAS protein. The destabilization of GDP/GTP occurred only in 1/50 simulations, emphasizing the need of guanine nucleotide exchange factors (GEFs) to accelerate such an extremely unfavorable process. This observation along with the other results presented in this article further support our previously hypothesized mechanism of GEF-assisted nucleotide exchange.

  19. In service design by simulations

    SciTech Connect

    Nasr H. Ghoniem

    2004-03-14

    Irradiation of materials by energetic particles (e.g. electrons, ions and neutrons) is associated with very high internal power dissipation, which can drive the underlying nano- and microstructure far from normal equilibrium conditions. One of the most unusual responses in this connection is the ability of the material's nano- and microstructure to self-assemble in well-organized, two- and three-dimensional periodic arrangements. We reviewed and assessed experimental evidence and theoretical models pertaining to the physical understanding of nano- and microstructure self-organization under irradiation conditions. Experimental observations on the formation of self-organized defect clusters, dislocation loops, voids and bubbles were presented and critically assessed. Implantation of metals with energetic helium results in remarkable self-assembled bubble super-lattices with wavelengths (super-lattice parameters) in the range of 5-8 nm. Ion and neutron irradiation produce a wide variety of self-assembled 3-D defect walls and void lattices, with wavelengths that can be tailored in the range of 10's to 100's of nanometers. Theoretical models aimed at explaining these observations were introduced, and a consistent description of many features is outlined. The primary focus of the most recent modeling efforts, which are based on stability theory and concepts of non-linear dynamics, was to determine criteria for the evolution and spatial symmetry of self-organized microstructures. The correspondence between this theoretical framework and experimental observations was also examined, highlighting areas of agreement and pointing out unresolved questions. The main objective of this research was to develop new computational tools for in-service design and performance prediction of advanced fusion material systems by computational simulation. We also need to develop these computational tools to assist in planning and assessment of corresponding radiation experiments. In the

  20. Students Design a Depression Simulation.

    ERIC Educational Resources Information Center

    Roessler, Michael

    1987-01-01

    This article describes how an eighth grade class developed a computer-based social studies simulation on the Great Depression. Included are objectives for such development activities, a set of steps for guiding development, a discussion of potential difficulties and rewards, data on student reactions to simulation development, and information on…

  1. Converging Lens Simulation Design and Image Predictions

    ERIC Educational Resources Information Center

    Bryan, J. A.; Slough, S. W.

    2009-01-01

    While computer technology continues to enhance the teaching and learning of all science disciplines, computer simulations, in particular, have become exceptionally beneficial in physics education. In addition to the manner in which physics instructors integrate computer simulations into their instructional practices, the design of a simulation may…

  2. Shuttle mission simulator hardware conceptual design report

    NASA Technical Reports Server (NTRS)

    Burke, J. F.

    1973-01-01

    The detailed shuttle mission simulator hardware requirements are discussed. The conceptual design methods, or existing technology, whereby those requirements will be fulfilled are described. Information of a general nature on the total design problem plus specific details on how these requirements are to be satisfied are reported. The configuration of the simulator is described and the capabilities for various types of training are identified.

  3. Simulation and Spacecraft Design: Engineering Mars Landings.

    PubMed

    Conway, Erik M

    2015-10-01

    A key issue in history of technology that has received little attention is the use of simulation in engineering design. This article explores the use of both mechanical and numerical simulation in the design of the Mars atmospheric entry phases of the Viking and Mars Pathfinder missions to argue that engineers used both kinds of simulation to develop knowledge of their designs' likely behavior in the poorly known environment of Mars. Each kind of simulation could be used as a warrant of the other's fidelity, in an iterative process of knowledge construction.

  4. Analysis of the diffusion of Ras2 in Saccharomyces cerevisiae using fluorescence recovery after photobleaching.

    PubMed

    Vinnakota, Kalyan C; Mitchell, David A; Deschenes, Robert J; Wakatsuki, Tetsuro; Beard, Daniel A

    2010-06-04

    Binding, lateral diffusion and exchange are fundamental dynamic processes involved in protein association with cellular membranes. In this study, we developed numerical simulations of lateral diffusion and exchange of fluorophores in membranes with arbitrary bleach geometry and exchange of the membrane-localized fluorophore with the cytosol during fluorescence recovery after photobleaching (FRAP) experiments. The model simulations were used to design FRAP experiments with varying bleach region sizes on plasma membrane-localized wild-type GFP-Ras2 with a dual lipid anchor and mutant GFP-Ras2C318S with a single lipid anchor in live yeast cells to investigate diffusional mobility and the presence of any exchange processes operating in the time scale of our experiments. Model parameters estimated using data from FRAP experiments with a 1 microm x 1 microm bleach region-of-interest (ROI) and a 0.5 microm x 0.5 microm bleach ROI showed that GFP-Ras2, single or dual lipid modified, diffuses as single species with no evidence of exchange with a cytoplasmic pool. This is the first report of Ras2 mobility in the yeast plasma membrane. The methods developed in this study are generally applicable for studying diffusion and exchange of membrane-associated fluorophores using FRAP on commercial confocal laser scanning microscopes.

  5. Haptics for Product Design and Manufacturing Simulation.

    PubMed

    Xia, Pingjun

    2016-01-01

    Product design and manufacturing simulation is a promising research and application area for haptics. By benefiting from its natural human-computer interaction and realistic force/torque feedback, haptics can change the traditional design and manufacturing approaches which are mainly based on physical mock-ups or CAD (Computer Aided Design) modes. This paper provides a detailed and comprehensive survey of haptics for product design and manufacturing simulation in the past 10 years, mainly from 2004-2014, including haptics for product design and shape modelling, haptics for machining simulation, and haptics for virtual assembly and maintenance simulation. The new haptic devices and rendering algorithms involved in this area are introduced, the major research efforts and the typical systems are discussed, and the new ideas and research progresses are investigated. Then, conclusions and future trends are summarized.

  6. Simulation of integrated beam experiment designs

    NASA Astrophysics Data System (ADS)

    Grote, D. P.; Sharp, W. M.

    2005-05-01

    Simulations of designs of an Integrated Beam Experiment (IBX) class accelerator have been carried out. These simulations are an important tool for validating such designs. Issues such as envelope mismatch and emittance growth can be examined in a self-consistent manner including the details of injection, accelerator transitions, long-term transport, and longitudinal compression. The simulations are three-dimensional and time dependent, and begin at the source. They continue up through the end of the acceleration region, where the data are passed on to a separate simulation of the drift compression. Results are presented.

  7. Simulation of integrated beam experiment designs

    SciTech Connect

    Grote, D.P.; Sharp, W.M.

    2004-06-11

    Simulation of designs of an Integrated Beam Experiment (IBX) class accelerator have been carried out. These simulations are an important tool for validating such designs. Issues such as envelope mismatch and emittance growth can be examined in a self-consistent manner, including the details of injection, accelerator transitions, long-term transport, and longitudinal compression. The simulations are three-dimensional and time-dependent, and begin at the source. They continue up through the end of the acceleration region, at which point the data is passed on to a separate simulation of the drift compression. Results are be presented.

  8. Simulator design for advanced ISDN satellite design and experiments

    NASA Technical Reports Server (NTRS)

    Pepin, Gerald R.

    1992-01-01

    This simulation design task completion report documents the simulation techniques associated with the network models of both the Interim Service ISDN (integrated services digital network) Satellite (ISIS) and the Full Service ISDN Satellite (FSIS) architectures. The ISIS network model design represents satellite systems like the Advanced Communication Technology Satellite (ACTS) orbiting switch. The FSIS architecture, the ultimate aim of this element of the Satellite Communications Applications Research (SCAR) program, moves all control and switching functions on-board the next generation ISDN communication satellite. The technical and operational parameters for the advanced ISDN communications satellite design will be obtained from the simulation of ISIS and FSIS engineering software models for their major subsystems. Discrete events simulation experiments will be performed with these models using various traffic scenarios, design parameters and operational procedures. The data from these simulations will be used to determine the engineering parameters for the advanced ISDN communications satellite.

  9. Prosthetic knee design by simulation

    SciTech Connect

    Hollerbach, K; Hollister, A

    1999-07-30

    Although 150,000 total knee replacement surgeries are performed annually in North America, current designs of knee prostheses have mechanical problems that include a limited range of motion, abnormal gait patterns, patellofemoral joint dysfunction, implant loosening or subsidence, and excessive wear. These problems fall into three categories: failure to reproduce normal joint kinematics, which results in altered limb function; bone-implant interface failure; and material failure. Modern computer technology can be used to design, prototype, and test new total knee implants. The design team uses the full range of CAD-CAM to design and produce implant prototypes for mechanical and clinical testing. Closer approximation of natural knee kinematics and kinetics is essential for improved patient function and diminished implant loads. Current knee replacement designs are based on 19th Century theories that the knee moves about a variable axis of rotation. Recent research has shown, however, that knee motion occurs about two fixed, offset axes of rotation. These aces are not perpendicular to the long axes of the bones or to each other, and the axes do not intersect. Bearing surfaces of mechanisms that move about axes of rotation are surfaces of revolution of those axes which advanced CAD technology can produce. Solids with surfaces of revolution for the two axes of rotation for the knee have been made using an HP9000 workstation and Structural Ideas Master Series CAD software at ArthroMotion. The implant's CAD model should closely replicate movements of the normal knee. The knee model will have a range of flexion-extension (FE) from -5 to 120 degrees. Movements include varus, valgus, internal and external rotation, as well as flexion and extension. The patellofemoral joint is aligned perpendicular to the FE axis and replicates the natural joint more closely than those of existing prostheses. The bearing surfaces will be more congruent than current designs and should

  10. Ras enhances Myc protein stability.

    PubMed

    Sears, R; Leone, G; DeGregori, J; Nevins, J R

    1999-02-01

    Various experiments have demonstrated a collaborative action of Myc and Ras, both in normal cell growth control as well as during oncogenesis. We now show that Ras enhances the accumulation of Myc activity by stabilizing the Myc protein. Whereas Myc has a very short half-life when produced in the absence of mitogenic signals, due to degradation by the 26S proteasome, the half-life of Myc increases markedly in growth-stimulated cells. This stabilization is dependent on the Ras/Raf/MAPK pathway and is not augmented by proteasome inhibition, suggesting that Ras inhibits the proteasome-dependent degradation of Myc. We propose that one aspect of Myc-Ras collaboration is an ability of Ras to enhance the accumulation of transcriptionally active Myc protein.

  11. Refinery burner simulation design architecture summary.

    SciTech Connect

    Pollock, Guylaine M.; McDonald, Michael James; Halbgewachs, Ronald D.

    2011-10-01

    This report describes the architectural design for a high fidelity simulation of a refinery and refinery burner, including demonstrations of impacts to the refinery if errors occur during the refinery process. The refinery burner model and simulation are a part of the capabilities within the Sandia National Laboratories Virtual Control System Environment (VCSE). Three components comprise the simulation: HMIs developed with commercial SCADA software, a PLC controller, and visualization software. All of these components run on different machines. This design, documented after the simulation development, incorporates aspects not traditionally seen in an architectural design, but that were utilized in this particular demonstration development. Key to the success of this model development and presented in this report are the concepts of the multiple aspects of model design and development that must be considered to capture the necessary model representation fidelity of the physical systems.

  12. Shuttle mission simulator software conceptual design

    NASA Technical Reports Server (NTRS)

    Burke, J. F.

    1973-01-01

    Software conceptual designs (SCD) are presented for meeting the simulator requirements for the shuttle missions. The major areas of the SCD discussed include: malfunction insertion, flight software, applications software, systems software, and computer complex.

  13. KAPAO Prime: Design and Simulation

    NASA Astrophysics Data System (ADS)

    McGonigle, Lorcan; Choi, P. I.; Severson, S. A.; Spjut, E.

    2013-01-01

    KAPAO (KAPAO A Pomona Adaptive Optics instrument) is a dual-band natural guide star adaptive optics system designed to measure and remove atmospheric aberration over UV-NIR wavelengths from Pomona College’s telescope atop Table Mountain. We present here, the final optical system, KAPAO Prime, designed in Zemax Optical Design Software that uses custom off-axis paraboloid mirrors (OAPs) to manipulate light appropriately for a Shack-Hartman wavefront sensor, deformable mirror, and science cameras. KAPAO Prime is characterized by diffraction limited imaging over the full 81” field of view of our optical camera at f/33 as well as over the smaller field of view of our NIR camera at f/50. In Zemax, tolerances of 1% on OAP focal length and off-axis distance were shown to contribute an additional 4 nm of wavefront error (98% confidence) over the field of view of our optical camera; the contribution from surface irregularity was determined analytically to be 40nm for OAPs specified to λ/10 surface irregularity (632.8nm). Modeling of the temperature deformation of the breadboard in SolidWorks revealed 70 micron contractions along the edges of the board for a decrease of 75°F when applied to OAP positions such displacements from the optimal layout are predicted to contribute an additional 20 nanometers of wavefront error. Flexure modeling of the breadboard due to gravity is on-going. We hope to begin alignment and testing of KAPAO Prime in Q1 2013.

  14. KAPAO Prime: Design and Simulation

    NASA Astrophysics Data System (ADS)

    McGonigle, Lorcan

    2012-11-01

    KAPAO (KAPAO A Pomona Adaptive Optics instrument) is a dual-band natural guide star adaptive optics system designed to measure and remove atmospheric aberration from Pomona College's telescope atop Table Mountain. We present here, the final optical system, referred to as Prime, designed in Zemax Optical Design Software. Prime is characterized by diffraction limited imaging over the full 73'' field of view of our Andor Camera at f/33 as well as for our NIR Xenics camera at f/50. In Zemax, tolerances of 1% on OAP focal length and off-axis distance were shown to contribute an additional 4 nm of wavefront error (98% confidence) over the field of view of the Andor camera; the contribution from surface irregularity was determined analytically to be 40nm for OAPs specified to l/10 surface irregularity. Modeling of the temperature deformation of the breadboard in SolidWorks revealed 70 micron contractions along the edges of the board for a decrease of 75 F; when applied to OAP positions such displacements from the optimal layout are predicted to contribute an additional 20 nanometers of wavefront error. Flexure modeling of the breadboard due to gravity is on-going. We hope to begin alignment and testing of ``Prime'' in Q1 2013.

  15. Simulation as an Aid to Experimental Design.

    ERIC Educational Resources Information Center

    Frazer, Jack W.; And Others

    1983-01-01

    Discusses simulation program to aid in the design of enzyme kinetic experimentation (includes sample runs). Concentration versus time profiles of any subset or all nine states of reactions can be displayed with/without simulated instrumental noise, allowing the user to estimate the practicality of any proposed experiment given known instrument…

  16. Simulation, Design Abstraction, and SystemC

    ERIC Educational Resources Information Center

    Harcourt, Ed

    2007-01-01

    SystemC is a system-level design and simulation language based on C++. We've been using SystemC for computer organization and design projects for the past several years. Because SystemC is embedded in C++ it contains the powerful abstraction mechanisms of C++ not found in traditional hardware description languages, such as support for…

  17. Design and simulation of a gyroklystron amplifier

    SciTech Connect

    Chauhan, M. S. Swati, M. V.; Jain, P. K.

    2015-03-15

    In the present paper, a design methodology of the gyroklystron amplifier has been described and subsequently used for the design of a typically selected 200 kW, Ka-band, four-cavity gyroklystron amplifier. This conceptual device design has been validated through the 3D particle-in-cell (PIC) simulation and nonlinear analysis. Commercially available PIC simulation code “MAGIC” has been used for the electromagnetic study at the different location of the device RF interaction structure for the beam-absent case, i.e., eigenmode study as well as for the electron beam and RF wave interaction behaviour study in the beam present case of the gyroklystron. In addition, a practical problem of misalignment of the RF cavities with drift tubes within the tube has been also investigated and its effect on device performance studied. The analytical and simulation results confirmed the validity of the gyroklystron device design. The PIC simulation results of the present gyroklystron produced a stable RF output power of ∼218 kW for 0% velocity spread at 35 GHz, with ∼45 dB gain, 37% efficiency, and a bandwidth of 0.3% for a 70 kV, 8.2 A gyrating electron beam. The simulated values of RF output power have been found in agreement with the nonlinear analysis results within ∼5%. Further, the PIC simulation has been extended to study a practical problem of misalignment of the cavities axis and drift tube axis of the gyroklystron amplifier and found that the RF output power is more sensitive to misalignments in comparison to the device bandwidth. The present paper, gyroklystron device design, nonlinear analysis, and 3D PIC simulation using commercially available code had been systematically described would be of use to the high-power gyro-amplifier tube designers and research scientists.

  18. Detector simulation needs for detector designers

    SciTech Connect

    Hanson, G.G.

    1987-11-01

    Computer simulation of the components of SSC detectors and of the complete detectors will be very important for the designs of the detectors. The ratio of events from interesting physics to events from background processes is very low, so detailed understanding of detector response to the backgrounds is needed. Any large detector for the SSC will be very complex and expensive and every effort must be made to design detectors which will have excellent performance and will not have to undergo major rebuilding. Some areas in which computer simulation is particularly needed are pattern recognition in tracking detectors and development of shower simulation code which can be trusted as an aid in the design and optimization of calorimeters, including their electron identification performance. Existing codes require too much computer time to be practical and need to be compared with test beam data at energies of several hundred GeV. Computer simulation of the processing of the data, including electronics response to the signals from the detector components, processing of the data by microprocessors on the detector, the trigger, and data acquisition will be required. In this report we discuss the detector simulation needs for detector designers.

  19. Design of penicillin fermentation process simulation system

    NASA Astrophysics Data System (ADS)

    Qi, Xiaoyu; Yuan, Zhonghu; Qi, Xiaoxuan; Zhang, Wenqi

    2011-10-01

    Real-time monitoring for batch process attracts increasing attention. It can ensure safety and provide products with consistent quality. The design of simulation system of batch process fault diagnosis is of great significance. In this paper, penicillin fermentation, a typical non-linear, dynamic, multi-stage batch production process, is taken as the research object. A visual human-machine interactive simulation software system based on Windows operation system is developed. The simulation system can provide an effective platform for the research of batch process fault diagnosis.

  20. Memory interface simulator: A computer design aid

    NASA Technical Reports Server (NTRS)

    Taylor, D. S.; Williams, T.; Weatherbee, J. E.

    1972-01-01

    Results are presented of a study conducted with a digital simulation model being used in the design of the Automatically Reconfigurable Modular Multiprocessor System (ARMMS), a candidate computer system for future manned and unmanned space missions. The model simulates the activity involved as instructions are fetched from random access memory for execution in one of the system central processing units. A series of model runs measured instruction execution time under various assumptions pertaining to the CPU's and the interface between the CPU's and RAM. Design tradeoffs are presented in the following areas: Bus widths, CPU microprogram read only memory cycle time, multiple instruction fetch, and instruction mix.

  1. The Process Design Courses at Pennsylvania: Impact of Process Simulators.

    ERIC Educational Resources Information Center

    Seider, Warren D.

    1984-01-01

    Describes the use and impact of process design simulators in process design courses. Discusses topics covered, texts used, computer design simulations, and how they are integrated into the process survey course as well as in plant design projects. (JM)

  2. [Vernier Anode Design and Image Simulation].

    PubMed

    Zhao, Ai-rong; Ni, Qi-liang; Song, Ke-fei

    2015-12-01

    Based-MCP position-sensitive anode photon-counting imaging detector is good at detecting extremely faint light, which includes micro-channel plate (MCP), position-sensitive anode and readout, and the performances of these detectors are mainly decided by the position-sensitive anode. As a charge division anode, Vernier anode using cyclically varying electrode areas which replaces the linearly varying electrodes of wedge-strip anode can get better resolution and greater electrode dynamic range. Simulation and design of the Vernier anode based on Vernier's decode principle are given here. Firstly, we introduce the decode and design principle of Vernier anode with nine electrodes in vector way, and get the design parameters which are the pitch, amplitude and the coarse wavelength of electrode. Secondly, we analyze the effect of every design parameters to the imaging of the detector. We simulate the electron cloud, the Vernier anode and the detector imaging using Labview software and get the relationship between the pitch and the coarse wavelength of the anode. Simultaneously, we get the corresponding electron cloud for the designing parameters. Based on the result of the simulation and the practical machining demand, a nine electrodes Vernier anode was designed and fabricated which has a pitch of 891 µm, insulation width of 25 µm, amplitude of 50 µm, coarse pixel numbers of 5. PMID:26964205

  3. [Vernier Anode Design and Image Simulation].

    PubMed

    Zhao, Ai-rong; Ni, Qi-liang; Song, Ke-fei

    2015-12-01

    Based-MCP position-sensitive anode photon-counting imaging detector is good at detecting extremely faint light, which includes micro-channel plate (MCP), position-sensitive anode and readout, and the performances of these detectors are mainly decided by the position-sensitive anode. As a charge division anode, Vernier anode using cyclically varying electrode areas which replaces the linearly varying electrodes of wedge-strip anode can get better resolution and greater electrode dynamic range. Simulation and design of the Vernier anode based on Vernier's decode principle are given here. Firstly, we introduce the decode and design principle of Vernier anode with nine electrodes in vector way, and get the design parameters which are the pitch, amplitude and the coarse wavelength of electrode. Secondly, we analyze the effect of every design parameters to the imaging of the detector. We simulate the electron cloud, the Vernier anode and the detector imaging using Labview software and get the relationship between the pitch and the coarse wavelength of the anode. Simultaneously, we get the corresponding electron cloud for the designing parameters. Based on the result of the simulation and the practical machining demand, a nine electrodes Vernier anode was designed and fabricated which has a pitch of 891 µm, insulation width of 25 µm, amplitude of 50 µm, coarse pixel numbers of 5.

  4. Design and Simulation of Hybridization Experiments

    1995-11-28

    DB EXP DESIGN is a suite of three UNIX shell-like programs, DWC which computes oligomer composition of DNA texts using directed acyclic word data structures; DWO, which simulates hybridization experiments; and DMI, which calculates the information contenet of individual probes, their mutual information content, and their joint information content through estimation of Markov trees.

  5. Dynamic Process Simulation for Analysis and Design.

    ERIC Educational Resources Information Center

    Nuttall, Herbert E., Jr.; Himmelblau, David M.

    A computer program for the simulation of complex continuous process in real-time in an interactive mode is described. The program is user oriented, flexible, and provides both numerical and graphic output. The program has been used in classroom teaching and computer aided design. Typical input and output are illustrated for a sample problem to…

  6. Designing Online Scaffolds for Interactive Computer Simulation

    ERIC Educational Resources Information Center

    Chen, Ching-Huei; Wu, I-Chia; Jen, Fen-Lan

    2013-01-01

    The purpose of this study was to examine the effectiveness of online scaffolds in computer simulation to facilitate students' science learning. We first introduced online scaffolds to assist and model students' science learning and to demonstrate how a system embedded with online scaffolds can be designed and implemented to help high…

  7. IAA RAS Radio Telescope Monitoring System

    NASA Astrophysics Data System (ADS)

    Mikhailov, A.; Lavrov, A.

    2007-07-01

    Institute of Applied Astronomy of the Russian Academy of Sciences (IAA RAS) has three identical radio telescopes, the receiving complex of which consists of five two-channel receivers of different bands, six cryogen systems, and additional devices: four local oscillators, phase calibration generators and IF commutator. The design, hardware and data communication protocol are described. The most convenient way to join the devices of the receiving complex into the common monitoring system is to use the interface which allows to connect numerous devices to the data bus. For the purpose of data communication regulation and to exclude conflicts, a data communication protocol has been designed, which operates with complex formatted data sequences. Formation of such sequences requires considerable data processing capability. That is provided by a microcontroller chip in each slave device. The test version of the software for the central computer has been developed in IAA RAS. We are developing the Mark IV FS software extension modules, which will allow us to control the receiving complex of the radio telescope by special SNAP commands from both operator input and schedule files. We are also developing procedures of automatic measurements of SEFD, system noise temperature and other parameters, available both in VLBI and single-dish modes of operation. The system described has been installed on all IAA RAS radio telescopes at "Svetloe", "Zelenchukskaya" and "Badary" observatories. It has proved to be working quite reliably and to show the perfonmance expected.

  8. [Role of RAS in prehypertension].

    PubMed

    Inaba, Shinji; Iwai, Masaru; Horiuchi, Masatsugu

    2008-08-01

    Hypertension has long been recognized as a major risk factor of several cardiovascular diseases. It is well known that the renin-angiotensin system(RAS) is involved in the pathogenesis of both hypertension and hypertensive end-organ damage. Untreated hypertension is self-accelerating condition through RAS stimulation. Activation of RAS contributes to the transition from borderline hypertension to established hypertension. Recently, "the Seventh Report of Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7)" proposed a new classification of borderline blood pressure levels, as "prehypertension". The therapeutic focus has begun to shift from the therapy of established hypertension to the prevention of hypertension. This review addressed the relationship between hypertension, prehypertension and the role of RAS. PMID:18700549

  9. Association Rate Constants of Ras-Effector Interactions Are Evolutionarily Conserved

    PubMed Central

    Kiel, Christina; Aydin, Dorothee; Serrano, Luis

    2008-01-01

    Evolutionary conservation of protein interaction properties has been shown to be a valuable indication for functional importance. Here we use homology interface modeling of 10 Ras-effector complexes by selecting ortholog proteins from 12 organisms representing the major eukaryotic branches, except plants. We find that with increasing divergence time the sequence similarity decreases with respect to the human protein, but the affinities and association rate constants are conserved as predicted by the protein design algorithm, FoldX. In parallel we have done computer simulations on a minimal network based on Ras-effector interactions, and our results indicate that in the absence of negative feedback, changes in kinetics that result in similar binding constants have strong consequences on network behavior. This, together with the previous results, suggests an important biological role, not only for equilibrium binding constants but also for kinetics in signaling processes involving Ras-effector interactions. Our findings are important to take into consideration in system biology approaches and simulations of biological networks. PMID:19096503

  10. Parachute system design, analysis, and simulation tool

    SciTech Connect

    Sundberg, W.D.; McBride, D.D.; Gwinn, K.W.; Waye, D.E.; Hailey, C.E.

    1992-01-01

    For over twenty years designers at Sandia National Laboratories have developed various parachute simulation codes to model deployment, inflation, loading, trajectories, aircraft downwash and line sail. In addition to these codes, material property data bases have been acquired. Recently we have initiated project to integrate these codes and data bases into a single software tool entitled SPARSYS (Sandia PARachute SYstem Simulation). We have constructed a graphical user interface as the driver and framework for SPARSYS. In this paper we present a status report on SPARSYS describing progress in developing and incorporating independent modules, in developing an integrated trajectory package, and in developing a materials data base including high-rate-of-strain data.

  11. Design and simulation of MEMS capacitive magnetometer

    NASA Astrophysics Data System (ADS)

    Jyoti, Aditi, Tripathi, C. C.; Gopal, Ram

    2016-04-01

    This paper presents the design and simulation of a MEMS Capacitive Magnetometer using FEM (Finite Element Method) tool COMSOL Multiphysics 4.3b and results from this simulation are closely matched with analytically calculated results. A comb drive structure is used for actuation purpose which operates at resonant frequency of device is 11.791 kHz to achieve maximum displacement. A magnetic field in z-axis can be detected by this comb drive structure. Quality factor of MEMS capacitive magnetometer obtained is 18 and it has good linear response in the magnetic field range of 100 µT.

  12. Fendiline Inhibits K-Ras Plasma Membrane Localization and Blocks K-Ras Signal Transmission

    PubMed Central

    van der Hoeven, Dharini; Cho, Kwang-jin; Ma, Xiaoping; Chigurupati, Sravanthi; Parton, Robert G.

    2013-01-01

    Ras proteins regulate signaling pathways important for cell growth, differentiation, and survival. Oncogenic mutant Ras proteins are commonly expressed in human tumors, with mutations of the K-Ras isoform being most prevalent. To be active, K-Ras must undergo posttranslational processing and associate with the plasma membrane. We therefore devised a high-content screening assay to search for inhibitors of K-Ras plasma membrane association. Using this assay, we identified fendiline, an L-type calcium channel blocker, as a specific inhibitor of K-Ras plasma membrane targeting with no detectable effect on the localization of H- and N-Ras. Other classes of L-type calcium channel blockers did not mislocalize K-Ras, suggesting a mechanism that is unrelated to calcium channel blockade. Fendiline did not inhibit K-Ras posttranslational processing but significantly reduced nanoclustering of K-Ras and redistributed K-Ras from the plasma membrane to the endoplasmic reticulum (ER), Golgi apparatus, endosomes, and cytosol. Fendiline significantly inhibited signaling downstream of constitutively active K-Ras and endogenous K-Ras signaling in cells transformed by oncogenic H-Ras. Consistent with these effects, fendiline blocked the proliferation of pancreatic, colon, lung, and endometrial cancer cell lines expressing oncogenic mutant K-Ras. Taken together, these results suggest that inhibitors of K-Ras plasma membrane localization may have utility as novel K-Ras-specific anticancer therapeutics. PMID:23129805

  13. Design and simulation tools for optical microresonators

    NASA Astrophysics Data System (ADS)

    Greedy, Stephen C.; Boriskina, Svetlana V.; Sewell, Phillip; Benson, Trevor M.

    2001-05-01

    Dielectric resonators promise high functionality components for future optoelectronic integrated circuit applications. Accurate modeling of these components is a prerequisite to their successful deployment in innovative configurations. This paper will compare and contrast a wide variety of simulation techniques, developed by ourselves, that can be used for design. These encompass, (1) ful wave analytical integral equation methods which yield high accuracy and fast computation but are structure specific, (2) direct numerical simulation based upon high performance finite difference schemes which offer significant flexibility at the cost of computational overheads, (3) fast yet accurate semi- analytical approaches which can often provide sufficiently accurate result for the purposes of practical design at a fraction of the effort, in terms of both computational and pre-processing analysis as required by the former methods. The relative merits of the methods will be illustrated through their application to the design of practical components for a variety of systems. These will include examining the resonant frequencies, the quality factors and the field profiles of the lower order modes and the whispering gallery modes of dielectric resonators. Specific applications of interest are in the fields of filters, coupling elements and lasers.

  14. Digital autopilots: Design considerations and simulator evaluations

    NASA Technical Reports Server (NTRS)

    Osder, S.; Neuman, F.; Foster, J.

    1971-01-01

    The development of a digital autopilot program for a transport aircraft and the evaluation of that system's performance on a transport aircraft simulator is discussed. The digital autopilot includes three axis attitude stabilization, automatic throttle control and flight path guidance functions with emphasis on the mode progression from descent into the terminal area through automatic landing. The study effort involved a sequence of tasks starting with the definition of detailed system block diagrams of control laws followed by a flow charting and programming phase and concluding with performance verification using the transport aircraft simulation. The autopilot control laws were programmed in FORTRAN 4 in order to isolate the design process from requirements peculiar to an individual computer.

  15. Simulated Data for High Temperature Composite Design

    NASA Technical Reports Server (NTRS)

    Chamis, Christos C.; Abumeri, Galib H.

    2006-01-01

    The paper describes an effective formal method that can be used to simulate design properties for composites that is inclusive of all the effects that influence those properties. This effective simulation method is integrated computer codes that include composite micromechanics, composite macromechanics, laminate theory, structural analysis, and multi-factor interaction model. Demonstration of the method includes sample examples for static, thermal, and fracture reliability for a unidirectional metal matrix composite as well as rupture strength and fatigue strength for a high temperature super alloy. Typical results obtained for a unidirectional composite show that the thermal properties are more sensitive to internal local damage, the longitudinal properties degrade slowly with temperature, the transverse and shear properties degrade rapidly with temperature as do rupture strength and fatigue strength for super alloys.

  16. Mechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region*

    PubMed Central

    Jang, Hyunbum; Abraham, Sherwin J.; Chavan, Tanmay S.; Hitchinson, Ben; Khavrutskii, Lyuba; Tarasova, Nadya I.; Nussinov, Ruth; Gaponenko, Vadim

    2015-01-01

    K-Ras4B belongs to a family of small GTPases that regulates cell growth, differentiation and survival. K-ras is frequently mutated in cancer. K-Ras4B association with the plasma membrane through its farnesylated and positively charged C-terminal hypervariable region (HVR) is critical to its oncogenic function. However, the structural mechanisms of membrane association are not fully understood. Here, using confocal microscopy, surface plasmon resonance, and molecular dynamics simulations, we observed that K-Ras4B can be distributed in rigid and loosely packed membrane domains. Its membrane binding domain interaction with phospholipids is driven by membrane fluidity. The farnesyl group spontaneously inserts into the disordered lipid microdomains, whereas the rigid microdomains restrict the farnesyl group penetration. We speculate that the resulting farnesyl protrusion toward the cell interior allows oligomerization of the K-Ras4B membrane binding domain in rigid microdomains. Unlike other Ras isoforms, K-Ras4B HVR contains a single farnesyl modification and positively charged polylysine sequence. The high positive charge not only modulates specific HVR binding to anionic phospholipids but farnesyl membrane orientation. Phosphorylation of Ser-181 prohibits spontaneous farnesyl membrane insertion. The mechanism illuminates the roles of HVR modifications in K-Ras4B targeting microdomains of the plasma membrane and suggests an additional function for HVR in regulation of Ras signaling. PMID:25713064

  17. Up-regulation of IGF-1R by mutant RAS in leukemia and potentiation of RAS signaling inhibitors by small molecule inhibition of IGF-1R

    PubMed Central

    Weisberg, Ellen; Nonami, Atsushi; Chen, Zhao; Nelson, Erik; Chen, Yongfei; Liu, Feiyang; Cho, Haeyeon; Zhang, Jianming; Sattler, Martin; Mitsiades, Constantine; Wong, Kwok-Kin; Liu, Qingsong; Gray, Nathanael; Griffin, James D.

    2014-01-01

    Purpose Activating mutations in the RAS oncogene occur frequently in human leukemias. Direct targeting of RAS has proven to be challenging, although targeting of downstream RAS mediators, such as MEK, is currently being tested clinically. Given the complexity of RAS signaling, it is likely that combinations of targeted agents will be more effective than single agents. Experimental Design A chemical screen using RAS-dependent leukemia cells was developed to identify compounds with unanticipated activity in the presence of a MEK inhibitor, and led to identification of inhibitors of IGF-1R. Results were validated using cell-based proliferation assays and apoptosis, cell cycle, and gene knockdown assays, immunoprecipitation and immunoblotting, and a non-invasive in vivo bioluminescence model of acute myeloid leukemia (AML). Results Mechanistically, IGF-1R protein expression/activity was substantially increased in mutant RAS-expressing cells, and suppression of RAS led to decreases in IGF-1R. Synergy between MEK and IGF-1R inhibitors correlated with induction of apoptosis, inhibition of cell cycle progression, and decreased phospho-S6 and phospho-4E-BP1. In vivo, NSG mice tail vein-injected with OCI-AML3-luc+ cells showed significantly lower tumor burden following one week of daily oral administration of 50 mg/kg NVP-AEW541 (IGF-1R inhibitor) combined with 25 mg/kg AZD6244 (MEK inhibitor), as compared to mice treated with either agent alone. Drug combination effects observed in cell-based assays were generalized to additional mutant RAS-positive neoplasms. Conclusions The finding that downstream inhibitors of RAS signaling and IGF-1R inhibitors have synergistic activity warrants further clinical investigation of IGF-1R and RAS signaling inhibition as a potential treatment strategy for RAS-driven malignancies. PMID:25186968

  18. Cardiac remodelling and RAS inhibition.

    PubMed

    Ferrario, Carlos M

    2016-06-01

    Risk factors such as hypertension and diabetes are known to augment the activity and tissue expression of angiotensin II (Ang II), the major effector peptide of the renin-angiotensin system (RAS). Overstimulation of the RAS has been implicated in a chain of events that contribute to the pathogenesis of cardiovascular (CV) disease, including the development of cardiac remodelling. This chain of events has been termed the CV continuum. The concept of CV disease existing as a continuum was first proposed in 1991 and it is believed that intervention at any point within the continuum can modify disease progression. Treatment with antihypertensive agents may result in regression of left ventricular hypertrophy, with different drug classes exhibiting different degrees of efficacy. The greatest decrease in left ventricular mass is observed following treatment with angiotensin converting enzyme inhibitors (ACE-Is), which inhibit Ang II formation. Although ACE-Is and angiotensin receptor blockers (ARBs) provide significant benefits in terms of CV events and stroke, mortality remains high. This is partly due to a failure to completely suppress the RAS, and, as our knowledge has increased, an escape phenomenon has been proposed whereby the human sequence of the 12 amino acid substrate angiotensin-(1-12) is converted to Ang II by the mast cell protease, chymase. Angiotensin-(1-12) is abundant in a wide range of organs and has been shown to increase blood pressure in animal models, an effect abolished by the presence of ACE-Is or ARBs. This review explores the CV continuum, in addition to examining the influence of the RAS. We also consider novel pathways within the RAS and how new therapeutic approaches that target this are required to further reduce Ang II formation, and so provide patients with additional benefits from a more complete blockade of the RAS. PMID:27105891

  19. Simulation-based design using wavelets

    NASA Astrophysics Data System (ADS)

    Williams, John R.; Amaratunga, Kevin S.

    1994-03-01

    The design of large-scale systems requires methods of analysis which have the flexibility to provide a fast interactive simulation capability, while retaining the ability to provide high-order solution accuracy when required. This suggests that a hierarchical solution procedure is required that allows us to trade off accuracy for solution speed in a rational manner. In this paper, we examine the properties of the biorthogonal wavelets recently constructed by Dahlke and Weinreich and show how they can be used to implement a highly efficient multiscale solution procedure for solving a certain class of one-dimensional problems.

  20. VOCs monitoring system simulation and design

    NASA Astrophysics Data System (ADS)

    Caldararu, Florin; Vasile, Alexandru; Vatra, Cosmin

    2010-11-01

    The designed and simulated system will be used in the tanning industry, for Volatile Organic Compound (VOC) measurements. In this industry, about 90% of the solvent contained in the emulsions evaporates during its application, giving rise to VOC, which are at the same time hazardous atmospheric pollutants and one of the sources of ground level photochemical ozone formation. It results that a monitoring system is necessary in a leather finishing process, in order to detect hazardous VOC concentration and conducting process in order of VOC concentration diminishing. The paper presents the design of a VOC monitoring system, which includes sensors for VOCs and temperature, the conditioning circuitry for these sensors, the suction system of the gas in the hood, the data acquisition and the computing system and graphic interface. The used sensor in the detection system is a semiconductor sensor, produced by Figaro Engineering Inc., characterized by a short response time, high sensitivity at almost all VOC substances. The design of the conditioning circuitry and data acquisition is done in order to compensate the sensor response variation with temperature and to maintain the low response time of the sensor. The temperature compensation is obtained by using a thermistor circuitry, and the compensation is done within the software design. A Mitsubishi PLC is used to receive the output signals of the circuits including the sensor and of the thermistor, respectively. The acquisition and computing system is done using Mitsubishi ALPHA 2 controller and a graphical terminal, GOT 1000.

  1. Simulation-based disassembly systems design

    NASA Astrophysics Data System (ADS)

    Ohlendorf, Martin; Herrmann, Christoph; Hesselbach, Juergen

    2004-02-01

    Recycling of Waste of Electrical and Electronic Equipment (WEEE) is a matter of actual concern, driven by economic, ecological and legislative reasons. Here, disassembly as the first step of the treatment process plays a key role. To achieve sustainable progress in WEEE disassembly, the key is not to limit analysis and planning to merely disassembly processes in a narrow sense, but to consider entire disassembly plants including additional aspects such as internal logistics, storage, sorting etc. as well. In this regard, the paper presents ways of designing, dimensioning, structuring and modeling different disassembly systems. Goal is to achieve efficient and economic disassembly systems that allow recycling processes complying with legal requirements. Moreover, advantages of applying simulation software tools that are widespread and successfully utilized in conventional industry sectors are addressed. They support systematic disassembly planning by means of simulation experiments including consecutive efficiency evaluation. Consequently, anticipatory recycling planning considering various scenarios is enabled and decisions about which types of disassembly systems evidence appropriateness for specific circumstances such as product spectrum, throughput, disassembly depth etc. is supported. Furthermore, integration of simulation based disassembly planning in a holistic concept with configuration of interfaces and data utilization including cost aspects is described.

  2. Mapping the functional versatility and fragility of Ras GTPase signaling circuits through in vitro network reconstitution.

    PubMed

    Coyle, Scott M; Lim, Wendell A

    2016-01-01

    The Ras-superfamily GTPases are central controllers of cell proliferation and morphology. Ras signaling is mediated by a system of interacting molecules: upstream enzymes (GEF/GAP) regulate Ras's ability to recruit multiple competing downstream effectors. We developed a multiplexed, multi-turnover assay for measuring the dynamic signaling behavior of in vitro reconstituted H-Ras signaling systems. By including both upstream regulators and downstream effectors, we can systematically map how different network configurations shape the dynamic system response. The concentration and identity of both upstream and downstream signaling components strongly impacted the timing, duration, shape, and amplitude of effector outputs. The distorted output of oncogenic alleles of Ras was highly dependent on the balance of positive (GAP) and negative (GEF) regulators in the system. We found that different effectors interpreted the same inputs with distinct output dynamics, enabling a Ras system to encode multiple unique temporal outputs in response to a single input. We also found that different Ras-to-GEF positive feedback mechanisms could reshape output dynamics in distinct ways, such as signal amplification or overshoot minimization. Mapping of the space of output behaviors accessible to Ras provides a design manual for programming Ras circuits, and reveals how these systems are readily adapted to produce an array of dynamic signaling behaviors. Nonetheless, this versatility comes with a trade-off of fragility, as there exist numerous paths to altered signaling behaviors that could cause disease. PMID:26765565

  3. Therapeutic Strategies for Targeting Ras Proteins

    PubMed Central

    Gysin, Stephan; Salt, Megan; Young, Amy; McCormick, Frank

    2011-01-01

    Ras genes are frequently activated in cancer. Attempts to develop drugs that target mutant Ras proteins have, so far, been unsuccessful. Tumors bearing these mutations, therefore, remain among the most difficult to treat. Most efforts to block activated Ras have focused on pathways downstream. Drugs that inhibit Raf kinase have shown clinical benefit in the treatment of malignant melanoma. However, these drugs have failed to show clinical benefit in Ras mutant tumors. It remains unclear to what extent Ras depends on Raf kinase for transforming activity, even though Raf proteins bind directly to Ras and are certainly major effectors of Ras action in normal cells and in development. Furthermore, Raf kinase inhibitors can lead to paradoxical activation of the MAPK pathway. MEK inhibitors block the Ras-MAPK pathway, but often activate the PI3’-kinase, and have shown little clinical benefit as single agents. This activation is mediated by EGF-R and other receptor tyrosine kinases through relief of a negative feedback loop from ERK. Drug combinations that target multiple points within the Ras signaling network are likely to be necessary to achieve substantial clinical benefit. Other effectors may also contribute to Ras signaling and provide a source of targets. In addition, unbiased screens for genes necessary for Ras transformation have revealed new potential targets and have added to our understanding of Ras cancer biology. PMID:21779505

  4. A solar simulator design for concentrating photovoltaics

    NASA Astrophysics Data System (ADS)

    Rehn, H.; Hartwig, U.

    2010-08-01

    In our contribution, we discuss an optical system which is able to provide sun-like radiation on a CPV module. This system is able to realize collimated light with more than 130 klx, with an angle of incidence of less than 0.26°. Special attention is given to a uniform light distribution on an illuminated area of 8 × 8 inches. The resulting optical efficiency of the system is 33%, much better than previously achieved with Xe flash lamp designs [1]. The design is based on a P-VIP 330/1.0 lamp, the latest in a series of OSRAM's P-VIP lamp types for video projectionwhich is featuring a peak luminance of approximately 9 Gcd/m2. As a result of the enormous operating pressure of the lamp, its spectrum is similar to the spectrum of the sun and will probably enable at least a class B simulator. The device based on the described design delivers continuous, sun-like radiation. This way, features of CPV modules as efficiency, angular sensitivity or tracking behavior can be tested during development or even in production.

  5. Muon RLA - design status and simulations

    NASA Astrophysics Data System (ADS)

    Beard, K. B.; Bogacz, S. A.; Morozov, V. S.; Roblin, Y. R.

    2013-02-01

    The Neutrino Factory baseline design involves a complex chain of accelerators beginning with a linac. This first pre-linac follows the capture and bunching section and accelerates the muons from about 244 to 900 MeV and must accept a high emittance beam about 30 cm wide with a 10% energy spread. It uses counterwound, shielded superconducting solenoids and 201 MHz superconducting cavities, and currently consists of 24 3 m and 24 5 m long cryomodules. The next stage is a 1st dogbone-shaped RLA that takes the total energy from 900 MeV to 3.6 GeV in 4.5 passes, followed by a 2nd RLA that takes the energy from 3.6 to 12.6 GeV in 4.5 passes. Simulations are in progress to optimize the optics and determine the radiation loads from beam loss and muon decay.

  6. Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches

    PubMed Central

    Pathan, Akbar Ali Khan; Panthi, Bhavana; Khan, Zahid; Koppula, Purushotham Reddy; Alanazi, Mohammed Saud; Sachchidanand; Parine, Narasimha Reddy; Chourasia, Mukesh

    2016-01-01

    Objective Kirsten rat sarcoma (K-Ras) protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted. Methods In the present study, we targeted the nucleotide-binding site in the “on” and “off” state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein. Results Interestingly, the designed compounds exhibit a binding preference for the “off” state over “on” state conformation of K-Ras protein. Moreover, the designed compounds’ interactions are similar to guanosine diphosphate and, thus, could presumably act as a potential lead for K-Ras. The predicted drug-likeness properties of these compounds suggest that these compounds follow the Lipinski’s rule of five and have tolerable absorption, distribution, metabolism, excretion and toxicity values. Conclusion Thus, through the current study, we propose targeting only “off” state conformations as a promising strategy for the design of reversible inhibitors to pharmacologically inhibit distinct conformations of K-Ras protein. PMID:27217775

  7. Ras in Cancer and Developmental Diseases

    PubMed Central

    Fernández-Medarde, Alberto; Santos, Eugenio

    2011-01-01

    Somatic, gain-of-function mutations in ras genes were the first specific genetic alterations identified in human cancer about 3 decades ago. Studies during the last quarter century have characterized the Ras proteins as essential components of signaling networks controlling cellular proliferation, differentiation, or survival. The oncogenic mutations of the H-ras, N-ras, or K-ras genes frequently found in human tumors are known to throw off balance the normal outcome of those signaling pathways, thus leading to tumor development. Oncogenic mutations in a number of other upstream or downstream components of Ras signaling pathways (including membrane RTKs or cytosolic kinases) have been detected more recently in association with a variety of cancers. Interestingly, the oncogenic Ras mutations and the mutations in other components of Ras/MAPK signaling pathways appear to be mutually exclusive events in most tumors, indicating that deregulation of Ras-dependent signaling is the essential requirement for tumorigenesis. In contrast to sporadic tumors, separate studies have identified germline mutations in Ras and various other components of Ras signaling pathways that occur in specific association with a number of different familial, developmental syndromes frequently sharing common phenotypic cardiofaciocutaneous features. Finally, even without being a causative force, defective Ras signaling has been cited as a contributing factor to many other human illnesses, including diabetes and immunological and inflammatory disorders. We aim this review at summarizing and updating current knowledge on the contribution of Ras mutations and altered Ras signaling to development of various tumoral and nontumoral pathologies. PMID:21779504

  8. Requirement of the NF-κB Subunit p65/RelA for K-Ras-Induced Lung Tumorigenesis

    PubMed Central

    Basseres, Daniela S.; Ebbs, Aaron; Levantini, Elena; Baldwin, Albert S.

    2010-01-01

    K-Ras-induced lung cancer is a very common disease, for which there are currently no effective therapies. Because therapy directly targeting the activity of oncogenic Ras has been unsuccessful, a different approach for novel therapy design is to identify critical Ras downstream oncogenic targets. Given that oncogenic Ras proteins activate the transcription factor NF-κB, and the importance of NF-κB in oncogenesis, we hypothesized that NF-κB would be an important K-Ras target in lung cancer. To address this hypothesis, we generated an NF-κB-EGFP reporter mouse model of K-Ras-induced lung cancer and determined that K-Ras activates NF-κB in lung tumors in situ. Furthermore, a mouse model was generated where activation of oncogenic K-Ras in lung cells was coupled with inactivation of the NF-κB subunit p65/RelA. In this model, deletion of p65/RelA reduces the number of K-Ras-induced lung tumors both in the presence and absence of the tumor suppressor p53. Lung tumors with loss of p65/RelA have higher numbers of apoptotic cells, reduced spread and lower grade. Using lung cell lines expressing oncogenic K-Ras, we show that NF-κB is activated in these cells in a K-Ras-dependent manner and that NF-κB activation by K-Ras requires IKKβ kinase activity. Taken together, these results demonstrate the importance of the NF-κB subunit p65/RelA in K-Ras induced lung transformation and identify IKKβ as a potential therapeutic target for K-Ras-induced lung cancer. PMID:20406971

  9. A computer simulator for development of engineering system design methodologies

    NASA Technical Reports Server (NTRS)

    Padula, S. L.; Sobieszczanski-Sobieski, J.

    1987-01-01

    A computer program designed to simulate and improve engineering system design methodology is described. The simulator mimics the qualitative behavior and data couplings occurring among the subsystems of a complex engineering system. It eliminates the engineering analyses in the subsystems by replacing them with judiciously chosen analytical functions. With the cost of analysis eliminated, the simulator is used for experimentation with a large variety of candidate algorithms for multilevel design optimization to choose the best ones for the actual application. Thus, the simulator serves as a development tool for multilevel design optimization strategy. The simulator concept, implementation, and status are described and illustrated with examples.

  10. Cloning and characterization of Ras-GRF2, a novel guanine nucleotide exchange factor for Ras.

    PubMed

    Fam, N P; Fan, W T; Wang, Z; Zhang, L J; Chen, H; Moran, M F

    1997-03-01

    Conversion of Ras proteins into an activated GTP-bound state able to bind effector proteins is catalyzed by specific guanine nucleotide exchange factors in response to a large number of extracellular stimuli. Here we report the isolation of mouse cDNAs encoding Ras-GRF2, a multidomain 135-kDa protein containing a COOH-terminal Cdc25-related domain that stimulates release of GDP from Ras but not other GTPases in vitro. Ras-GRF2 bound specifically to immobilized Ras lacking bound nucleotides, suggesting stabilization of the nucleotide-free form of Ras as a mechanism of catalyzing nucleotide exchange. The NH2-terminal region of Ras-GRF2 is predicted to contain features common to various signaling proteins including two pleckstrin homology domains and a Dbl homology region. Ras-GRF2 also contains an IQ motif which was required for its apparent constitutive association with calmodulin in epithelial cells ectopically expressing Ras-GRF2. Transient expression of Ras-GRF2 in kidney epithelial cells stimulated GTP binding by Ras and potentiated calcium ionophore-induced activation of mitogen-activated protein kinase (ERK1) dependent upon the IQ motif. Calcium influx caused Ras-GRF2 subcellular localization to change from cytosolic to peripheral, suggesting a possible mechanism for controlling Ras-GRF2 interactions with Ras at the plasma membrane. Epithelial cells overexpressing Ras-GRF2 are morphologically transformed and grow in a disorganized manner with minimal intercellular contacts. Northern analysis indicated a 9-kb GRF2 transcript in brain and lung, where p135 Ras-GRF2 is known to be expressed, and RNAs of 12 kb and 2.2 kb were detected in several tissues. Thus, Ras-GRF2 proteins with different domain structures may be widely expressed and couple diverse extracellular signals to Ras activation.

  11. Simulation Tools Model Icing for Aircraft Design

    NASA Technical Reports Server (NTRS)

    2012-01-01

    Here s a simple science experiment to try: Place an unopened bottle of distilled water in your freezer. After 2-3 hours, if the water is pure enough, you will notice that it has not frozen. Carefully pour the water into a bowl with a piece of ice in it. When it strikes the ice, the water will instantly freeze. One of the most basic and commonly known scientific facts is that water freezes at around 32 F. But this is not always the case. Water lacking any impurities for ice crystals to form around can be supercooled to even lower temperatures without freezing. High in the atmosphere, water droplets can achieve this delicate, supercooled state. When a plane flies through clouds containing these droplets, the water can strike the airframe and, like the supercooled water hitting the ice in the experiment above, freeze instantly. The ice buildup alters the aerodynamics of the plane - reducing lift and increasing drag - affecting its performance and presenting a safety issue if the plane can no longer fly effectively. In certain circumstances, ice can form inside aircraft engines, another potential hazard. NASA has long studied ways of detecting and countering atmospheric icing conditions as part of the Agency s efforts to enhance aviation safety. To do this, the Icing Branch at Glenn Research Center utilizes a number of world-class tools, including the Center s Icing Research Tunnel and the NASA 607 icing research aircraft, a "flying laboratory" for studying icing conditions. The branch has also developed a suite of software programs to help aircraft and icing protection system designers understand the behavior of ice accumulation on various surfaces and in various conditions. One of these innovations is the LEWICE ice accretion simulation software. Initially developed in the 1980s (when Glenn was known as Lewis Research Center), LEWICE has become one of the most widely used tools in icing research and aircraft design and certification. LEWICE has been transformed over

  12. Inhibition of malignant thyroid carcinoma cell proliferation by Ras and galectin-3 inhibitors

    PubMed Central

    Menachem, A; Bodner, O; Pastor, J; Raz, A; Kloog, Y

    2015-01-01

    Anaplastic Thyroid carcinoma is an extremely aggressive solid tumor that resists most treatments and is almost always fatal. Galectin-3 (Gal-3) is an important marker for thyroid carcinomas and a scaffold of the K-Ras protein. S-trans, transfarnesylthiosalicylic acid (FTS; Salirasib) is a Ras inhibitor that inhibits the active forms of Ras proteins. Modified citrus pectin (MCP) is a water-soluble citrus-fruit-derived polysaccharide fiber that specifically inhibits Gal-3. The aim of this study was to develop a novel drug combination designed to treat aggressive anaplastic thyroid carcinoma. Combined treatment with FTS and MCP inhibited anaplastic thyroid cells proliferation in vitro by inducing cell cycle arrest and increasing apoptosis rate. Immunoblot analysis revealed a significant decrease in Pan-Ras, K-Ras, Ras-GTP, p-ERK, p53, and Gal-3 expression levels and significant increase in p21 expression levels. In nude mice, treatment with FTS and MCP inhibited tumor growth. Levels of Gal-3, K-Ras-GTP, and p-ERK were significantly decreased. To conclude, our results suggest K-Ras and Gal-3 as potential targets in anaplastic thyroid tumors and herald a novel treatment for highly aggressive anaplastic thyroid carcinoma. PMID:27551476

  13. Inhibition of malignant thyroid carcinoma cell proliferation by Ras and galectin-3 inhibitors.

    PubMed

    Menachem, A; Bodner, O; Pastor, J; Raz, A; Kloog, Y

    2015-01-01

    Anaplastic Thyroid carcinoma is an extremely aggressive solid tumor that resists most treatments and is almost always fatal. Galectin-3 (Gal-3) is an important marker for thyroid carcinomas and a scaffold of the K-Ras protein. S-trans, transfarnesylthiosalicylic acid (FTS; Salirasib) is a Ras inhibitor that inhibits the active forms of Ras proteins. Modified citrus pectin (MCP) is a water-soluble citrus-fruit-derived polysaccharide fiber that specifically inhibits Gal-3. The aim of this study was to develop a novel drug combination designed to treat aggressive anaplastic thyroid carcinoma. Combined treatment with FTS and MCP inhibited anaplastic thyroid cells proliferation in vitro by inducing cell cycle arrest and increasing apoptosis rate. Immunoblot analysis revealed a significant decrease in Pan-Ras, K-Ras, Ras-GTP, p-ERK, p53, and Gal-3 expression levels and significant increase in p21 expression levels. In nude mice, treatment with FTS and MCP inhibited tumor growth. Levels of Gal-3, K-Ras-GTP, and p-ERK were significantly decreased. To conclude, our results suggest K-Ras and Gal-3 as potential targets in anaplastic thyroid tumors and herald a novel treatment for highly aggressive anaplastic thyroid carcinoma. PMID:27551476

  14. Designing with Ada for satellite simulation: A case study

    NASA Technical Reports Server (NTRS)

    Agresti, W. W.; Church, V. E.; Card, D. N.; Lo, P. L.

    1986-01-01

    A FORTRAN oriented and an Ada oriented design for the same system are compared to learn whether an essentially different design was produced using Ada. The designs were produced by an experiment that involves the parallel development of software for a spacecraft dynamics simulator. Design differences are identified in the use of abstractions, system structure, and simulator operations. Although the designs were vastly different, this result may be influenced by some special characteristics discussed.

  15. Designing with Ada for satellite simulation: A case study

    NASA Technical Reports Server (NTRS)

    Agresti, William W.; Church, Victor E.; Card, David N.; Lo, P. L.

    1986-01-01

    A FORTRAN-operated and an Ada-oriented design for the same system are compared to learn whether an essentially different design was produced using Ada. The designs were produced by an experiment that involves the parallel development of software for a spacecraft dynamics simulator. Design differences are identified in the use of abstractions, system structure, and simulator operations. Although the designs were significantly different, this result may be influenced by some special characteristics discussed.

  16. Design and simulation of lithium rechargeable batteries

    SciTech Connect

    Doyle, C.M.

    1995-08-01

    Lithium -based rechargeable batteries that utilize insertion electrodes are being considered for electric-vehicle applications because of their high energy density and inherent reversibility. General mathematical models are developed that apply to a wide range of lithium-based systems, including the recently commercialized lithium-ion cell. The modeling approach is macroscopic, using porous electrode theory to treat the composite insertion electrodes and concentrated solution theory to describe the transport processes in the solution phase. The insertion process itself is treated with a charge-transfer process at the surface obeying Butler-Volmer kinetics, followed by diffusion of the lithium ion into the host structure. These models are used to explore the phenomena that occur inside of lithium cells under conditions of discharge, charge, and during periods of relaxation. Also, in order to understand the phenomena that limit the high-rate discharge of these systems, we focus on the modeling of a particular system with well-characterized material properties and system parameters. The system chosen is a lithium-ion cell produced by Bellcore in Red Bank, NJ, consisting of a lithium-carbon negative electrode, a plasticized polymer electrolyte, and a lithium-manganese-oxide spinel positive electrode. This battery is being marketed for consumer electronic applications. The system is characterized experimentally in terms of its transport and thermodynamic properties, followed by detailed comparisons of simulation results with experimental discharge curves. Next, the optimization of this system for particular applications is explored based on Ragone plots of the specific energy versus average specific power provided by various designs.

  17. RAS oncogenes: weaving a tumorigenic web

    PubMed Central

    Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna

    2013-01-01

    RAS proteins are essential components of signalling pathways that emanate from cell surface receptors. Oncogenic activation of these proteins owing to missense mutations is frequently detected in several types of cancer. A wealth of biochemical and genetic studies indicates that RAS proteins control a complex molecular circuitry that consists of a wide array of interconnecting pathways. In this Review, we describe how RAS oncogenes exploit their extensive signalling reach to affect multiple cellular processes that drive tumorigenesis. PMID:21993244

  18. Ras Regulates Rb via NORE1A.

    PubMed

    Barnoud, Thibaut; Donninger, Howard; Clark, Geoffrey J

    2016-02-01

    Mutations in the Ras oncogene are one of the most frequent events in human cancer. Although Ras regulates numerous growth-promoting pathways to drive transformation, it can paradoxically promote an irreversible cell cycle arrest known as oncogene-induced senescence. Although senescence has clearly been implicated as a major defense mechanism against tumorigenesis, the mechanisms by which Ras can promote such a senescent phenotype remain poorly defined. We have shown recently that the Ras death effector NORE1A plays a critical role in promoting Ras-induced senescence and connects Ras to the regulation of the p53 tumor suppressor. We now show that NORE1A also connects Ras to the regulation of a second major prosenescent tumor suppressor, the retinoblastoma (Rb) protein. We show that Ras induces the formation of a complex between NORE1A and the phosphatase PP1A, promoting the activation of the Rb tumor suppressor by dephosphorylation. Furthermore, suppression of Rb reduces NORE1A senescence activity. These results, together with our previous findings, suggest that NORE1A acts as a critical tumor suppressor node, linking Ras to both the p53 and the Rb pathways to drive senescence.

  19. AVCS Simulator Test Plan and Design Guide

    NASA Technical Reports Server (NTRS)

    Shelden, Stephen

    2001-01-01

    Internal document for communication of AVCS direction and documentation of simulator functionality. Discusses methods for AVCS simulation evaluation of pilot functions, implementation strategy of varying functional representation of pilot tasks (by instantiations of a base AVCS to reasonably approximate the interface of various vehicles -- e.g. Altair, GlobalHawk, etc.).

  20. Phobos: Simulation-Driven Design for Exploration

    NASA Technical Reports Server (NTRS)

    Crues, Edwin

    2015-01-01

    Dr. Edwin "Zack" Crues presented an overview of the current use of modeling and simulation technologies by the NASA Exploration Systems Simulations (NExSyS) team in investigating the spacecraft and missions for the human exploration of Mars' moon Phobos.

  1. Binding of calcium ions to Ras promotes Ras guanine nucleotide exchange under emulated physiological conditions.

    PubMed

    Liao, Jun-Ming; Mo, Zhong-Ying; Wu, Ling-Jia; Chen, Jie; Liang, Yi

    2008-11-01

    Both Ras protein and calcium play significant roles in various cellular processes via complex signaling transduction networks. However, it is not well understood whether and how Ca(2+) can directly regulate Ras function. Here we demonstrate by isothermal titration calorimetry that Ca(2+) directly binds to the H-Ras.GDP.Mg(2+) complex with moderate affinity at the first binding site followed by two weak binding events. The results from limited proteinase degradation show that Ca(2+) protects the fragments of H-Ras from being further degraded by trypsin and by proteinase K. HPLC studies together with fluorescence spectroscopic measurements indicate that binding of Ca(2+) to the H-Ras.GDP.Mg(2+) complex remarkably promotes guanine nucleotide exchange on H-Ras under emulated physiological Ca(2+) concentration conditions. Addition of high concentrations of either of two macromolecular crowding agents, Ficoll 70 and dextran 70, dramatically enhances H-Ras guanine nucleotide exchange extent in the presence of Ca(2+) at emulated physiological concentrations, and the nucleotide exchange extent increases significantly with the concentrations of crowding agents. Together, these results indicate that binding of calcium ions to H-Ras remarkably promotes H-Ras guanine nucleotide exchange under emulated physiological conditions. We thus propose that Ca(2+) may activate Ras signaling pathway by interaction with Ras, providing clues to understand the role of calcium in regulating Ras function in physiological environments.

  2. The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B

    PubMed Central

    Lu, Shaoyong; Jang, Hyunbum; Nussinov, Ruth; Zhang, Jian

    2016-01-01

    Ras mediates cell proliferation, survival and differentiation. Mutations in K-Ras4B are predominant at residues G12, G13 and Q61. Even though all impair GAP-assisted GTP → GDP hydrolysis, the mutation frequencies of K-Ras4B in human cancers vary. Here we aim to figure out their mechanisms and differential oncogenicity. In total, we performed 6.4 μs molecular dynamics simulations on the wild-type K-Ras4B (K-Ras4BWT-GTP/GDP) catalytic domain, the K-Ras4BWT-GTP–GAP complex, and the mutants (K-Ras4BG12C/G12D/G12V-GTP/GDP, K-Ras4BG13D-GTP/GDP, K-Ras4BQ61H-GTP/GDP) and their complexes with GAP. In addition, we simulated ‘exchanged’ nucleotide states. These comprehensive simulations reveal that in solution K-Ras4BWT-GTP exists in two, active and inactive, conformations. Oncogenic mutations differentially elicit an inactive-to-active conformational transition in K-Ras4B-GTP; in K-Ras4BG12C/G12D-GDP they expose the bound nucleotide which facilitates the GDP-to-GTP exchange. These mechanisms may help elucidate the differential mutational statistics in K-Ras4B-driven cancers. Exchanged nucleotide simulations reveal that the conformational transition is more accessible in the GTP-to-GDP than in the GDP-to-GTP exchange. Importantly, GAP not only donates its R789 arginine finger, but stabilizes the catalytically-competent conformation and pre-organizes catalytic residue Q61; mutations disturb the R789/Q61 organization, impairing GAP-mediated GTP hydrolysis. Together, our simulations help provide a mechanistic explanation of key mutational events in one of the most oncogenic proteins in cancer. PMID:26902995

  3. Some Current Problems in Simulator Design, Testing and Use.

    ERIC Educational Resources Information Center

    Caro, Paul W.

    Concerned with the general problem of the effectiveness of simulator training, this report reflects information developed during the conduct of aircraft simulator training research projects sponsored by the Air Force, Army, Navy, and Coast Guard. Problems are identified related to simulator design, testing, and use, all of which impact upon…

  4. Ras-mediated deregulation of the circadian clock in cancer.

    PubMed

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  5. Ras-Mediated Deregulation of the Circadian Clock in Cancer

    PubMed Central

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  6. Design of a general portable communication signal simulator

    NASA Astrophysics Data System (ADS)

    Zhu, Qinghua; Ruan, Xiaofen; Jin, Guoqing; Li, Shengyong

    2009-12-01

    A design scheme of a general portable communication simulator is proposed. The simulator is capable to provide VHF frequency-fixed signals, frequency-hopping signals, and spread spectrum signals. The detailed technical designs of key modules are presented, and so are their engineering implementation methods. Applying results demonstrate its capability of producing realistic communication signals as well as promising prospect of engineering applications.

  7. Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

    PubMed

    Cox, Adrienne D; Der, Channing J; Philips, Mark R

    2015-04-15

    RAS proteins require membrane association for their biologic activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTI) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anticancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes, and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated posttranslational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development. Clin Cancer Res; 21(8); 1819-27. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers." PMID:25878363

  8. Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

    PubMed

    Cox, Adrienne D; Der, Channing J; Philips, Mark R

    2015-04-15

    RAS proteins require membrane association for their biologic activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTI) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anticancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes, and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated posttranslational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development. Clin Cancer Res; 21(8); 1819-27. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers."

  9. Evidence-centered design for simulation-based assessment.

    PubMed

    Mislevy, Robert J

    2013-10-01

    Simulations provide opportunities for people to learn and to develop skills for situations that are expensive, time-consuming, or dangerous. Careful design can support their learning by tailoring the features of situations to their levels of skill, allowing repeated attempts, and providing timely feedback. The same environments provide opportunities for assessing people's capabilities to act in these situations. This article describes an assessment design framework that can help projects develop effective simulation-based assessments. It reviews the rationale and terminology of the "evidence-centered" assessment design framework, discusses how it aligns with the principles of simulation design, and illustrates ideas with examples from engineering and medicine. Advice is offered for designing a new simulation-based assessment and for adapting an existing simulation system for assessment purposes.

  10. Degradation of Activated K-Ras Orthologue via K-Ras-specific Lysine Residues Is Required for Cytokinesis*

    PubMed Central

    Sumita, Kazutaka; Yoshino, Hirofumi; Sasaki, Mika; Majd, Nazanin; Kahoud, Emily Rose; Takahashi, Hidenori; Takeuchi, Koh; Kuroda, Taruho; Lee, Susan; Charest, Pascale G.; Takeda, Kosuke; Asara, John M.; Firtel, Richard A.; Anastasiou, Dimitrios; Sasaki, Atsuo T.

    2014-01-01

    Mammalian cells encode three closely related Ras proteins, H-Ras, N-Ras, and K-Ras. Oncogenic K-Ras mutations frequently occur in human cancers, which lead to dysregulated cell proliferation and genomic instability. However, mechanistic role of the Ras isoform regulation have remained largely unknown. Furthermore, the dynamics and function of negative regulation of GTP-loaded K-Ras have not been fully investigated. Here, we demonstrate RasG, the Dictyostelium orthologue of K-Ras, is targeted for degradation by polyubiquitination. Both ubiquitination and degradation of RasG were strictly associated with RasG activity. High resolution tandem mass spectrometry (LC-MS/MS) analysis indicated that RasG ubiquitination occurs at C-terminal lysines equivalent to lysines found in human K-Ras but not in H-Ras and N-Ras homologues. Substitution of these lysine residues with arginines (4KR-RasG) diminished RasG ubiquitination and increased RasG protein stability. Cells expressing 4KR-RasG failed to undergo proper cytokinesis and resulted in multinucleated cells. Ectopically expressed human K-Ras undergoes polyubiquitin-mediated degradation in Dictyostelium, whereas human H-Ras and a Dictyostelium H-Ras homologue (RasC) are refractory to ubiquitination. Our results indicate the existence of GTP-loaded K-Ras orthologue-specific degradation system in Dictyostelium, and further identification of the responsible E3-ligase may provide a novel therapeutic approach against K-Ras-mutated cancers. PMID:24338482

  11. Optimizing depuration of salmon in RAS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fish cultured within water recirculating aquaculture systems (RAS) can acquire "earthy" or "musty" off-flavors due to bioaccumulation of the compounds geosmin and 2-methylisoborneol (MIB), respectively, which are produced by certain bacterial species present in RAS biosolids and microbial biofilms. ...

  12. Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1

    PubMed Central

    Iwig, Jeffrey S; Vercoulen, Yvonne; Das, Rahul; Barros, Tiago; Limnander, Andre; Che, Yan; Pelton, Jeffrey G; Wemmer, David E; Roose, Jeroen P; Kuriyan, John

    2013-01-01

    RasGRP1 and SOS are Ras-specific nucleotide exchange factors that have distinct roles in lymphocyte development. RasGRP1 is important in some cancers and autoimmune diseases but, in contrast to SOS, its regulatory mechanisms are poorly understood. Activating signals lead to the membrane recruitment of RasGRP1 and Ras engagement, but it is unclear how interactions between RasGRP1 and Ras are suppressed in the absence of such signals. We present a crystal structure of a fragment of RasGRP1 in which the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface of RasGRP1 is hidden within a dimerization interface that may be stabilized by the C-terminal oligomerization domain. NMR data demonstrate that calcium binding to the regulatory module generates substantial conformational changes that are incompatible with the inactive assembly. These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals. DOI: http://dx.doi.org/10.7554/eLife.00813.001 PMID:23908768

  13. Simulation Packages Expand Aircraft Design Options

    NASA Technical Reports Server (NTRS)

    2013-01-01

    In 2001, NASA released a new approach to computational fluid dynamics that allows users to perform automated analysis on complex vehicle designs. In 2010, Palo Alto, California-based Desktop Aeronautics acquired a license from Ames Research Center to sell the technology. Today, the product assists organizations in the design of subsonic aircraft, space planes, spacecraft, and high speed commercial jets.

  14. Design and Simulation of MEMS Enabled Systems

    NASA Astrophysics Data System (ADS)

    da Silva, Mark

    2001-03-01

    Over the past two decades considerable progress in microsystems (MEMS) fabrication technologies has been made resulting in a variety of commercially successful devices. Most of these devices have required application specific fabrication steps, which must be developed, and the lack of proper design tools often resulted in repeated prototyping that was expensive and time consuming. Further development of MEMS enabled commercial products and reduction of the time to market requires implementation of a concurrent design methodology through better design tools and standardization of the fabrication processes. The cross-disciplinary nature of MEMS-Enabled Systems necessitates designers with different backgrounds to work together in understanding the effects of one sub-system on another and this requires a top-down approach to integrated system design. Design tools that can facilitate this communication and reduce the need for excessive prototype fabrication and test iterations and significantly reduce cost and time-to-market are vitally important. The main focus of this article is to describe the top-down design methodology and and ongoing research on tools that facilitate concurrent design of MEMS enabled systems.

  15. A New View of Ras Isoforms in Cancers.

    PubMed

    Nussinov, Ruth; Tsai, Chung-Jung; Chakrabarti, Mayukh; Jang, Hyunbum

    2016-01-01

    Does small GTPase K-Ras4A have a single state or two states, one resembling K-Ras4B and the other N-Ras? A recent study of K-Ras4A made the remarkable observation that even in the absence of the palmitoyl, K-Ras4A can be active at the plasma membrane. Importantly, this suggests that K-Ras4A may exist in two distinct signaling states. In state 1, K-Ras4A is only farnesylated, like K-Ras4B; in state 2, farnesylated and palmitoylated, like N-Ras. The K-Ras4A hypervariable region sequence is positively charged, in between K-Ras4B and N-Ras. Taken together, this raises the possibility that the farnesylated but nonpalmitoylated state 1, like K-Ras4B, binds calmodulin and is associated with colorectal and other adenocarcinomas like lung cancer and pancreatic ductal adenocarcinoma. On the other hand, state 2 may be associated with melanoma and other cancers where N-Ras is a major contributor, such as acute myeloid leukemia. Importantly, H-Ras has two, singly and doubly, palmitoylated states that may also serve distinct functional roles. The multiple signaling states of palmitoylated Ras isoforms question the completeness of small GTPase Ras isoform statistics in different cancer types and call for reevaluation of concepts and protocols. They may also call for reconsideration of oncogenic Ras therapeutics. PMID:26659836

  16. Estimation of Channel-Forming Discharge and Large-Event Geomorphic Response Using HEC-RAS

    NASA Astrophysics Data System (ADS)

    Hamilton, P.; Strom, K.; Hosseiny, S. M. H.

    2015-12-01

    The goal of the present work was to consider the functionality and applicability of HEC-RAS sediment transport simulations in two situations. The first was as a mode for obtaining quick estimates of the effective discharge, one measure of channel-forming discharge, and the second was as a mode to quickly estimate sediment transport and the commensurate potential erosion and deposition during large flood events. Though there are many other sediment transport and morphodynamic models available, e.g., CCHE1D, Nays2DH, we were interested in using HEC-RAS since this is the model of choice for many regulatory bodies, e.g., FEMA, cities, and counties. This makes using the sediment transport capability of HEC-RAS a natural extension of models that already otherwise exist and are well calibrated. In first looking at the utility of these models, we wanted to estimate the effective discharge of streams. Effective discharge is one way of defining the channel-forming discharge for a stream and is therefore an important parameter in natural channel design and restoration efforts. By running this range of floods, one can easily obtain an estimate for recurrence interval most responsible for moving the majority of sediment over a long time period. Results were compared to data collected within our research group on the Brazos River (TX). Effective discharge is an important estimate, particularly in understanding the equilibrium channel condition. Nevertheless, large floods are contemporaneously catastrophic and understanding their potential effects is desirable. Finally, we performed some sensitivity analysis to better understand the underlying assumptions of the various sediment transport model options and how they might affect the outcome of the aforementioned computations.

  17. Space shuttle visual simulation system design study

    NASA Technical Reports Server (NTRS)

    1973-01-01

    The current and near-future state-of-the-art in visual simulation equipment technology is related to the requirements of the space shuttle visual system. Image source, image sensing, and displays are analyzed on a subsystem basis, and the principal conclusions are used in the formulation of a recommended baseline visual system. Perceptibility and visibility are also analyzed.

  18. Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?

    PubMed Central

    Cox, Adrienne D.; Der, Channing J.; Philips, Mark R.

    2015-01-01

    RAS proteins require membrane association for their biological activity, making this association a logical target for anti-RAS therapeutics. Lipid modification of RAS proteins by a farnesyl isoprenoid is an obligate step in that association, and is an enzymatic process. Accordingly, farnesyltransferase inhibitors (FTIs) were developed as potential anti-RAS drugs. The lack of efficacy of FTIs as anti-cancer drugs was widely seen as indicating that blocking RAS membrane association was a flawed approach to cancer treatment. However, a deeper understanding of RAS modification and trafficking has revealed that this was an erroneous conclusion. In the presence of FTIs, KRAS and NRAS, which are the RAS isoforms most frequently mutated in cancer, become substrates for alternative modification, can still associate with membranes, and can still function. Thus, FTIs failed not because blocking RAS membrane association is an ineffective approach, but because FTIs failed to accomplish that task. Recent findings regarding RAS isoform trafficking and the regulation of RAS subcellular localization have rekindled interest in efforts to target these processes. In particular, improved understanding of the palmitoylation/depalmitoylation cycle that regulates RAS interaction with the plasma membrane, endomembranes and cytosol, and of the potential importance of RAS chaperones, have led to new approaches. Efforts to validate and target other enzymatically regulated post-translational modifications are also ongoing. In this review, we revisit lessons learned, describe the current state of the art, and highlight challenging but promising directions to achieve the goal of disrupting RAS membrane association and subcellular localization for anti-RAS drug development. PMID:25878363

  19. An HLA based design of space system simulation environment

    NASA Astrophysics Data System (ADS)

    Li, Yinghua; Li, Yong; Liu, Jie

    2007-06-01

    Space system simulation is involved in many application fields, such as space remote sensing and space communication, etc. A simulation environment which can be shared by different space system simulation is needed. Two rules, called object template towing and hierarchical reusability, are proposed. Based on these two rules, the architecture, the network structure and the function structure of the simulation environment are designed. Then, the mechanism of utilizing data resources, inheriting object models and running simulation systems are also constructed. These mechanisms make the simulation objects defined in advance be easily inherited by different HLA federates, the fundamental simulation models be shared by different simulation systems. Therefore, the simulation environment is highly universal and reusable.

  20. M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells

    PubMed Central

    Castro, Ariel F.; Campos, Tania; Babcock, Justin T.; Armijo, Marisol E.; Martinez-Conde, Alfonso; Pincheira, Roxana; Quilliam, Lawrence A.

    2011-01-01

    Constitutive activation of M-Ras has previously been reported to cause morphologic and growth transformation of murine cells, suggesting that M-Ras plays a role in tumorigenesis. Cell transformation by M-Ras correlated with weak activation of the Raf/MEK/ERK pathway, although contributions from other downstream effectors were suggested. Recent studies indicate that signaling events distinct from the Raf/MEK/ERK cascade are critical for human tumorigenesis. However, it is unknown what signaling events M-Ras triggers in human cells. Using constitutively active M-Ras (Q71L) containing additional mutations within its effector binding loop, we found that M-Ras induces MEK/ERK-dependent and -independent Elk1 activation as well as PI3K/Akt and JNK/cJun activation in human MCF-7 breast cancer cells. Among several human cell lines examined, M-Ras-induced MEK/ERK-independent Elk1 activation was only detected in MCF-7 cells, and correlated with Rlf /M-Ras interaction and Ral /JNK activation. Supporting a role for M-Ras signaling in breast cancer, EGF activated M-Ras and promoted its interaction with endogenous Rlf. In addition, constitutive activation of M-Ras induced estrogen-independent growth of MCF-7 cells that was dependent on PI3K/Akt, MEK/ERK and JNK activation. Thus, our studies demonstrate that M-Ras signaling activity differs between human cells, highlighting the importance of defining Ras protein signaling within each cell type, especially when designing treatments for Ras-induced cancer. These findings also demonstrate that M-Ras activity may be important for progression of EGFR-dependent tumors. PMID:22121046

  1. Design and Test of Advanced Thermal Simulators for an Alkali Metal-Cooled Reactor Simulator

    NASA Technical Reports Server (NTRS)

    Garber, Anne E.; Dickens, Ricky E.

    2011-01-01

    The Early Flight Fission Test Facility (EFF-TF) at NASA Marshall Space Flight Center (MSFC) has as one of its primary missions the development and testing of fission reactor simulators for space applications. A key component in these simulated reactors is the thermal simulator, designed to closely mimic the form and function of a nuclear fuel pin using electric heating. Continuing effort has been made to design simple, robust, inexpensive thermal simulators that closely match the steady-state and transient performance of a nuclear fuel pin. A series of these simulators have been designed, developed, fabricated and tested individually and in a number of simulated reactor systems at the EFF-TF. The purpose of the thermal simulators developed under the Fission Surface Power (FSP) task is to ensure that non-nuclear testing can be performed at sufficiently high fidelity to allow a cost-effective qualification and acceptance strategy to be used. Prototype thermal simulator design is founded on the baseline Fission Surface Power reactor design. Recent efforts have been focused on the design, fabrication and test of a prototype thermal simulator appropriate for use in the Technology Demonstration Unit (TDU). While designing the thermal simulators described in this paper, effort were made to improve the axial power profile matching of the thermal simulators. Simultaneously, a search was conducted for graphite materials with higher resistivities than had been employed in the past. The combination of these two efforts resulted in the creation of thermal simulators with power capacities of 2300-3300 W per unit. Six of these elements were installed in a simulated core and tested in the alkali metal-cooled Fission Surface Power Primary Test Circuit (FSP-PTC) at a variety of liquid metal flow rates and temperatures. This paper documents the design of the thermal simulators, test program, and test results.

  2. Optimal Living Environments for the Elderly: A Design Simulation Approach.

    ERIC Educational Resources Information Center

    Hoffman, Stephanie B.; And Others

    PLANNED AGE (Planned Alternatives for Gerontological Environments) is a consumer/advocate-oriented design simulation package that provides: (a) a medium for user-planner interaction in the design of living and service environments for the aged; (b) an educational, planning, design, and evaluation tool that can be used by the elderly, their…

  3. Design, construction and evaluation of a simulated geothermal flow system

    SciTech Connect

    Mackanic, J.C.

    1980-07-28

    A system was designed and built to simulate the flow from a geothermal well. The simulated flow will be used to power a Lysholm engine, the performance of which will then be evaluated for different simulated geothermal flows. Two main subjects are covered: 1) the design, construction and evaluation of the behavior of the system that simulates the geothermal flow; included in that topic is a discussion of the probable behavior of the Lysholm engine when it is put into operation, and 2) the investigation of the use of dynamic modeling techniques to determine whether they can provide a suitable means for predicting the behavior of the system.

  4. Physiological Based Simulator Fidelity Design Guidance

    NASA Technical Reports Server (NTRS)

    Schnell, Thomas; Hamel, Nancy; Postnikov, Alex; Hoke, Jaclyn; McLean, Angus L. M. Thom, III

    2012-01-01

    The evolution of the role of flight simulation has reinforced assumptions in aviation that the degree of realism in a simulation system directly correlates to the training benefit, i.e., more fidelity is always better. The construct of fidelity has several dimensions, including physical fidelity, functional fidelity, and cognitive fidelity. Interaction of different fidelity dimensions has an impact on trainee immersion, presence, and transfer of training. This paper discusses research results of a recent study that investigated if physiological-based methods could be used to determine the required level of simulator fidelity. Pilots performed a relatively complex flight task consisting of mission task elements of various levels of difficulty in a fixed base flight simulator and a real fighter jet trainer aircraft. Flight runs were performed using one forward visual channel of 40 deg. field of view for the lowest level of fidelity, 120 deg. field of view for the middle level of fidelity, and unrestricted field of view and full dynamic acceleration in the real airplane. Neuro-cognitive and physiological measures were collected under these conditions using the Cognitive Avionics Tool Set (CATS) and nonlinear closed form models for workload prediction were generated based on these data for the various mission task elements. One finding of the work described herein is that simple heart rate is a relatively good predictor of cognitive workload, even for short tasks with dynamic changes in cognitive loading. Additionally, we found that models that used a wide range of physiological and neuro-cognitive measures can further boost the accuracy of the workload prediction.

  5. JEFF: Air transport system design simulation

    NASA Technical Reports Server (NTRS)

    1992-01-01

    Jeff is a remotely piloted vehicle designed by the Blue Team, a division of AE441, Inc., to fulfill the mission proposed by G-Dome Enterprises: to build a cost efficient aircraft to service Aeroworld with overnight cargo delivery. The design of Jeff was most significantly influenced by the need to minimize costs. This objective was pursued by building fewer large planes as opposed to many small planes. Thus, by building an aircraft with a large payload capacity, G-Dome Enterprises will be able to minimize the large costs and the large number of cycles that are associated with a large fleet. Another factor which had a significant influence on our design was the constraint that our design had to fit into a 2'x2'x5' storage container. This constraint meant that unless we wanted to build foldable wings that Jeff's span would be limited to 10 feet. Since this was not enough lifting surface to suit our needs a canard configuration was chosen to get the needed lifting surface and avoid the structural dilemma of foldable wings. The aircraft is constructed mainly of balsa, with spruce wing and canard spars and a monokote covering. It was designed to support a maximum payload weight of 35 oz. (total aircraft weight of 108 oz.) and withstand a maximum load factor of 2.5.

  6. Dynamics of adaptive structures: Design through simulations

    NASA Technical Reports Server (NTRS)

    Park, K. C.; Alexander, S.

    1993-01-01

    The use of a helical bi-morph actuator/sensor concept by mimicking the change of helical waveform in bacterial flagella is perhaps the first application of bacterial motions (living species) to longitudinal deployment of space structures. However, no dynamical considerations were analyzed to explain the waveform change mechanisms. The objective is to review various deployment concepts from the dynamics point of view and introduce the dynamical considerations from the outset as part of design considerations. Specifically, the impact of the incorporation of the combined static mechanisms and dynamic design considerations on the deployment performance during the reconfiguration stage is studied in terms of improved controllability, maneuvering duration, and joint singularity index. It is shown that intermediate configurations during articulations play an important role for improved joint mechanisms design and overall structural deployability.

  7. Pyrometry simulator (pyrosim) for diagnostic design.

    SciTech Connect

    Dolan, Daniel H., III

    2011-10-01

    Signal estimates are crucial to the design of time-resolved pyrometry measurements. These estimates affect fundamental design decisions, including the optical relay (fiber versus open beam), spectral range (visible or infrared), and amplification needs (possibly at the expense of time resolution). The pyrosim program makes such estimates, allowing the collected power, photon flux, and measured signal to be determined in a broad range of pyrometry measurements. Geometrical collection limits can be applied; sample emissivity, transfer efficiency, and detector sensitivity may also be specified, either as constants or functions of wavelength.

  8. Monitoring Ras Interactions with the Nucleotide Exchange Factor Son of Sevenless (Sos) Using Site-specific NMR Reporter Signals and Intrinsic Fluorescence*

    PubMed Central

    Vo, Uybach; Vajpai, Navratna; Flavell, Liz; Bobby, Romel; Breeze, Alexander L.; Embrey, Kevin J.; Golovanov, Alexander P.

    2016-01-01

    The activity of Ras is controlled by the interconversion between GTP- and GDP-bound forms partly regulated by the binding of the guanine nucleotide exchange factor Son of Sevenless (Sos). The details of Sos binding, leading to nucleotide exchange and subsequent dissociation of the complex, are not completely understood. Here, we used uniformly 15N-labeled Ras as well as [13C]methyl-Met,Ile-labeled Sos for observing site-specific details of Ras-Sos interactions in solution. Binding of various forms of Ras (loaded with GDP and mimics of GTP or nucleotide-free) at the allosteric and catalytic sites of Sos was comprehensively characterized by monitoring signal perturbations in the NMR spectra. The overall affinity of binding between these protein variants as well as their selected functional mutants was also investigated using intrinsic fluorescence. The data support a positive feedback activation of Sos by Ras·GTP with Ras·GTP binding as a substrate for the catalytic site of activated Sos more weakly than Ras·GDP, suggesting that Sos should actively promote unidirectional GDP → GTP exchange on Ras in preference of passive homonucleotide exchange. Ras·GDP weakly binds to the catalytic but not to the allosteric site of Sos. This confirms that Ras·GDP cannot properly activate Sos at the allosteric site. The novel site-specific assay described may be useful for design of drugs aimed at perturbing Ras-Sos interactions. PMID:26565026

  9. Monitoring Ras Interactions with the Nucleotide Exchange Factor Son of Sevenless (Sos) Using Site-specific NMR Reporter Signals and Intrinsic Fluorescence.

    PubMed

    Vo, Uybach; Vajpai, Navratna; Flavell, Liz; Bobby, Romel; Breeze, Alexander L; Embrey, Kevin J; Golovanov, Alexander P

    2016-01-22

    The activity of Ras is controlled by the interconversion between GTP- and GDP-bound forms partly regulated by the binding of the guanine nucleotide exchange factor Son of Sevenless (Sos). The details of Sos binding, leading to nucleotide exchange and subsequent dissociation of the complex, are not completely understood. Here, we used uniformly (15)N-labeled Ras as well as [(13)C]methyl-Met,Ile-labeled Sos for observing site-specific details of Ras-Sos interactions in solution. Binding of various forms of Ras (loaded with GDP and mimics of GTP or nucleotide-free) at the allosteric and catalytic sites of Sos was comprehensively characterized by monitoring signal perturbations in the NMR spectra. The overall affinity of binding between these protein variants as well as their selected functional mutants was also investigated using intrinsic fluorescence. The data support a positive feedback activation of Sos by Ras·GTP with Ras·GTP binding as a substrate for the catalytic site of activated Sos more weakly than Ras·GDP, suggesting that Sos should actively promote unidirectional GDP → GTP exchange on Ras in preference of passive homonucleotide exchange. Ras·GDP weakly binds to the catalytic but not to the allosteric site of Sos. This confirms that Ras·GDP cannot properly activate Sos at the allosteric site. The novel site-specific assay described may be useful for design of drugs aimed at perturbing Ras-Sos interactions.

  10. Designing a SCADA system simulator for fast breeder reactor

    NASA Astrophysics Data System (ADS)

    Nugraha, E.; Abdullah, A. G.; Hakim, D. L.

    2016-04-01

    SCADA (Supervisory Control and Data Acquisition) system simulator is a Human Machine Interface-based software that is able to visualize the process of a plant. This study describes the results of the process of designing a SCADA system simulator that aims to facilitate the operator in monitoring, controlling, handling the alarm, accessing historical data and historical trend in Nuclear Power Plant (NPP) type Fast Breeder Reactor (FBR). This research used simulation to simulate NPP type FBR Kalpakkam in India. This simulator was developed using Wonderware Intouch software 10 and is equipped with main menu, plant overview, area graphics, control display, set point display, alarm system, real-time trending, historical trending and security system. This simulator can properly simulate the principle of energy flow and energy conversion process on NPP type FBR. This SCADA system simulator can be used as training media for NPP type FBR prospective operators.

  11. Modeling and Simulation for Mission Operations Work System Design

    NASA Technical Reports Server (NTRS)

    Sierhuis, Maarten; Clancey, William J.; Seah, Chin; Trimble, Jay P.; Sims, Michael H.

    2003-01-01

    Work System analysis and design is complex and non-deterministic. In this paper we describe Brahms, a multiagent modeling and simulation environment for designing complex interactions in human-machine systems. Brahms was originally conceived as a business process design tool that simulates work practices, including social systems of work. We describe our modeling and simulation method for mission operations work systems design, based on a research case study in which we used Brahms to design mission operations for a proposed discovery mission to the Moon. We then describe the results of an actual method application project-the Brahms Mars Exploration Rover. Space mission operations are similar to operations of traditional organizations; we show that the application of Brahms for space mission operations design is relevant and transferable to other types of business processes in organizations.

  12. Two types of RAS mutants that dominantly interfere with activators of RAS.

    PubMed Central

    Jung, V; Wei, W; Ballester, R; Camonis, J; Mi, S; Van Aelst, L; Wigler, M; Broek, D

    1994-01-01

    In the fission yeast Schizosaccharomyces pombe, ras1 regulates both sexual development (conjugation and sporulation) and cellular morphology. Two types of dominant interfering mutants were isolated in a genetic screen for ras1 mutants that blocked sexual development. The first type of mutation, at Ser-22, analogous to the H-rasAsn-17 mutant (L. A. Feig and G. M. Cooper, Mol. Cell. Biol. 8:3235-3243, 1988), blocked only conjugation, whereas a second type of mutation, at Asp-62, interfered with conjugation, sporulation, and cellular morphology. Analogous mutations at position 64 of Saccharomyces cerevisiae RAS2 or position 57 of human H-ras also resulted in dominant interfering mutants that interfered specifically and more profoundly than mutants of the first type with RAS-associated pathways in both S. pombe or S. cerevisiae. Genetic evidence indicating that both types of interfering mutants function upstream of RAS is provided. Biochemical evidence showing that the mutants are altered in their interaction with the CDC25 class of exchange factors is presented. We show that both H-rasAsn-17 and H-rasTyr-57, compared with wild-type H-ras, are defective in their guanine nucleotide-dependent release from human cdc25 and that this defect is more severe for the H-rasTyr-57 mutant. Such a defect would allow the interfering mutants to remain bound to, thereby sequestering RAS exchange factors. The more severe interference phenotype of this novel interfering mutant suggests that it functions by titrating out other positive regulators of RAS besides those encoded by ste6 and CDC25. Images PMID:8196614

  13. Absolute Quantification of Endogenous Ras Isoform Abundance

    PubMed Central

    Mageean, Craig J.; Griffiths, John R.; Smith, Duncan L.; Clague, Michael J.; Prior, Ian A.

    2015-01-01

    Ras proteins are important signalling hubs situated near the top of networks controlling cell proliferation, differentiation and survival. Three almost identical isoforms, HRAS, KRAS and NRAS, are ubiquitously expressed yet have differing biological and oncogenic properties. In order to help understand the relative biological contributions of each isoform we have optimised a quantitative proteomics method for accurately measuring Ras isoform protein copy number per cell. The use of isotopic protein standards together with selected reaction monitoring for diagnostic peptides is sensitive, robust and suitable for application to sub-milligram quantities of lysates. We find that in a panel of isogenic SW48 colorectal cancer cells, endogenous Ras proteins are highly abundant with ≥260,000 total Ras protein copies per cell and the rank order of isoform abundance is KRAS>NRAS≥HRAS. A subset of oncogenic KRAS mutants exhibit increased total cellular Ras abundance and altered the ratio of mutant versus wild type KRAS protein. These data and methodology are significant because Ras protein copy number is required to parameterise models of signalling networks and informs interpretation of isoform-specific Ras functional data. PMID:26560143

  14. Simulation in the Service of Design - Asking the Right Questions

    SciTech Connect

    Donn, Michael; Selkowitz, Stephen; Bordass, Bill

    2009-03-01

    This paper proposes an approach to the creation of design tools that address the real information needs of designers in the early stages of design of nonresidential buildings. Traditional simplified design tools are typically too limited to be of much use, even in conceptual design. The proposal is to provide access to the power of detailed simulation tools, at a stage in design when little is known about the final building, but at a stage also when the freedom to explore options is greatest. The proposed approach to tool design has been derived from consultation with design analysis teams as part of the COMFEN tool development. The paper explores how tools like COMFEN have been shaped by this consultation and how requests from these teams for real-world relevance might shape such tools in the future, drawing into the simulation process the lessons from Post Occupancy Evaluation (POE) of buildings.

  15. Metabolic Dependencies in RAS-Driven Cancers.

    PubMed

    Kimmelman, Alec C

    2015-04-15

    The ability to inhibit the RAS oncogene has been the holy grail of oncology because of the critical role of this gene in a multitude of tumor types. In addition, RAS-mutant tumors are among the most aggressive and refractory to treatment. Although directly targeting the RAS oncogene has proven challenging, an alternative approach for treating RAS-driven cancers is to inhibit critical downstream events that are required for tumor maintenance. Indeed, much focus has been put on inhibiting signaling cascades downstream of RAS. Recent studies have shown that oncogenic RAS promotes a metabolic reprogramming of tumor cells, shifting them toward an anabolic metabolism necessary to produce biomass to support unconstrained proliferation. These cancers also use a diverse set of fuel sources to meet their metabolic needs and have even developed a variety of mechanisms to act as metabolic scavengers to obtain necessary metabolic substrates from both extracellular and intracellular sources. Collectively, these adaptations can create "metabolic bottlenecks" whereby tumor cells rely on particular pathways or rate-limiting metabolites. In this regard, inhibiting individual or combinations of these metabolic pathways can attenuate growth in preclinical models. Because these dependencies are tumor selective and downstream of oncogenic RAS, there is the opportunity for therapeutic intervention. Although targeting tumor metabolism is still in the early days of translation to patients, our continued advances in understanding critical metabolic adaptations in RAS-driven cancers, as well as the ability to study this altered metabolism in relevant tumor models, will accelerate the development of new therapeutic approaches. Clin Cancer Res; 21(8); 1828-34. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers." PMID:25878364

  16. Design of Object-Oriented Distributed Simulation Classes

    NASA Technical Reports Server (NTRS)

    Schoeffler, James D.

    1995-01-01

    Distributed simulation of aircraft engines as part of a computer aided design package being developed by NASA Lewis Research Center for the aircraft industry. The project is called NPSS, an acronym for "Numerical Propulsion Simulation System". NPSS is a flexible object-oriented simulation of aircraft engines requiring high computing speed. It is desirable to run the simulation on a distributed computer system with multiple processors executing portions of the simulation in parallel. The purpose of this research was to investigate object-oriented structures such that individual objects could be distributed. The set of classes used in the simulation must be designed to facilitate parallel computation. Since the portions of the simulation carried out in parallel are not independent of one another, there is the need for communication among the parallel executing processors which in turn implies need for their synchronization. Communication and synchronization can lead to decreased throughput as parallel processors wait for data or synchronization signals from other processors. As a result of this research, the following have been accomplished. The design and implementation of a set of simulation classes which result in a distributed simulation control program have been completed. The design is based upon MIT "Actor" model of a concurrent object and uses "connectors" to structure dynamic connections between simulation components. Connectors may be dynamically created according to the distribution of objects among machines at execution time without any programming changes. Measurements of the basic performance have been carried out with the result that communication overhead of the distributed design is swamped by the computation time of modules unless modules have very short execution times per iteration or time step. An analytical performance model based upon queuing network theory has been designed and implemented. Its application to realistic configurations has not

  17. Design of object-oriented distributed simulation classes

    NASA Technical Reports Server (NTRS)

    Schoeffler, James D. (Principal Investigator)

    1995-01-01

    Distributed simulation of aircraft engines as part of a computer aided design package is being developed by NASA Lewis Research Center for the aircraft industry. The project is called NPSS, an acronym for 'Numerical Propulsion Simulation System'. NPSS is a flexible object-oriented simulation of aircraft engines requiring high computing speed. It is desirable to run the simulation on a distributed computer system with multiple processors executing portions of the simulation in parallel. The purpose of this research was to investigate object-oriented structures such that individual objects could be distributed. The set of classes used in the simulation must be designed to facilitate parallel computation. Since the portions of the simulation carried out in parallel are not independent of one another, there is the need for communication among the parallel executing processors which in turn implies need for their synchronization. Communication and synchronization can lead to decreased throughput as parallel processors wait for data or synchronization signals from other processors. As a result of this research, the following have been accomplished. The design and implementation of a set of simulation classes which result in a distributed simulation control program have been completed. The design is based upon MIT 'Actor' model of a concurrent object and uses 'connectors' to structure dynamic connections between simulation components. Connectors may be dynamically created according to the distribution of objects among machines at execution time without any programming changes. Measurements of the basic performance have been carried out with the result that communication overhead of the distributed design is swamped by the computation time of modules unless modules have very short execution times per iteration or time step. An analytical performance model based upon queuing network theory has been designed and implemented. Its application to realistic configurations has

  18. Arrow 227: Air transport system design simulation

    NASA Technical Reports Server (NTRS)

    Bontempi, Michael; Bose, Dave; Brophy, Georgeann; Cashin, Timothy; Kanarios, Michael; Ryan, Steve; Peterson, Timothy

    1992-01-01

    The Arrow 227 is a student-designed commercial transport for use in a overnight package delivery network. The major goal of the concept was to provide the delivery service with the greatest potential return on investment. The design objectives of the Arrow 227 were based on three parameters; production cost, payload weight, and aerodynamic efficiency. Low production cost helps to reduce initial investment. Increased payload weight allows for a decrease in flight cycles and, therefore, less fuel consumption than an aircraft carrying less payload weight and requiring more flight cycles. In addition, fewer flight cycles will allow a fleet to last longer. Finally, increased aerodynamic efficiency in the form of high L/D will decrease fuel consumption.

  19. Hypervelocity impact simulation for micrometeorite and debris shield design

    NASA Technical Reports Server (NTRS)

    Fahrenthold, Eric P.

    1992-01-01

    A new capability has been developed for direct computer simulation of hypervelocity impacts on multi-plate orbital debris shields, for combinations of low shield thickness and wide shield spacing which place extreme demands on conventional Eulerian analysis techniques. The modeling methodology represents a novel approach to debris cloud dynamics simulation, a problem of long term interest in the design of space structures. Software implementation of the modeling methodology provides a new design tool for engineering analysis of proposed orbital debris protection systems.

  20. The Design, Development, and Evaluation of an Evaluative Computer Simulation.

    ERIC Educational Resources Information Center

    Ehrlich, Lisa R.

    This paper discusses evaluation design considerations for a computer based evaluation simulation developed at the University of Iowa College of Medicine in Cardiology to assess the diagnostic skills of primary care physicians and medical students. The simulation developed allows for the assessment of diagnostic skills of physicians in the…

  1. Telescope simulators for Hubble: an overview of optical designs.

    PubMed

    Davila, P; Wood, H J; Atcheson, P D; Saunders, R; Sullivan, J; Vaughan, A H; Saisse, M

    1993-04-01

    Various optical configurations for Hubble Space Telescope simulators have been proposed, and some are being built for use as verification tools to characterize the performance of second-generation instruments during ground testing. We describe the Hubble Space Telescope, present an overview of three optical designs for simulators, and discuss the relative advantages and disadvantages of each configuration.

  2. Design Model for Learner-Centered, Computer-Based Simulations.

    ERIC Educational Resources Information Center

    Hawley, Chandra L.; Duffy, Thomas M.

    This paper presents a model for designing computer-based simulation environments within a constructivist framework for the K-12 school setting. The following primary criteria for the development of simulations are proposed: (1) the problem needs to be authentic; (2) the cognitive demand in learning should be authentic; (3) scaffolding supports a…

  3. Effectively design and simulate thermosyphon reboiler systems. Part 1

    SciTech Connect

    Martin, G.R.; Sloley, A.W.

    1995-06-01

    Thermosyphon reboilers provide a simple, low-maintenance design for distillation tower reboiler systems. With an understanding of all the factors involved, thermosyphon designs should be more reliable than most other reboiler systems due to an absence of moving parts (pumps) in the process circulation loop. Design of true thermosyphon exchangers requires an intimate knowledge of a distillation tower`s heat balance, temperature levels and pressure balance in there boiler loop. Temperature levels vary strongly with composition gradients depending on the system relative volatilities. Case studies of two industrial units demonstrate implications on exchanger design of the correct and incorrect simulation configuration. The two cases compare a low relative-volatility {alpha} system (ethylene-ethane splitter) and a high {alpha} system (FCCU deethanizer). Main factors include impact on equipment size and design. Proper design criteria for thermosyphon exchanger and distillation tower simulation and for integrating process and equipment design are also shown.

  4. SINERGIA laparoscopic virtual reality simulator: didactic design and technical development.

    PubMed

    Lamata, Pablo; Gómez, Enrique J; Sánchez-Margallo, Francisco M; López, Oscar; Monserrat, Carlos; García, Verónica; Alberola, Carlos; Florido, Miguel Angel Rodríguez; Ruiz, Juan; Usón, Jesús

    2007-03-01

    VR laparoscopic simulators have demonstrated its validity in recent studies, and research should be directed towards a high training effectiveness and efficacy. In this direction, an insight into simulators' didactic design and technical development is provided, by describing the methodology followed in the building of the SINERGIA simulator. It departs from a clear analysis of training needs driven by a surgical training curriculum. Existing solutions and validation studies are an important reference for the definition of specifications, which are described with a suitable use of simulation technologies. Five new didactic exercises are proposed to train some of the basic laparoscopic skills. Simulator construction has required existing algorithms and the development of a particle-based biomechanical model, called PARSYS, and a collision handling solution based in a multi-point strategy. The resulting VR laparoscopic simulator includes new exercises and enhanced simulation technologies, and is finding a very good acceptance among surgeons.

  5. Biochemical similarity of Schizosaccharomyces pombe ras1 protein with RAS2 protein of Saccharomyces cervisiae.

    PubMed

    Onozawa, T; Danjoh, I; Fujiyama, A

    1995-07-01

    Schizosaccharomyces pombe contains single ras oncogene homologue, ras1, that functions in the signal transduction pathway conducting the cell's mating processes. To understand the biochemical basis of yeast ras proteins, we have purified the ras1 protein and compared the major biochemical constants with those of RAS2 protein from Saccharomyces cerevisiae and mammalian ras proteins. The purified ras1 protein showed a remarkably high Kd value for GDP binding (178 nM) and for binding with ATP. In contrast, the Kd value for GTP binding and the rate of GTPase activity were 64 nM and 77 x 10(-6) s-1 at 37 degrees C, respectively; both were higher than normal p21ras protein, but at the same level as the RAS2 protein. We directly measured rate of GTP binding and GDP binding which were 3.9 x 10(-3) s-1 and 1.8 x 10(-3) s-1 at 30 degrees C, respectively. On the other hand, exchange rates between bound and free nucleotides remained almost constant throughout the tested combination of GTP and GDP, and were several-fold lower than the binding rate. These results suggest that the release of the guanine nucleotide is the rate-limiting step in the ras-GTP/GDP cycle. As a whole, the biochemical properties of the ras1 protein are close to those of the RAS2 protein, although these two proteins function differently in the signal transduction pathway in the cells. PMID:7483844

  6. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling.

    PubMed

    Athuluri-Divakar, Sai Krishna; Vasquez-Del Carpio, Rodrigo; Dutta, Kaushik; Baker, Stacey J; Cosenza, Stephen C; Basu, Indranil; Gupta, Yogesh K; Reddy, M V Ramana; Ueno, Lynn; Hart, Jonathan R; Vogt, Peter K; Mulholland, David; Guha, Chandan; Aggarwal, Aneel K; Reddy, E Premkumar

    2016-04-21

    Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inactivation of RAS signaling. PMID:27104980

  7. Ras moves to stay in place.

    PubMed

    Schmick, Malte; Kraemer, Astrid; Bastiaens, Philippe I H

    2015-04-01

    Ras is a major intracellular signaling hub. This elevated position comes at a precarious cost: a single point mutation can cause aberrant signaling. The capacity of Ras for signaling is inextricably linked to its enrichment at the plasma membrane (PM). This PM localization is dynamically maintained by three essential elements: alteration of membrane affinities via lipidation and membrane-interaction motifs; trapping on specific membranes coupled with unidirectional vesicular transport to the PM; and regulation of diffusion via interaction with a solubilization factor. This system constitutes a cycle that primarily corrects for the entropic equilibration of Ras to all membranes that dilutes its signaling capacity. We illuminate how this reaction-diffusion system maintains an out-of-equilibrium localization of Ras GTPases and thereby confers signaling functionality to the PM.

  8. Design Factors for Educationally Effective Animations and Simulations

    ERIC Educational Resources Information Center

    Plass, Jan L.; Homer, Bruce D.; Hayward, Elizabeth O.

    2009-01-01

    This paper reviews research on learning from dynamic visual representations and offers principles for the design of animations and simulations that assure their educational effectiveness. In addition to established principles, new and revised design principle are presented that have been derived from recent research. Our review focuses on the…

  9. Simulations Using a Computer/Videodisc System: Instructional Design Considerations.

    ERIC Educational Resources Information Center

    Ehrlich, Lisa R.

    Instructional design considerations involved in using level four videodisc systems when designing simulations are explored. Discussion of the hardware and software system characteristics notes that computer based training offers the features of text, graphics, color, animation, and highlighting techniques, while a videodisc player offers all of…

  10. Advanced Simulation and Computing Co-Design Strategy

    SciTech Connect

    Ang, James A.; Hoang, Thuc T.; Kelly, Suzanne M.; McPherson, Allen; Neely, Rob

    2015-11-01

    This ASC Co-design Strategy lays out the full continuum and components of the co-design process, based on what we have experienced thus far and what we wish to do more in the future to meet the program’s mission of providing high performance computing (HPC) and simulation capabilities for NNSA to carry out its stockpile stewardship responsibility.

  11. Design and Performance Frameworks for Constructing Problem-Solving Simulations

    ERIC Educational Resources Information Center

    Stevens, Rons; Palacio-Cayetano, Joycelin

    2003-01-01

    Rapid advancements in hardware, software, and connectivity are helping to shorten the times needed to develop computer simulations for science education. These advancements, however, have not been accompanied by corresponding theories of how best to design and use these technologies for teaching, learning, and testing. Such design frameworks…

  12. Design by Dragging: An Interface for Creative Forward and Inverse Design with Simulation Ensembles

    PubMed Central

    Coffey, Dane; Lin, Chi-Lun; Erdman, Arthur G.; Keefe, Daniel F.

    2014-01-01

    We present an interface for exploring large design spaces as encountered in simulation-based engineering, design of visual effects, and other tasks that require tuning parameters of computationally-intensive simulations and visually evaluating results. The goal is to enable a style of design with simulations that feels as-direct-as-possible so users can concentrate on creative design tasks. The approach integrates forward design via direct manipulation of simulation inputs (e.g., geometric properties, applied forces) in the same visual space with inverse design via “tugging” and reshaping simulation outputs (e.g., scalar fields from finite element analysis (FEA) or computational fluid dynamics (CFD)). The interface includes algorithms for interpreting the intent of users’ drag operations relative to parameterized models, morphing arbitrary scalar fields output from FEA and CFD simulations, and in-place interactive ensemble visualization. The inverse design strategy can be extended to use multi-touch input in combination with an as-rigid-as-possible shape manipulation to support rich visual queries. The potential of this new design approach is confirmed via two applications: medical device engineering of a vacuum-assisted biopsy device and visual effects design using a physically based flame simulation. PMID:24051845

  13. NAM: The 2004 RAS National Astronomy Meeting

    NASA Astrophysics Data System (ADS)

    Jones, Barrie; Norton, Andrew

    2004-06-01

    This year's RAS National Astronomy Meeting was held at the Open University's Milton Keynes campus from 29 March to 2 April. The event was organized by members of the OU Physics & Astronomy Department and Planetary & Space Science Research Institute. Around 450 people attended the meeting, at which more than 220 talks were presented, along with around 90 posters. Co-chairs of RAS NAM04, Barrie Jones and Andrew Norton, summarize.

  14. Inhibition of RAS in diabetic nephropathy

    PubMed Central

    Yacoub, Rabi; Campbell, Kirk N

    2015-01-01

    Diabetic kidney disease (DKD) is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin–angiotensin system (RAS) is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII), the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population. PMID:25926752

  15. ASPP1 and ASPP2 bind active RAS, potentiate RAS signalling and enhance p53 activity in cancer cells

    PubMed Central

    Wang, Y; Godin-Heymann, N; Dan Wang, X; Bergamaschi, D; Llanos, S; Lu, X

    2013-01-01

    RAS mutations occur frequently in human cancer and activated RAS signalling contributes to tumour development and progression. Apart from its oncogenic effects on cell growth, active RAS has tumour-suppressive functions via its ability to induce cellular senescence and apoptosis. RAS is known to induce p53-dependent cell cycle arrest, yet its effect on p53-dependent apoptosis remains unclear. We report here that apoptosis-stimulating protein of p53 (ASPP) 1 and 2, two activators of p53, preferentially bind active RAS via their N-terminal RAS-association domains (RAD). Additionally, ASPP2 colocalises with and contributes to RAS cellular membrane localisation and potentiates RAS signalling. In cancer cells, ASPP1 and ASPP2 cooperate with oncogenic RAS to enhance the transcription and apoptotic function of p53. Thus, loss of ASPP1 and ASPP2 in human cancer cells may contribute to the full transforming property of RAS oncogene. PMID:23392125

  16. Evolutionary Design and Simulation of a Tube Crawling Inspection Robot

    NASA Technical Reports Server (NTRS)

    Craft, Michael; Howsman, Tom; ONeil, Daniel; Howell, Joe T. (Technical Monitor)

    2002-01-01

    The Space Robotics Assembly Team Simulation (SpaceRATS) is an expansive concept that will hopefully lead to a space flight demonstration of a robotic team cooperatively assembling a system from its constitutive parts. A primary objective of the SpaceRATS project is to develop a generalized evolutionary design approach for multiple classes of robots. The portion of the overall SpaceRats program associated with the evolutionary design and simulation of an inspection robot's morphology is the subject of this paper. The vast majority of this effort has concentrated on the use and modification of Darwin2K, a robotic design and simulation software package, to analyze the design of a tube crawling robot. This robot is designed for carrying out inspection duties in relatively inaccessible locations within a liquid rocket engine similar to the SSME. A preliminary design of the tube crawler robot was completed, and the mechanical dynamics of the system were simulated. An evolutionary approach to optimizing a few parameters of the system was utilized, resulting in a more optimum design.

  17. A WXW motif is required for the anticancer activity of the TAT-RasGAP317-326 peptide.

    PubMed

    Barras, David; Chevalier, Nadja; Zoete, Vincent; Dempsey, Rosemary; Lapouge, Karine; Olayioye, Monilola A; Michielin, Olivier; Widmann, Christian

    2014-08-22

    TAT-RasGAP317-326, a cell-permeable 10-amino acid-long peptide derived from the N2 fragment of p120 Ras GTPase-activating protein (RasGAP), sensitizes tumor cells to apoptosis induced by various anticancer therapies. This RasGAP-derived peptide, by targeting the deleted in liver cancer-1 (DLC1) tumor suppressor, also hampers cell migration and invasion by promoting cell adherence and by inhibiting cell movement. Here, we systematically investigated the role of each amino acid within the RasGAP317-326 sequence for the anticancer activities of TAT-RasGAP317-326. We report here that the first three amino acids of this sequence, tryptophan, methionine, and tryptophan (WMW), are necessary and sufficient to sensitize cancer cells to cisplatin-induced apoptosis and to reduce cell migration. The WMW motif was found to be critical for the binding of fragment N2 to DLC1. These results define the interaction mode between the active anticancer sequence of RasGAP and DLC1. This knowledge will facilitate the design of small molecules bearing the tumor-sensitizing and antimetastatic activities of TAT-RasGAP317-326.

  18. Design, simulation, evaluation, and technological verification of arrayed waveguide gratings

    NASA Astrophysics Data System (ADS)

    Seyringer, Dana; Schmid, Patrick; Bielik, Michal; Uherek, Frantisek; Chovan, Jozef; Kuzma, Anton

    2014-07-01

    We present the design, simulation, evaluation, and technological verification of various low-index optical demultiplexers based on arrayed waveguide gratings (AWGs). When designing such optical demultiplexers, a set of input geometrical parameters must be first calculated. They are essential to create AWG layout that will be then simulated using commercial photonics tools. However, these tools do not support or support only partially such a fundamental calculation. Therefore, a new stand-alone tool called AWG-Parameters was developed, which strongly reduces the time needed for the design. From the calculated geometrical parameters, the AWG layouts were created and simulated using three commercial photonic tools: Optiwave, (Ottawa, Ontario, Canada), Apollo Photonics, (Ancaster, Ontario, Canada), and R-Soft, (Pasadena, California). The designs were also technologically verified. The simulated/measured transmission characteristics were evaluated by our newly developed AWG-Analyzer tool. This tool provides calculations of AWG transmission parameters, which are also missing in commercial photonic tools. Additionally, the tool provides clear definitions of calculated transmission parameters together with their textual and graphical representations. Finally, the transmission characteristics and parameters achieved from different photonic tools were compared with each other and discussed in detail. The simulated results were also compared with the measurements. Very good agreement was achieved between theoretical (AWG-Parameters tool), simulated (commercial photonic tools), and fabricated AWG transmission parameters.

  19. Binding hotspots on K-ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis.

    PubMed

    Prakash, Priyanka; Hancock, John F; Gorfe, Alemayehu A

    2015-05-01

    We have used probe-based molecular dynamics (pMD) simulations to search for interaction hotspots on the surface of the therapeutically highly relevant oncogenic K-Ras G12D. Combining the probe-based query with an ensemble-based pocket identification scheme and an analysis of existing Ras-ligand complexes, we show that (i) pMD is a robust and cost-effective strategy for binding site identification, (ii) all four of the previously reported ligand binding sites are suitable for structure-based ligand design, and (iii) in some cases probe binding and expanded sampling of configurational space enable pocket expansion and increase the likelihood of site identification. Furthermore, by comparing the distribution of hotspots in nonpocket-like regions with known protein- and membrane-interacting interfaces, we propose that pMD has the potential to predict surface patches responsible for protein-biomolecule interactions. These observations have important implications for future drug design efforts and will facilitate the search for potential interfaces responsible for the proposed transient oligomerization or interaction of Ras with other biomolecules in the cellular milieu.

  20. Mapping the functional versatility and fragility of Ras GTPase signaling circuits through in vitro network reconstitution

    PubMed Central

    Coyle, Scott M; Lim, Wendell A

    2016-01-01

    The Ras-superfamily GTPases are central controllers of cell proliferation and morphology. Ras signaling is mediated by a system of interacting molecules: upstream enzymes (GEF/GAP) regulate Ras’s ability to recruit multiple competing downstream effectors. We developed a multiplexed, multi-turnover assay for measuring the dynamic signaling behavior of in vitro reconstituted H-Ras signaling systems. By including both upstream regulators and downstream effectors, we can systematically map how different network configurations shape the dynamic system response. The concentration and identity of both upstream and downstream signaling components strongly impacted the timing, duration, shape, and amplitude of effector outputs. The distorted output of oncogenic alleles of Ras was highly dependent on the balance of positive (GAP) and negative (GEF) regulators in the system. We found that different effectors interpreted the same inputs with distinct output dynamics, enabling a Ras system to encode multiple unique temporal outputs in response to a single input. We also found that different Ras-to-GEF positive feedback mechanisms could reshape output dynamics in distinct ways, such as signal amplification or overshoot minimization. Mapping of the space of output behaviors accessible to Ras provides a design manual for programming Ras circuits, and reveals how these systems are readily adapted to produce an array of dynamic signaling behaviors. Nonetheless, this versatility comes with a trade-off of fragility, as there exist numerous paths to altered signaling behaviors that could cause disease. DOI: http://dx.doi.org/10.7554/eLife.12435.001 PMID:26765565

  1. Ras pathway signaling accelerates programmed cell death in the pathogenic fungus Candida albicans.

    PubMed

    Phillips, Andrew J; Crowe, Jonathan D; Ramsdale, Mark

    2006-01-17

    A better understanding of the molecular basis of programmed cell death (PCD) in fungi could provide information that is useful in the design of antifungal drugs that combat life-threatening fungal infections. Harsh environmental stresses, such as acetic acid or hydrogen peroxide, have been shown to induce PCD in the pathogenic fungus Candida albicans. In this study, we show that dying cells progress from an apoptotic state to a secondary necrotic state and that the rate at which this change occurs is proportional to the intensity of the stimulus. Also, we found that the temporal response is modulated by Ras-cAMP-PKA signals. Mutations that block Ras-cAMP-PKA signaling (ras1Delta, cdc35Delta, tpk1Delta, and tpk2Delta) suppress or delay the apoptotic response, whereas mutations that stimulate signaling (RAS1(val13) and pde2Delta) accelerate the rate of entry of cells into apoptosis. Pharmacological stimulation or inhibition of Ras signaling reinforces these findings. Transient increases in endogenous cAMP occur under conditions that stimulate apoptosis but not growth arrest. Death-specific changes in the abundance of different isoforms of the PKA regulatory subunit, Bcy1p, are also observed. Activation of Ras signals may regulate PCD of C. albicans, either by inhibiting antiapoptotic functions (such as stress responses) or by activating proapoptotic functions. PMID:16407097

  2. Biologically-inspired hexapod robot design and simulation

    NASA Technical Reports Server (NTRS)

    Espenschied, Kenneth S.; Quinn, Roger D.

    1994-01-01

    The design and construction of a biologically-inspired hexapod robot is presented. A previously developed simulation is modified to include models of the DC drive motors, the motor driver circuits and their transmissions. The application of this simulation to the design and development of the robot is discussed. The mechanisms thought to be responsible for the leg coordination of the walking stick insect were previously applied to control the straight-line locomotion of a robot. We generalized these rules for a robot walking on a plane. This biologically-inspired control strategy is used to control the robot in simulation. Numerical results show that the general body motion and performance of the simulated robot is similar to that of the robot based on our preliminary experimental results.

  3. VPS35 binds farnesylated N-Ras in the cytosol to regulate N-Ras trafficking.

    PubMed

    Zhou, Mo; Wiener, Heidi; Su, Wenjuan; Zhou, Yong; Liot, Caroline; Ahearn, Ian; Hancock, John F; Philips, Mark R

    2016-08-15

    Ras guanosine triphosphatases (GTPases) regulate signaling pathways only when associated with cellular membranes through their C-terminal prenylated regions. Ras proteins move between membrane compartments in part via diffusion-limited, fluid phase transfer through the cytosol, suggesting that chaperones sequester the polyisoprene lipid from the aqueous environment. In this study, we analyze the nature of the pool of endogenous Ras proteins found in the cytosol. The majority of the pool consists of farnesylated, but not palmitoylated, N-Ras that is associated with a high molecular weight (HMW) complex. Affinity purification and mass spectrographic identification revealed that among the proteins found in the HMW fraction is VPS35, a latent cytosolic component of the retromer coat. VPS35 bound to N-Ras in a farnesyl-dependent, but neither palmitoyl- nor guanosine triphosphate (GTP)-dependent, fashion. Silencing VPS35 increased N-Ras's association with cytoplasmic vesicles, diminished GTP loading of Ras, and inhibited mitogen-activated protein kinase signaling and growth of N-Ras-dependent melanoma cells. PMID:27502489

  4. Computer simulation as a NOx reduction design tool

    SciTech Connect

    Liu, G.; Higgins, B.S.

    2008-10-15

    Nalco Mobotec engineers were charged with reducing emissions on a utility boiler converted from burning oil to eastern bituminous coal using the company's Rotamix selective noncatalytic reduction (SNCR) system which injects urea into the furnace. A CFD simulation of the existing boiler was first conducted and then the furnace was simulated with the SNCR system added and the design was optimised. Operating and capital costs were minimised by optimal placement of 50 injector ports. 6 figs., 2 tabs.

  5. New tools for the simulation and design of calorimeters

    SciTech Connect

    Womersley, W.J.

    1989-07-10

    Two new approaches to the simulation and design of large hermetic calorimeters are presented. Firstly, the Shower Library scheme used in the fast generation of showers in the Monte Carlo of the calorimeter for the D-Zero experiment at the Fermilab Tevatron is described. Secondly, a tool for the design future calorimeters is described, which can be integrated with a computer aided design system to give engineering designers an immediate idea of the relative physics capabilities of different geometries. 9 refs., 6 figs., 1 tab.

  6. Designing and implementing full immersion simulation as a research tool.

    PubMed

    Munroe, Belinda; Buckley, Thomas; Curtis, Kate; Morris, Richard

    2016-05-01

    Simulation is a valuable research tool used to evaluate the clinical performance of devices, people and systems. The simulated setting may address concerns unique to complex clinical environments such as the Emergency Department, which make the conduct of research challenging. There is limited evidence available to inform the development of simulated clinical scenarios for the purpose of evaluating practice in research studies, with the majority of literature focused on designing simulated clinical scenarios for education and training. Distinct differences exist in scenario design when implemented in education compared with use in clinical research studies. Simulated scenarios used to assess practice in clinical research must not comprise of any purposeful or planned teaching and be developed with a high degree of validity and reliability. A new scenario design template was devised to develop two standardised simulated clinical scenarios for the evaluation of a new assessment framework for emergency nurses. The scenario development and validation processes undertaken are described and provide an evidence-informed guide to scenario development for future clinical research studies. PMID:26917415

  7. RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors.

    PubMed

    Golec, Dominic P; Henao Caviedes, Laura M; Baldwin, Troy A

    2016-09-01

    T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation. PMID:27465532

  8. Design and use of an interactive simulation display generator

    SciTech Connect

    Patterson, D.R.; Rhodes, J.J.

    1983-03-31

    As part of a continuing applied research effort into interactive graphics utilization, we have developed an interactive Simulation Display Generator (SDG). This SDG operates in response to menu selections chosen via a graphics tablet and textual information entered using a keyboard. It has the capability to create, display, modify, store, and retrieve either a complete display or individual components of a display which can later be used by a variety of simulation models. This paper discusses the development of the requirement for the SDG as well as the decisions and tradeoffs that went into the design and implementation. Its use in creating displays for a typical simulation is illustrated.

  9. An Integrated Approach for Entry Mission Design and Flight Simulations

    NASA Technical Reports Server (NTRS)

    Lu, Ping; Rao, Prabhakara

    2004-01-01

    An integrated approach for entry trajectory design, guidance, and simulation is proposed. The key ingredients for this approach are an on-line 3 degree-of-freedom entry trajectory planning algorithm and the entry guidance algorithm that generates the guidance gains automatically. When fully developed, such a tool could enable end-bend entry mission design and simulations in 3DOF and 6DOF mode from de-orbit burn to the TAEM interface and beyond, all in one key stroke. Some preliminary examples of such a capability are presented in this paper that demonstrate the potential of this type of integrated environment.

  10. SCALED SIMULATION DESIGN OF HIGH QUALITY LASER WAKEFIELD ACCELERATOR STAGES

    SciTech Connect

    Geddes, C.G.R.; Cormier-Michel, E.; Esarey, E.; Schroeder, C.B.; Leemans, W.P.; Bruhwiler, D.L.; Cowan, B.; Nieter, C.; Paul, K.; Cary, J.R.

    2009-05-04

    Design of efficient, high gradient laser driven wakefield accelerator (LWFA) stages using explicit particle-incell simulations with physical parameters scaled by plasma density is presented. LWFAs produce few percent energy spread electron bunches at 0.1-1 GeV with high accelerating gradients. Design tools are now required to predict and improve performance and efficiency of future LWFA stages. Scaling physical parameters extends the reach of explicit simulations to address applications including 10 GeV stages and stages for radiation sources, and accurately resolves deep laser depletion to evaluate efficient stages.

  11. Optimization of a neutron detector design using adjoint transport simulation

    SciTech Connect

    Yi, C.; Manalo, K.; Huang, M.; Chin, M.; Edgar, C.; Applegate, S.; Sjoden, G.

    2012-07-01

    A synthetic aperture approach has been developed and investigated for Special Nuclear Materials (SNM) detection in vehicles passing a checkpoint at highway speeds. SNM is postulated to be stored in a moving vehicle and detector assemblies are placed on the road-side or in chambers embedded below the road surface. Neutron and gamma spectral awareness is important for the detector assembly design besides high efficiencies, so that different SNMs can be detected and identified with various possible shielding settings. The detector assembly design is composed of a CsI gamma-ray detector block and five neutron detector blocks, with peak efficiencies targeting different energy ranges determined by adjoint simulations. In this study, formulations are derived using adjoint transport simulations to estimate detector efficiencies. The formulations is applied to investigate several neutron detector designs for Block IV, which has its peak efficiency in the thermal range, and Block V, designed to maximize the total neutron counts over the entire energy spectrum. Other Blocks detect different neutron energies. All five neutron detector blocks and the gamma-ray block are assembled in both MCNP and deterministic simulation models, with detector responses calculated to validate the fully assembled design using a 30-group library. The simulation results show that the 30-group library, collapsed from an 80-group library using an adjoint-weighting approach with the YGROUP code, significantly reduced the computational cost while maintaining accuracy. (authors)

  12. An R package for simulation experiments evaluating clinical trial designs.

    PubMed

    Wang, Yuanyuan; Day, Roger

    2010-01-01

    This paper presents an open-source application for evaluating competing clinical trial (CT) designs using simulations. The S4 system of classes and methods is utilized. Using object-oriented programming provides extensibility through careful, clear interface specification; using R, an open-source widely-used statistical language, makes the application extendible by the people who design CTs: biostatisticians. Four key classes define the specifications of the population models, CT designs, outcome models and evaluation criteria. Five key methods define the interfaces for generating patient baseline characteristics, stopping rule, assigning treatment, generating patient outcomes and calculating the criteria. Documentation of their connections with the user input screens, with the central simulation loop, and with each other faciliates the extensibility. New subclasses and instances of existing classes meeting these interfaces can integrate immediately into the application. To illustrate the application, we evaluate the effect of patient pharmacokinetic heterogeneity on the performance of a common Phase I "3+3" design. PMID:21347151

  13. Specific repression of mutant K-RAS by 10-23 DNAzyme: Sensitizing cancer cell to anti-cancer therapies

    SciTech Connect

    Yu, S.-H.; Wang, T.-H.; Au, L.-C.

    2009-01-09

    Point mutations of the Ras family are frequently found in human cancers at a prevalence rate of 30%. The most common mutation K-Ras(G12V), required for tumor proliferation, survival, and metastasis due to its constitutively active GTPase activity, has provided an ideal target for cancer therapy. 10-23 DNAzyme, an oligodeoxyribonucleotide-based ribonuclease consisting of a 15-nucleotide catalytical domain flanked by two target-specific complementary arms, has been shown to effectively cleave the target mRNA at purine-pyrimidine dinucleotide. Taking advantage of this specific property, 10-23 DNAzyme was designed to cleave mRNA of K-Ras(G12V)(GGU {yields} GUU) at the GU dinucleotide while left the wild-type (WT) K-Ras mRNA intact. The K-Ras(G12V)-specific 10-23 DNAzyme was able to reduce K-Ras(G12V) at both mRNA and protein levels in SW480 cell carrying homozygous K-Ras(G12V). No effect was observed on the WT K-Ras in HEK cells. Although K-Ras(G12V)-specific DNAzymes alone did not inhibit proliferation of SW480 or HEK cells, pre-treatment of this DNAzyme sensitized the K-Ras(G12V) mutant cells to anti-cancer agents such as doxorubicin and radiation. These results offer a potential of using allele-specific 10-23 DNAzyme in combination with other cancer therapies to achieve better effectiveness on cancer treatment.

  14. Design of a neural network simulator on a transputer array

    NASA Technical Reports Server (NTRS)

    Mcintire, Gary; Villarreal, James; Baffes, Paul; Rua, Monica

    1987-01-01

    A brief summary of neural networks is presented which concentrates on the design constraints imposed. Major design issues are discussed together with analysis methods and the chosen solutions. Although the system will be capable of running on most transputer architectures, it currently is being implemented on a 40-transputer system connected to a toroidal architecture. Predictions show a performance level equivalent to that of a highly optimized simulator running on the SX-2 supercomputer.

  15. Enhanced avatar design using cognitive map-based simulation.

    PubMed

    Lee, Kun Chang; Moon, Byung Suk

    2007-12-01

    With the advent of the Internet era and the maturation of electronic commerce, strategic avatar design has become an important way of keeping up with market changes and customer tastes. In this study, we propose a new approach to an adaptive avatar design that uses cognitive map (CM) as a what-if simulation vehicle. The main virtue of the new design is its ability to change specific avatar design features with objective consideration of the subsequent effects upon other design features, thereby enhancing user satisfaction. Statistical analyses of focus group interview results with a group of experts majoring in avatars and CM showed that our proposed approach could be used to effectively analyze avatar design in an adaptive and practical manner when the market situation is changing. PMID:18085962

  16. The design and development of a finger joint simulator.

    PubMed

    Joyce, Thomas J

    2016-05-01

    Artificial finger joints lack the long-term clinical success seen with hip and knee prostheses. In part, this can be explained by the challenges of rheumatoid arthritis, a progressive disease which attacks surrounding tissues as well as the joint itself. Therefore, the natural finger joints' biomechanics are adversely affected, and consequently, this imbalance due to subluxing forces further challenges any prosthesis. Many different designs of finger prosthesis have been offered over a period of greater than 50 years. Most of these designs have failed, and it is likely that many of these failures could have been identified had the prostheses been appropriately tested prior to implantation into patients. While finger joint simulators have been designed, arguably only those from a single centre have been able to reproduce clinical-type failures of the finger prostheses tested in them. This article describes the design and development of a finger simulator at Durham University, UK. It explains and justifies the engineering decisions made and thus the evolution of the finger simulator. In vitro results and their linkage to clinical-type failures are outlined to help to show the effectiveness of the simulator. Failures of finger implants in vivo continue to occur, and the need for appropriate in vitro testing of finger prostheses remains strong.

  17. Visible Light Communication Physical Layer Design for Jist Simulation

    NASA Astrophysics Data System (ADS)

    Tomaš, Boris

    2014-12-01

    Current advances in computer networking consider using visible light spectrum to encode and decode digital data. This approach is relatively non expensive. However, designing appropriate MAC or any other upper layer protocol for Visible Light Communication (VLC) requires appropriate hardware. This paper proposes and implements such hardware simulation (physical layer) that is compatible with existing network stack.

  18. Numerical simulation and design of a thermionic electron gun

    NASA Astrophysics Data System (ADS)

    Hoseinzade, M.; Nijatie, M.; Sadighzadeh, A.

    2016-05-01

    This paper reports the simulation of an electron gun. The effects on the beam quality of some parameters on the beam quality were studied and optimal choices were identified. It gives numerical beam qualities for a common electrostatic triode gun, and the dependencies on design parameters such as electrode geometries and bias voltages to these electrodes are shown. An electron beam of diameter 5 mm with energy of 5 keV was assumed for the simulation process. Some design parameters were identified as variable parameters in the presence of space charge. These parameters are the inclination angle of emission electrode, the applied voltage to the focusing electrode, the gap width between the emission electrode and the focusing electrode and the diameter of the focusing electrode. The triode extraction system is designed and optimized by using CST software (for Particle Beam Simulations). The physical design of the extraction system is given in this paper. From the simulation results, it is concluded that the inclination angle of the emission electrode is optimized at 22.5°, the applied voltage to the focusing electrode was optimized and found to be V foc = ‑600 V, the optimal separation distance (gap between emission electrode and focusing electrode) is 4 mm, and the optimal diameter of the emission electrode is 14 mm. Initial results for these efforts aimed at emittance improvement are also given.

  19. Simulation, design, and analysis of azeotropic distillation operations

    SciTech Connect

    Bossen, B.S.; Joergensen, S.B.; Gani, R. )

    1993-04-01

    The computational tools needed for simulation, design, and analysis of azeotropic distillation operations are described. These tools include simple methods to identify the existence of binary and ternary azeotropes and to classify ternary mixtures as homogeneous or heterogeneous. The tools also include more complex methods to compute the phase diagram (or a heterogeneous liquid boiling surface), predict liquid-vapor phase equilibrium, and/or predict liquid-liquid-vapor phase equilibrium for simulations of batch and continuous distillation column operations. Important new features of these tools are the incorporation of a fast and efficient method for test of phase stability in simulation of distillation operations, the ability to handle a large range of mixtures (including mixtures with supercritical compounds), and the ability for computations covering wide ranges of temperature and pressure. On the basis of these tools, simple and consistent design algorithms are developed. The applicability of the design algorithms is verified through process simulation and analysis of the predicted behavior and data from the open literature. Conditions are given for examples illustrating (when and how possible distillation boundaries can be crossed) how multiple steady states can be obtained. Finally, the effect of changes in operating on the dynamic behavior of the azeotropic distillation columns and the sensitivity of design to the prediction of phase equilibria are presented.

  20. Black Blizzard: Designing Role-Play Simulations for Education

    ERIC Educational Resources Information Center

    Linser, Roni; Ree-Lindstad, Nina; Vold, Tone

    2007-01-01

    This paper outlines and analyses some key design issues we encountered in the process of creating an online role-play simulation (RPS) for a course targeting personnel involved in crisis management. Titled "Black Blizzard" the RPS aims to enable an exploration of typical issues and problems that arise in cross and multi-cultural international…

  1. The design and development of a finger joint simulator.

    PubMed

    Joyce, Thomas J

    2016-05-01

    Artificial finger joints lack the long-term clinical success seen with hip and knee prostheses. In part, this can be explained by the challenges of rheumatoid arthritis, a progressive disease which attacks surrounding tissues as well as the joint itself. Therefore, the natural finger joints' biomechanics are adversely affected, and consequently, this imbalance due to subluxing forces further challenges any prosthesis. Many different designs of finger prosthesis have been offered over a period of greater than 50 years. Most of these designs have failed, and it is likely that many of these failures could have been identified had the prostheses been appropriately tested prior to implantation into patients. While finger joint simulators have been designed, arguably only those from a single centre have been able to reproduce clinical-type failures of the finger prostheses tested in them. This article describes the design and development of a finger simulator at Durham University, UK. It explains and justifies the engineering decisions made and thus the evolution of the finger simulator. In vitro results and their linkage to clinical-type failures are outlined to help to show the effectiveness of the simulator. Failures of finger implants in vivo continue to occur, and the need for appropriate in vitro testing of finger prostheses remains strong. PMID:26833697

  2. Study, simulation and design of a 3D clinostat

    NASA Astrophysics Data System (ADS)

    Pavone, Valentina; Guarnieri, Vincenzo; Lobascio, Cesare; Soma, Aurelio; Bosso, Nicola; Lamantea, Matteo Maria

    High cost and limited number of physically executable experiments in space have introduced the need for ground simulation systems that enable preparing experiments to be carried out on board, identifying phenomena associated with the altered gravity conditions, and taking advantage of these conditions, as in Biotechnology. Among systems developed to simulate microgravity, especially for life sciences experiments, different types of clinostats were realized. This work deals with mechanical design of a three-dimensional clinostat and simulation of the dynamic behavior of the system by varying the operating parameters. The design and simulation phase was preceded by a careful analysis of the state of art and by the review of the most recent results, in particular from the major investigators of Life Sciences in Space. The mechanical design is quite innovative by adoption of a structure entirely in aluminum, which allows robustness while reducing the overall weight. The transmission system of motion has been optimized by means of brushless DC micro motors, light and compact, which helped to reduce weight, dimensions, power consumption and increase the reliability and durability of the system. The study of the dynamic behavior using SIMPACK, a multibody simulation software, led to results in line with those found in the most important and recent scientific publications. This model was also appropriately configured to represent any desired operating condition, and for eventual system scalability. It would be interesting to generate simulated hypogravity - e.g.: 0.38-g (Mars) or 0.17-g (Moon). This would allow to investigate how terrestrial life forms can grow in other planetary habitats, or to determine the gravity threshold response of different organisms. At the moment, such a system can only be achieved by centrifuges in real microgravity. We are confident that simulation and associated tests with our 3D clinostat can help adjusting the parameters allowing variable g

  3. Regulation of Ras proteins by reactive nitrogen species.

    PubMed

    Davis, Michael F; Vigil, Dom; Campbell, Sharon L

    2011-08-01

    Ras GTPases have been a subject of intense investigation since the early 1980s, when single point mutations in Ras were shown to cause deregulated cell growth control. Subsequently, Ras was identified as the most prevalent oncogene found in human cancer. Ras proteins regulate a host of pathways involved in cell growth, differentiation, and apoptosis by cycling between inactive GDP-bound and active GTP-bound states. Regulation of Ras activity is controlled by cellular factors that alter guanine nucleotide cycling. Oncogenic mutations prevent protein regulatory factors from down-regulating Ras activity, thereby maintaining Ras in a chronically activated state. The central dogma in the field is that protein modulatory factors are the primary regulators of Ras activity. Since the mid-1990s, however, evidence has accumulated that small molecule reactive nitrogen species (RNS) can also influence Ras guanine nucleotide cycling. Herein, we review the basic chemistry behind RNS formation and discuss the mechanism through which various RNS enhance nucleotide exchange in Ras proteins. In addition, we present studies that demonstrate the physiological relevance of RNS-mediated Ras activation within the context of immune system function, brain function, and cancer development. We also highlight future directions and experimental methods that may enhance our ability to detect RNS-mediated activation in cell cultures and in vivo. The development of such methods may ultimately pave new directions for detecting and elucidating how Ras proteins are regulated by redox species, as well as for targeting redox-activated Ras in cancer and other disease states.

  4. Design and Simulation of an Anode Stalk Support Insulator

    SciTech Connect

    Wang, L; Houck, T; Westenskow, G

    2005-05-16

    An anode stalk support insulator in a magnetically insulated transmission line was designed and modeled. One of the important design criteria is that within space constraints, the electric field along the insulator surface has to be minimized in order to prevent a surface flashover. In order to further reduce the field on the insulator surface, metal rings between insulator layers were also specially shaped. To facilitate the design process, electric field simulations were performed to determine the maximum field stress on the insulator surfaces and the transmission line chamber.

  5. Cosmic Reionization on Computers. I. Design and Calibration of Simulations

    NASA Astrophysics Data System (ADS)

    Gnedin, Nickolay Y.

    2014-09-01

    Cosmic Reionization On Computers is a long-term program of numerical simulations of cosmic reionization. Its goal is to model fully self-consistently (albeit not necessarily from the first principles) all relevant physics, from radiative transfer to gas dynamics and star formation, in simulation volumes of up to 100 comoving Mpc, and with spatial resolution approaching 100 pc in physical units. In this method paper, we describe our numerical method, the design of simulations, and the calibration of numerical parameters. Using several sets (ensembles) of simulations in 20 h -1 Mpc and 40 h -1 Mpc boxes with spatial resolution reaching 125 pc at z = 6, we are able to match the observed galaxy UV luminosity functions at all redshifts between 6 and 10, as well as obtain reasonable agreement with the observational measurements of the Gunn-Peterson optical depth at z < 6.

  6. Design of Accelerator Online Simulator Server Using Structured Data

    SciTech Connect

    Shen, Guobao; Chu, Chungming; Wu, Juhao; Kraimer, Martin; /Argonne

    2012-07-06

    Model based control plays an important role for a modern accelerator during beam commissioning, beam study, and even daily operation. With a realistic model, beam behaviour can be predicted and therefore effectively controlled. The approach used by most current high level application environments is to use a built-in simulation engine and feed a realistic model into that simulation engine. Instead of this traditional monolithic structure, a new approach using a client-server architecture is under development. An on-line simulator server is accessed via network accessible structured data. With this approach, a user can easily access multiple simulation codes. This paper describes the design, implementation, and current status of PVData, which defines the structured data, and PVAccess, which provides network access to the structured data.

  7. Computational Aerodynamic Simulations of a Spacecraft Cabin Ventilation Fan Design

    NASA Technical Reports Server (NTRS)

    Tweedt, Daniel L.

    2010-01-01

    Quieter working environments for astronauts are needed if future long-duration space exploration missions are to be safe and productive. Ventilation and payload cooling fans are known to be dominant sources of noise, with the International Space Station being a good case in point. To address this issue cost effectively, early attention to fan design, selection, and installation has been recommended, leading to an effort by NASA to examine the potential for small-fan noise reduction by improving fan aerodynamic design. As a preliminary part of that effort, the aerodynamics of a cabin ventilation fan designed by Hamilton Sundstrand has been simulated using computational fluid dynamics codes, and the computed solutions analyzed to quantify various aspects of the fan aerodynamics and performance. Four simulations were performed at the design rotational speed: two at the design flow rate and two at off-design flow rates. Following a brief discussion of the computational codes, various aerodynamic- and performance-related quantities derived from the computed flow fields are presented along with relevant flow field details. The results show that the computed fan performance is in generally good agreement with stated design goals.

  8. Carcinogen and dietary lipid regulate ras expression and localization in rat colon without affecting farnesylation kinetics.

    PubMed

    Davidson, L A; Lupton, J R; Jiang, Y H; Chapkin, R S

    1999-05-01

    Epidemiological and experimental data suggest that dietary fiber and fat are major determinants of colorectal cancer. However, the mechanisms by which these dietary constituents alter the incidence of colon cancer have not been elucidated. Evidence indicates that dominant gain-of-function mutations short-circuit protooncogenes and contribute to the pathogenesis of cancer. Therefore, we began to dissect the mechanisms whereby dietary fat and fiber, fed during the initiation, promotion and progression stages of colon tumorigenesis, regulate ras p21 localization, expression and mutation frequency. Male Sprague-Dawley rats (140) were provided with corn oil or fish oil and pectin or cellulose plus or minus the carcinogen azoxymethane (AOM) in a 2 x 2 x 2 factorial design and killed after 34 weeks. We have previously shown adenocarcinoma incidence in these animals to be 70.3% (52/74) for corn oil + AOM and 56.1% (37/66) for fish oil + AOM (P < 0.05). Total ras expression as well as ras membrane:cytosol ratio was 4- to 6-fold higher in colon tumors than in mucosa from AOM- or saline-injected rats. Expression of ras in the mucosal membrane fraction was 13% higher for animals fed corn oil compared with fish oil feeding (P < 0.05), which is noteworthy since ras must be localized at the plasma membrane to function. The elevated ras membrane:cytosol ratio in tumors was not due to increased farnesyl protein transferase activity or prenylation state, as nearly all detectable ras was in the prenylated form. Phosphorylated p42 and p44 mitogen activated protein kinase (ERK) expression was two-fold higher in tumor extracts compared with uninvolved mucosa from AOM- and saline-injected rats (P < 0.05). The frequency of K-ras mutations was not significantly different between the various groups, but there was a trend toward a greater incidence of mutations in tumors from corn oil fed rats (85%) compared with fish oil fed rats (58%). Our results indicate that the carcinogen

  9. RAS Symposium Draws Hundreds of Attendees | Poster

    Cancer.gov

    They call themselves “rasologists”: scientists who study the RAS family of genes and the cancers that can arise due to mutations within them. This field of research is at the heart of some sobering numbers. Almost a third of all human cancers, including 95 percent of pancreatic cancers, are driven by mutated RAS genes. The American Cancer Society estimates there were 48,960 new cases of pancreatic cancer in the United States in 2015 and 40,560 deaths from the disease.

  10. Cavity design and beam simulations for the APS rf gun

    SciTech Connect

    Borland, M.

    1991-11-15

    An earlier note discussed the preliminary design of the 1-1/2 cell RF cavity for the APS RF gun. This note describes the final design, including cavity properties and simulation results from the program rf gun. The basic idea for the new design was that the successful SSRL design could be improved upon by reducing fields that had nonlinear dependence on radius. As discussed previously, this would reduce the emittance and produce tighter momentum and time distributions. In addition, it was desirable to increase the fields in the first half-cell relative to the fields in the second half-cell, in order to allow more rapid initial acceleration, which would reduce the effects of space charge. Both of these goals were accomplished in the new design.

  11. RAS Projects at the NCI Frederick National Lab

    Cancer.gov

    The RAS Initiative involves a number of projects focusing on ways to inhibit the proliferation of cancer cells by mutant RAS proteins. Projects are conducted at the FNLCR hub, with collaboration from the research community nationwide.

  12. The RAS Problem: Turning Off a Broken Switch

    Cancer.gov

    The RAS gene is commonly mutated in cancer and researchers are working to better understand how to develop drugs that can target the RAS protein, which for many years has been considered to be “undruggable.”

  13. Calmodulin binds to K-Ras, but not to H- or N-Ras, and modulates its downstream signaling.

    PubMed

    Villalonga, P; López-Alcalá, C; Bosch, M; Chiloeches, A; Rocamora, N; Gil, J; Marais, R; Marshall, C J; Bachs, O; Agell, N

    2001-11-01

    Activation of Ras induces a variety of cellular responses depending on the specific effector activated and the intensity and amplitude of this activation. We have previously shown that calmodulin is an essential molecule in the down-regulation of the Ras/Raf/MEK/extracellularly regulated kinase (ERK) pathway in cultured fibroblasts and that this is due at least in part to an inhibitory effect of calmodulin on Ras activation. Here we show that inhibition of calmodulin synergizes with diverse stimuli (epidermal growth factor, platelet-derived growth factor, bombesin, or fetal bovine serum) to induce ERK activation. Moreover, even in the absence of any added stimuli, activation of Ras by calmodulin inhibition was observed. To identify the calmodulin-binding protein involved in this process, calmodulin affinity chromatography was performed. We show that Ras and Raf from cellular lysates were able to bind to calmodulin. Furthermore, Ras binding to calmodulin was favored in lysates with large amounts of GTP-bound Ras, and it was Raf independent. Interestingly, only one of the Ras isoforms, K-RasB, was able to bind to calmodulin. Furthermore, calmodulin inhibition preferentially activated K-Ras. Interaction between calmodulin and K-RasB is direct and is inhibited by the calmodulin kinase II calmodulin-binding domain. Thus, GTP-bound K-RasB is a calmodulin-binding protein, and we suggest that this binding may be a key element in the modulation of Ras signaling.

  14. Comparing simulated emission from molecular clouds using experimental design

    SciTech Connect

    Yeremi, Miayan; Flynn, Mallory; Loeppky, Jason; Rosolowsky, Erik; Offner, Stella

    2014-03-10

    We propose a new approach to comparing simulated observations that enables us to determine the significance of the underlying physical effects. We utilize the methodology of experimental design, a subfield of statistical analysis, to establish a framework for comparing simulated position-position-velocity data cubes to each other. We propose three similarity metrics based on methods described in the literature: principal component analysis, the spectral correlation function, and the Cramer multi-variate two-sample similarity statistic. Using these metrics, we intercompare a suite of mock observational data of molecular clouds generated from magnetohydrodynamic simulations with varying physical conditions. Using this framework, we show that all three metrics are sensitive to changing Mach number and temperature in the simulation sets, but cannot detect changes in magnetic field strength and initial velocity spectrum. We highlight the shortcomings of one-factor-at-a-time designs commonly used in astrophysics and propose fractional factorial designs as a means to rigorously examine the effects of changing physical properties while minimizing the investment of computational resources.

  15. Effectively design and simulate thermosyphon reboiler systems: Part 2

    SciTech Connect

    Martin, G.R.; Sloley, A.W.

    1995-07-01

    Thermosyphon reboilers provide a simple, low-maintenance design for distillation tower reboiler systems. With an understanding of all the factors involved, thermosyphon designs should be more reliable than most other reboiler systems due to an absence of moving parts (pumps) in the process circulation loop. Design of true thermosyphon exchangers requires an intimate knowledge of a distillation tower`s heat balance, temperature levels and pressure balance in the reboiler loop. Temperature levels vary strongly with composition gradients depending on the system`s relative volatilities. Case studies of two industrial units demonstrate implications on exchanger design of the correct and incorrect simulation configuration. The two cases compare a low relative-volatility ({alpha}) system (ethylene-ethane splitter) and a high {alpha} system (FCCU deethanizer). Part 1 covered basic thermosyphon design, advantages and disadvantages. Also, simulation requirements, {alpha} impacts and one-heat-source configurations were discussed. Part 2 continues with configurations of two heat sources at the same and difference temperatures. In addition, comparisons are made between the different designs to show an optimum for each case.

  16. Parachute system design, analysis, and simulation tool. Status report

    SciTech Connect

    Sundberg, W.D.; McBride, D.D.; Gwinn, K.W.; Waye, D.E.; Hailey, C.E.

    1992-12-31

    For over twenty years designers at Sandia National Laboratories have developed various parachute simulation codes to model deployment, inflation, loading, trajectories, aircraft downwash and line sail. In addition to these codes, material property data bases have been acquired. Recently we have initiated project to integrate these codes and data bases into a single software tool entitled SPARSYS (Sandia PARachute SYstem Simulation). We have constructed a graphical user interface as the driver and framework for SPARSYS. In this paper we present a status report on SPARSYS describing progress in developing and incorporating independent modules, in developing an integrated trajectory package, and in developing a materials data base including high-rate-of-strain data.

  17. ASPP2 Is a Novel Pan-Ras Nanocluster Scaffold

    PubMed Central

    Posada, Itziar M. D.; Serulla, Marc; Zhou, Yong; Oetken-Lindholm, Christina

    2016-01-01

    Ras-induced senescence mediated through ASPP2 represents a barrier to tumour formation. It is initiated by ASPP2’s interaction with Ras at the plasma membrane, which stimulates the Raf/MEK/ERK signaling cascade. Ras to Raf signalling requires Ras to be organized in nanoscale signalling complexes, called nanocluster. We therefore wanted to investigate whether ASPP2 affects Ras nanoclustering. Here we show that ASPP2 increases the nanoscale clustering of all oncogenic Ras isoforms, H-ras, K-ras and N-ras. Structure-function analysis with ASPP2 truncation mutants suggests that the nanocluster scaffolding activity of ASPP2 converges on its α-helical domain. While ASPP2 increased effector recruitment and stimulated ERK and AKT phosphorylation, it did not increase colony formation of RasG12V transformed NIH/3T3 cells. By contrast, ASPP2 was able to suppress the transformation enhancing ability of the nanocluster scaffold Gal-1, by competing with the specific effect of Gal-1 on H-rasG12V- and K-rasG12V-nanoclustering, thus imposing ASPP2’s ERK and AKT signalling signature. Similarly, ASPP2 robustly induced senescence and strongly abrogated mammosphere formation irrespective of whether it was expressed alone or together with Gal-1, which by itself showed the opposite effect in Ras wt or H-ras mutant breast cancer cells. Our results suggest that Gal-1 and ASPP2 functionally compete in nanocluster for active Ras on the plasma membrane. ASPP2 dominates the biological outcome, thus switching from a Gal-1 supported growth-promoting setting to a senescence inducing and stemness suppressive program in cancer cells. Our results support Ras nanocluster as major integrators of tumour fate decision events. PMID:27437940

  18. Simulation-Guided DNA Probe Design for Consistently Ultraspecific Hybridization

    PubMed Central

    Wang, J. Sherry; Zhang, David Yu

    2015-01-01

    Hybridization of complementary sequences is one of the central tenets of nucleic acid chemistry; however, the unintended binding of closely related sequences limits the accuracy of hybridization-based approaches for analyzing nucleic acids. Thermodynamics-guided probe design and empirical optimization of reaction conditions have been used to enable discrimination of single nucleotide variants, but typically these approaches provide only an approximate 25-fold difference in binding affinity. Here we show that simulations of the binding kinetics are both necessary and sufficient to design nucleic acid probe systems with consistently high specificity as they enable the discovery of an optimal combination of thermodynamic parameters. Simulation-guided probe systems designed against 44 different target single nucleotide variants sequences showed between 200- and 3000-fold (median 890) higher binding affinity than their corresponding wildtype sequences. As a demonstration of the usefulness of this simulation-guided design approach we developed probes which, in combination with PCR amplification, we use to detect low concentrations of variant alleles (1%) in human genomic DNA. PMID:26100802

  19. Simulation-guided DNA probe design for consistently ultraspecific hybridization

    NASA Astrophysics Data System (ADS)

    Wang, Juexiao Sherry; Zhang, David Yu

    2015-07-01

    Hybridization of complementary sequences is one of the central tenets of nucleic acid chemistry; however, the unintended binding of closely related sequences limits the accuracy of hybridization-based approaches to analysing nucleic acids. Thermodynamics-guided probe design and empirical optimization of the reaction conditions have been used to enable the discrimination of single-nucleotide variants, but typically these approaches provide only an approximately 25-fold difference in binding affinity. Here we show that simulations of the binding kinetics are both necessary and sufficient to design nucleic acid probe systems with consistently high specificity as they enable the discovery of an optimal combination of thermodynamic parameters. Simulation-guided probe systems designed against 44 sequences of different target single-nucleotide variants showed between a 200- and 3,000-fold (median 890) higher binding affinity than their corresponding wild-type sequences. As a demonstration of the usefulness of this simulation-guided design approach, we developed probes that, in combination with PCR amplification, detect low concentrations of variant alleles (1%) in human genomic DNA.

  20. The Design and Implementation of the Swim Integrated Plasma Simulator

    SciTech Connect

    Elwasif, Wael R; Bernholdt, David E; Shet, Aniruddha G; Foley, Samantha S; Bramley, Randall B; Batchelor, Donald B; Berry, Lee A

    2010-01-01

    As computing capabilities have increased, the coupling of computational models has become an increasingly viable and therefore important way of improving the physical fidelity of simulations. Applications currently using some form of multicode or multi-component coupling include climate modeling, rocket simulations, and chemistry. In recent years, the plasma physics community has also begun to pursue integrated multiphysics simulations for space weather and fusion energy applications. Such model coupling generally exposes new issues in the physical, mathematical, and computational aspects of the problem. This paper focuses on the computational aspects of one such effort, detailing the design, and implementation of the Integrated Plasma Simulator (IPS) for the Center for Simulation of Wave Interactions with Magnetohydrodynamics (SWIM). The IPS framework focuses on maximizing flexibility for the creators of loosely-coupled component-based simulations, and provides services for execution coordination, resource management, data management, and inter-component communication. It also serves as a proving ground for a concurrent 'multi-tasking' execution model to improve resource utilization, and application-level fault tolerance. We also briefly describe how the IPS has been applied to several problems of interest to the fusion community.

  1. Programmable multi-node quantum network design and simulation

    NASA Astrophysics Data System (ADS)

    Dasari, Venkat R.; Sadlier, Ronald J.; Prout, Ryan; Williams, Brian P.; Humble, Travis S.

    2016-05-01

    Software-defined networking offers a device-agnostic programmable framework to encode new network functions. Externally centralized control plane intelligence allows programmers to write network applications and to build functional network designs. OpenFlow is a key protocol widely adopted to build programmable networks because of its programmability, flexibility and ability to interconnect heterogeneous network devices. We simulate the functional topology of a multi-node quantum network that uses programmable network principles to manage quantum metadata for protocols such as teleportation, superdense coding, and quantum key distribution. We first show how the OpenFlow protocol can manage the quantum metadata needed to control the quantum channel. We then use numerical simulation to demonstrate robust programmability of a quantum switch via the OpenFlow network controller while executing an application of superdense coding. We describe the software framework implemented to carry out these simulations and we discuss near-term efforts to realize these applications.

  2. Design of 3D simulation engine for oilfield safety training

    NASA Astrophysics Data System (ADS)

    Li, Hua-Ming; Kang, Bao-Sheng

    2015-03-01

    Aiming at the demand for rapid custom development of 3D simulation system for oilfield safety training, this paper designs and implements a 3D simulation engine based on script-driven method, multi-layer structure, pre-defined entity objects and high-level tools such as scene editor, script editor, program loader. A scripting language been defined to control the system's progress, events and operating results. Training teacher can use this engine to edit 3D virtual scenes, set the properties of entity objects, define the logic script of task, and produce a 3D simulation training system without any skills of programming. Through expanding entity class, this engine can be quickly applied to other virtual training areas.

  3. On the design of script languages for neural simulation.

    PubMed

    Brette, Romain

    2012-01-01

    In neural network simulators, models are specified according to a language, either specific or based on a general programming language (e.g. Python). There are also ongoing efforts to develop standardized languages, for example NeuroML. When designing these languages, efforts are often focused on expressivity, that is, on maximizing the number of model types than can be described and simulated. I argue that a complementary goal should be to minimize the cognitive effort required on the part of the user to use the language. I try to formalize this notion with the concept of "language entropy", and I propose a few practical guidelines to minimize the entropy of languages for neural simulation.

  4. An automated methodology development. [software design for combat simulation

    NASA Technical Reports Server (NTRS)

    Hawley, L. R.

    1985-01-01

    The design methodology employed in testing the applicability of Ada in large-scale combat simulations is described. Ada was considered as a substitute for FORTRAN to lower life cycle costs and ease the program development efforts. An object-oriented approach was taken, which featured definitions of military targets, the capability of manipulating their condition in real-time, and one-to-one correlation between the object states and real world states. The simulation design process was automated by the problem statement language (PSL)/problem statement analyzer (PSA). The PSL/PSA system accessed the problem data base directly to enhance the code efficiency by, e.g., eliminating non-used subroutines, and provided for automated report generation, besides allowing for functional and interface descriptions. The ways in which the methodology satisfied the responsiveness, reliability, transportability, modifiability, timeliness and efficiency goals are discussed.

  5. Robust Multivariable Optimization and Performance Simulation for ASIC Design

    NASA Technical Reports Server (NTRS)

    DuMonthier, Jeffrey; Suarez, George

    2013-01-01

    Application-specific-integrated-circuit (ASIC) design for space applications involves multiple challenges of maximizing performance, minimizing power, and ensuring reliable operation in extreme environments. This is a complex multidimensional optimization problem, which must be solved early in the development cycle of a system due to the time required for testing and qualification severely limiting opportunities to modify and iterate. Manual design techniques, which generally involve simulation at one or a small number of corners with a very limited set of simultaneously variable parameters in order to make the problem tractable, are inefficient and not guaranteed to achieve the best possible results within the performance envelope defined by the process and environmental requirements. What is required is a means to automate design parameter variation, allow the designer to specify operational constraints and performance goals, and to analyze the results in a way that facilitates identifying the tradeoffs defining the performance envelope over the full set of process and environmental corner cases. The system developed by the Mixed Signal ASIC Group (MSAG) at the Goddard Space Flight Center is implemented as a framework of software modules, templates, and function libraries. It integrates CAD tools and a mathematical computing environment, and can be customized for new circuit designs with only a modest amount of effort as most common tasks are already encapsulated. Customization is required for simulation test benches to determine performance metrics and for cost function computation.

  6. Simulation models and designs for advanced Fischer-Tropsch technology

    SciTech Connect

    Choi, G.N.; Kramer, S.J.; Tam, S.S.

    1995-12-31

    Process designs and economics were developed for three grass-roots indirect Fischer-Tropsch coal liquefaction facilities. A baseline and an alternate upgrading design were developed for a mine-mouth plant located in southern Illinois using Illinois No. 6 coal, and one for a mine-mouth plane located in Wyoming using Power River Basin coal. The alternate design used close-coupled ZSM-5 reactors to upgrade the vapor stream leaving the Fischer-Tropsch reactor. ASPEN process simulation models were developed for all three designs. These results have been reported previously. In this study, the ASPEN process simulation model was enhanced to improve the vapor/liquid equilibrium calculations for the products leaving the slurry bed Fischer-Tropsch reactors. This significantly improved the predictions for the alternate ZSM-5 upgrading design. Another model was developed for the Wyoming coal case using ZSM-5 upgrading of the Fischer-Tropsch reactor vapors. To date, this is the best indirect coal liquefaction case. Sensitivity studies showed that additional cost reductions are possible.

  7. Simulation Environment for Orion Launch Abort System Control Design Studies

    NASA Technical Reports Server (NTRS)

    McMinn, J. Dana; Jackson, E. Bruce; Christhilf, David M.

    2007-01-01

    The development and use of an interactive environment to perform control system design and analysis of the proposed Crew Exploration Vehicle Launch Abort System is described. The environment, built using a commercial dynamic systems design package, includes use of an open-source configuration control software tool and a collaborative wiki to coordinate between the simulation developers, control law developers and users. A method for switching between multiple candidate control laws and vehicle configurations is described. Aerodynamic models, especially in a development program, change rapidly, so a means for automating the implementation of new aerodynamic models is described.

  8. Modeling and simulation role in designing a Teleradiology system.

    PubMed

    Alaoui, Adil; Vasilescu, Eugen; Lindisch, David; Subbiah, Nishant; Mun, Seong K

    2003-01-01

    In designing complex systems, Engineers, Developers and Systems Architects always have to make quantitative assumptions in order to satisfy anticipated loads and expectations of the final product. Many questions are asked before any complex system design that relate to systems performance, infrastructure and components configuration, behavior prediction and bottlenecks fixes. All these questions can be answered using modeling and simulation tools that allow engineers to predict systems behaviors in different settings and optimize systems in production by identifying bottlenecks and flaws in the infrastructure or workflow.

  9. Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases.

    PubMed

    Ye, Min; Shima, Fumi; Muraoka, Shin; Liao, Jingling; Okamoto, Hidetsugu; Yamamoto, Masaki; Tamura, Atsuo; Yagi, Naoto; Ueki, Tatzuo; Kataoka, Tohru

    2005-09-01

    Although some members of Ras family small GTPases, including M-Ras, share the primary structure of their effector regions with Ras, they exhibit vastly different binding properties to Ras effectors such as c-Raf-1. We have solved the crystal structure of M-Ras in the GDP-bound and guanosine 5'-(beta,gamma-imido)triphosphate (Gpp(NH)p)-bound forms. The overall structure of M-Ras resembles those of H-Ras and Rap2A, except that M-Ras-Gpp(NH)p exhibits a distinctive switch I conformation, which is caused by impaired intramolecular interactions between Thr-45 (corresponding to Thr-35 of H-Ras) of the effector region and the gamma-phosphate of Gpp(NH)p. Previous 31P NMR studies showed that H-Ras-Gpp(NH)p exists in two interconverting conformations, states 1 and 2. Whereas state 2 is a predominant form of H-Ras and corresponds to the "on" conformation found in the complex with effectors, state 1 is thought to represent the "off" conformation, whose tertiary structure remains unknown. 31P NMR analysis shows that free M-Ras-Gpp(NH)p predominantly assumes the state 1 conformation, which undergoes conformational transition to state 2 upon association with c-Raf-1. These results indicate that the solved structure of M-Ras-Gp-p(NH)p corresponds to the state 1 conformation. The predominance of state 1 in M-Ras is likely to account for its weak binding ability to the Ras effectors, suggesting the importance of the tertiary structure factor in small GTPase-effector interaction. Further, the first determination of the state 1 structure provides a molecular basis for developing novel anti-cancer drugs as compounds that hold Ras in the state 1 "off" conformation. PMID:15994326

  10. Design, Fabrication, and Testing of a Hopper Spacecraft Simulator

    NASA Astrophysics Data System (ADS)

    Mucasey, Evan Phillip Krell

    A robust test bed is needed to facilitate future development of guidance, navigation, and control software for future vehicles capable of vertical takeoff and landings. Specifically, this work aims to develop both a hardware and software simulator that can be used for future flight software development for extra-planetary vehicles. To achieve the program requirements of a high thrust to weight ratio with large payload capability, the vehicle is designed to have a novel combination of electric motors and a micro jet engine is used to act as the propulsion elements. The spacecraft simulator underwent several iterations of hardware development using different materials and fabrication methods. The final design used a combination of carbon fiber and fiberglass that was cured under vacuum to serve as the frame of the vehicle which provided a strong, lightweight platform for all flight components and future payloads. The vehicle also uses an open source software development platform, Arduino, to serve as the initial flight computer and has onboard accelerometers, gyroscopes, and magnetometers to sense the vehicles attitude. To prevent instability due to noise, a polynomial kalman filter was designed and this fed the sensed angles and rates into a robust attitude controller which autonomously control the vehicle' s yaw, pitch, and roll angles. In addition to the hardware development of the vehicle itself, both a software simulation and a real time data acquisition interface was written in MATLAB/SIMULINK so that real flight data could be taken and then correlated to the simulation to prove the accuracy of the analytical model. In result, the full scale vehicle was designed and own outside of the lab environment and data showed that the software model accurately predicted the flight dynamics of the vehicle.

  11. Design, modelling and simulation aspects of an ankle rehabilitation device

    NASA Astrophysics Data System (ADS)

    Racu, C. M.; Doroftei, I.

    2016-08-01

    Ankle injuries are amongst the most common injuries of the lower limb. Besides initial treatment, rehabilitation of the patients plays a crucial role for future activities and proper functionality of the foot. Traditionally, ankle injuries are rehabilitated via physiotherapy, using simple equipment like elastic bands and rollers, requiring intensive efforts of therapists and patients. Thus, the need of robotic devices emerges. In this paper, the design concept and some modelling and simulation aspects of a novel ankle rehabilitation device are presented.

  12. On the acoustic wedge design and simulation of anechoic chamber

    NASA Astrophysics Data System (ADS)

    Jiang, Changyong; Zhang, Shangyu; Huang, Lixi

    2016-10-01

    This study proposes an alternative to the classic wedge design for anechoic chambers, which is the uniform-then-gradient, flat-wall (UGFW) structure. The working mechanisms of the proposed structure and the traditional wedge are analyzed. It is found that their absorption patterns are different. The parameters of both structures are optimized for achieving minimum absorber depth, under the condition of absorbing 99% of normal incident sound energy. It is found that, the UGFW structure achieves a smaller total depth for the cut-off frequencies ranging from 100 Hz to 250 Hz. This paper also proposes a modification for the complex source image (CSI) model for the empirical simulation of anechoic chambers, originally proposed by Bonfiglio et al. [J. Acoust. Soc. Am. 134 (1), 285-291 (2013)]. The modified CSI model considers the non-locally reactive effect of absorbers at oblique incidence, and the improvement is verified by a full, finite-element simulation of a small chamber. With the modified CSI model, the performance of both decorations with the optimized parameters in a large chamber is simulated. The simulation results are analyzed and checked against the tolerance of 1.5 dB deviation from the inverse square law, stipulated in the ISO standard 3745(2003). In terms of the total decoration depth and anechoic chamber performance, the UGFW structure is better than the classic wedge design.

  13. Design of transient light signal simulator based on FPGA

    NASA Astrophysics Data System (ADS)

    Kang, Jing; Chen, Rong-li; Wang, Hong

    2014-11-01

    A design scheme of transient light signal simulator based on Field Programmable gate Array (FPGA) was proposed in this paper. Based on the characteristics of transient light signals and measured feature points of optical intensity signals, a fitted curve was created in MATLAB. And then the wave data was stored in a programmed memory chip AT29C1024 by using SUPERPRO programmer. The control logic was realized inside one EP3C16 FPGA chip. Data readout, data stream cache and a constant current buck regulator for powering high-brightness LEDs were all controlled by FPGA. A 12-Bit multiplying CMOS digital-to-analog converter (DAC) DAC7545 and an amplifier OPA277 were used to convert digital signals to voltage signals. A voltage-controlled current source constituted by a NPN transistor and an operational amplifier controlled LED array diming to achieve simulation of transient light signal. LM3405A, 1A Constant Current Buck Regulator for Powering LEDs, was used to simulate strong background signal in space. Experimental results showed that the scheme as a transient light signal simulator can satisfy the requests of the design stably.

  14. Qatargas exporting LNG from Qatar`s new Ras Laffan Port

    SciTech Connect

    1997-02-24

    When the 135,000 cu m LNG carrier Al Zubarah departed Ras Laffan Port in December, Qatar entered a new era of commerce that will both boost the emirate`s economic development and influence energy trade around the world. The event capped more than a decade of planning, design, and construction of Ras Laffan Port--the world`s newest and largest LNG exporting facility. During the 1980s, the focus in Qatar was on exploration and development of North field, which holds the world`s largest reserves of nonassociated natural gas. In the 1990s, efforts concentrated on establishing a direct production and export link between North field, the new multi-billion-dollar Qatar Liquefied Gas Co. (Qatargas) gas liquefaction plant at Ras Laffan, and LNG export facilities at the 8.5 sq km Ras Laffan Port. Markets of the Far East will be first to be served by LNG from Ras Laffan Port. Two 25-year LNG supply contracts have been signed with buyers in Japan and South Korea, and negotiations are under way with potential customers from China, Taiwan, and Thailand. The paper describes the port, its operations, and export projects.

  15. The value of genomics in dissecting the RAS-network and in guiding therapeutics for RAS-driven cancers.

    PubMed

    Shrestha, Gajendra; MacNeil, Shelley M; McQuerry, Jasmine A; Jenkins, David F; Sharma, Sunil; Bild, Andrea H

    2016-10-01

    The rise in genomic knowledge over the past decade has revealed the molecular etiology of many diseases, and has identified intricate signaling network activity in human cancers. Genomics provides the opportunity to determine genome structure and capture the activity of thousands of molecular events concurrently, which is important for deciphering highly complex genetic diseases such as cancer. In this review, we focus on genomic efforts directed towards one of cancer's most frequently mutated networks, the RAS pathway. Genomic tools such as gene expression signatures and assessment of mutations across the RAS network enable the capture of RAS signaling complexity. Due to this high level of interaction and cross-talk within the network, efforts to target RAS signaling in the clinic have generally failed, and we currently lack the ability to directly inhibit the RAS protein with high efficacy. We propose that the use of gene expression data can identify effective treatments that broadly inhibit the RAS network as this approach measures pathway activity independent of mutation status or any single mechanism of activation. Here, we review the genomic studies that map the complexity of the RAS network in cancer, and that show how genomic measurements of RAS pathway activation can identify effective RAS inhibition strategies. We also address the challenges and future directions for treating RAS-driven tumors. In summary, genomic assessment of RAS signaling provides a level of complexity necessary to accurately map the network that matches the intricacy of RAS pathway interactions in cancer.

  16. The Differential Palmitoylation States of N-Ras and H-Ras Determine Their Distinct Golgi Sub-compartment Localizations

    PubMed Central

    Lynch, Stephen J.; Snitkin, Harriet; Gumper, Iwona; Philips, Mark R.; Sabatini, David; Pellicer, Angel

    2014-01-01

    Despite a high degree of structural homology and shared exchange factors, effectors and GTPase activating proteins, a large body of evidence suggests functional heterogeneity among Ras isoforms. One aspect of Ras biology that may explain this heterogeneity is the differential subcellular localizations driven by the C-terminal hypervariable regions of Ras proteins. Spatial heterogeneity has been documented at the level of organelles: palmitoylated Ras isoforms (H-Ras and N-Ras) localize on the Golgi apparatus whereas K-Ras4B does not. We tested the hypothesis that spatial heterogeneity also exists at the sub-organelle level by studying the localization of differentially palmitoylated Ras isoforms within the Golgi apparatus. Using confocal, live cell fluorescent imaging and immunogold electron microscopy we found that, whereas the doubly palmitoylated H-Ras is distributed throughout the Golgi stacks, the singly palmitoylated N-Ras is polarized with a relative paucity of expression on the trans Golgi. Using palmitoylation mutants we show that the different sub-Golgi distributions of the Ras proteins are a consequence of their differential degree of palmitoylation. Thus, the acylation state of Ras proteins controls not only their distribution between the Golgi apparatus and the plasma membrane but also their distribution within the Golgi stacks. PMID:25158650

  17. The value of genomics in dissecting the RAS-network and in guiding therapeutics for RAS-driven cancers.

    PubMed

    Shrestha, Gajendra; MacNeil, Shelley M; McQuerry, Jasmine A; Jenkins, David F; Sharma, Sunil; Bild, Andrea H

    2016-10-01

    The rise in genomic knowledge over the past decade has revealed the molecular etiology of many diseases, and has identified intricate signaling network activity in human cancers. Genomics provides the opportunity to determine genome structure and capture the activity of thousands of molecular events concurrently, which is important for deciphering highly complex genetic diseases such as cancer. In this review, we focus on genomic efforts directed towards one of cancer's most frequently mutated networks, the RAS pathway. Genomic tools such as gene expression signatures and assessment of mutations across the RAS network enable the capture of RAS signaling complexity. Due to this high level of interaction and cross-talk within the network, efforts to target RAS signaling in the clinic have generally failed, and we currently lack the ability to directly inhibit the RAS protein with high efficacy. We propose that the use of gene expression data can identify effective treatments that broadly inhibit the RAS network as this approach measures pathway activity independent of mutation status or any single mechanism of activation. Here, we review the genomic studies that map the complexity of the RAS network in cancer, and that show how genomic measurements of RAS pathway activation can identify effective RAS inhibition strategies. We also address the challenges and future directions for treating RAS-driven tumors. In summary, genomic assessment of RAS signaling provides a level of complexity necessary to accurately map the network that matches the intricacy of RAS pathway interactions in cancer. PMID:27338857

  18. Designing a Distributed Space Systems Simulation in Accordance with the Simulation Interoperability Standards Organization (SISO)

    NASA Technical Reports Server (NTRS)

    Cowen, Benjamin

    2011-01-01

    Simulations are essential for engineering design. These virtual realities provide characteristic data to scientists and engineers in order to understand the details and complications of the desired mission. A standard development simulation package known as Trick is used in developing a source code to model a component (federate in HLA terms). The runtime executive is integrated into an HLA based distributed simulation. TrickHLA is used to extend a Trick simulation for a federation execution, develop a source code for communication between federates, as well as foster data input and output. The project incorporates international cooperation along with team collaboration. Interactions among federates occur throughout the simulation, thereby relying on simulation interoperability. Communication through the semester went on between participants to figure out how to create this data exchange. The NASA intern team is designing a Lunar Rover federate and a Lunar Shuttle federate. The Lunar Rover federate supports transportation across the lunar surface and is essential for fostering interactions with other federates on the lunar surface (Lunar Shuttle, Lunar Base Supply Depot and Mobile ISRU Plant) as well as transporting materials to the desired locations. The Lunar Shuttle federate transports materials to and from lunar orbit. Materials that it takes to the supply depot include fuel and cargo necessary to continue moon-base operations. This project analyzes modeling and simulation technologies as well as simulation interoperability. Each team from participating universities will work on and engineer their own federate(s) to participate in the SISO Spring 2011 Workshop SIW Smackdown in Boston, Massachusetts. This paper will focus on the Lunar Rover federate.

  19. Design and simulation of silicon photonic schematics and layouts

    NASA Astrophysics Data System (ADS)

    Chrostowski, Lukas; Lu, Zeqin; Flueckiger, Jonas; Wang, Xu; Klein, Jackson; Liu, Amy; Jhoja, Jaspreet; Pond, James

    2016-05-01

    Electronic circuit designers commonly start their design process with a schematic, namely an abstract representation of the physical circuit. In integrated photonics on the other hand, it is common for the design to begin at the physical component level, and create a layout by connecting components with interconnects. In this paper, we discuss how to create a schematic from the physical layout via netlist extraction, which enables circuit simulations. Post-layout extraction can also be used to predict how fabrication variability and non-uniformity will impact circuit performance. This is based on the component position information, compact models that are parameterized for dimensional variations, and manufacturing variability models such as a simulated wafer thickness map. This final step is critical in understanding how real-world silicon photonic circuits will behave. We present an example based on treating the ring resonator as a circuit. A silicon photonics design kit, as described here, is available for download at http://github.com/lukasc-ubc/SiEPIC_EBeam_PDK.

  20. Design and Simulation of the nuSTORM Pion Beamline

    SciTech Connect

    Liu, A.; Neuffer, D.; Bross, A.

    2015-08-15

    The nuSTORM (neutrinos from STORed Muons) proposal presents a detailed design for a neutrino facility based on a muon storage ring, with muon decay in the production straight section of the ring providing well defined neutrino beams. The facility includes a primary high-energy proton beam line, a target station with pion production and collection, and a pion beamline for pion transportation and injection into a muon decay ring. The nuSTORM design uses “stochastic injection”, in which pions are directed by a chicane, referred to as the Orbit Combination Section (OCS), into the production straight section of the storage ring. Pions that decay within that straight section provide muons within the circulating acceptance of the ring. Furthermore, the design enables injection without kickers or a separate pion decay transport line. The beam line that the pions traverse before being extracted from the decay ring is referred to as the pion beamline. Our paper describes the design and simulation of the pion beamline, and includes full beam dynamics simulations of the system.

  1. Design and Simulation of an Electrothermal Actuator Based Rotational Drive

    NASA Astrophysics Data System (ADS)

    Beeson, Sterling; Dallas, Tim

    2008-10-01

    As a participant in the Micro and Nano Device Engineering (MANDE) Research Experience for Undergraduates program at Texas Tech University, I learned how MEMS devices operate and the limits of their operation. Using specialized AutoCAD-based design software and the ANSYS simulation program, I learned the MEMS fabrication process used at Sandia National Labs, the design limitations of this process, the abilities and drawbacks of micro devices, and finally, I redesigned a MEMS device called the Chevron Torsional Ratcheting Actuator (CTRA). Motion is achieved through electrothermal actuation. The chevron (bent-beam) actuators cause a ratcheting motion on top of a hub-less gear so that as voltage is applied the CTRA spins. The voltage applied needs to be pulsed and the frequency of the pulses determine the angular frequency of the device. The main objective was to design electromechanical structures capable of transforming the electrical signals into mechanical motion without overheating. The design was optimized using finite element analysis in ANSYS allowing multi-physics simulations of our model system.

  2. Design and Simulation of the nuSTORM Pion Beamline

    DOE PAGESBeta

    Liu, A.; Neuffer, D.; Bross, A.

    2015-08-15

    The nuSTORM (neutrinos from STORed Muons) proposal presents a detailed design for a neutrino facility based on a muon storage ring, with muon decay in the production straight section of the ring providing well defined neutrino beams. The facility includes a primary high-energy proton beam line, a target station with pion production and collection, and a pion beamline for pion transportation and injection into a muon decay ring. The nuSTORM design uses “stochastic injection”, in which pions are directed by a chicane, referred to as the Orbit Combination Section (OCS), into the production straight section of the storage ring. Pionsmore » that decay within that straight section provide muons within the circulating acceptance of the ring. Furthermore, the design enables injection without kickers or a separate pion decay transport line. The beam line that the pions traverse before being extracted from the decay ring is referred to as the pion beamline. Our paper describes the design and simulation of the pion beamline, and includes full beam dynamics simulations of the system.« less

  3. Design and simulation of the nuSTORM facility

    SciTech Connect

    Liu, Ao

    2015-04-01

    This thesis provides a full design and simulation of the nuSTORM beam line facility including the pion beam line , the pion and muon orbit combination section, and the muon decay ring. The study also includes the development of numerical optimization methods and their application to the design. At nuSTORM, one proton batch from the Main Injector (MI) is extracted and transported to the target station to bombard a solid target. A magnetic horn is used as the collection device for the secondary particles such as pions and kaons. A pion beam line is designed to transport the secondary particles downstream to the muon decay ring. In order to avoid the use of a fast kicker with a large aperture for the injection, an Orbit Combination Section (OCS) was designed to combine the reference pion orbit with the circulating muon orbit. This ful lls the stochastic injection scheme proposed in the 1980s. It is shown through the simulation that the pion beam line is able to deliver 0.011 muons per proton on target within the acceptance of the ring. In order to improve the circulating muon ux, an optimization of the magnetic collection horn was studied. A Multi-Objective Genetic Algorithm (MOGA), that was modi ed to integrate Message Passing Interface (MPI) in the process, is applied to the optimization. The number of muons within the ring acceptance from the pion decay is estimated by the pions after the collection horn. This new method was proposed to lower the requirement on the computing resources for the optimization. The study gives a new and better target and horn con guration after a full investigation of the system. The nuSTORM ring is examined with two optics designs. With di erent features, the two designs are optimized via correcting the nonlinearities with sextupolar eld distribution in the ring. A modi ed MPI-based Simulated Annealing (SA) algorithm was applied to obtain the optimal ring acceptance. The comparison with the GA shows good agreements on the achieved

  4. EGFR phosphorylates FAM129B to promote Ras activation

    PubMed Central

    Ji, Haitao; Lee, Jong-Ho; Wang, Yugang; Pang, Yilin; Zhang, Tao; Xia, Yan; Zhong, Lianjin; Lyu, Jianxin; Lu, Zhimin

    2016-01-01

    Ras GTPase-activating proteins (GAPs) are important regulators for Ras activation, which is instrumental in tumor development. However, the mechanism underlying this regulation remains elusive. We demonstrate here that activated EGFR phosphorylates the Y593 residue of the protein known as family with sequence similarity 129, member B (FAM129B), which is overexpressed in many types of human cancer. FAM129B phosphorylation increased the interaction between FAM129B and Ras, resulting in reduced binding of p120-RasGAP to Ras. FAM129B phosphorylation promoted Ras activation, increasing ERK1/2- and PKM2-dependent β-catenin transactivation and leading to the enhanced glycolytic gene expression and the Warburg effect; promoting tumor cell proliferation and invasion; and supporting brain tumorigenesis. Our studies unearthed a novel and important mechanism underlying EGFR-mediated Ras activation in tumor development. PMID:26721396

  5. Dynamic simulation for IGCC process and control design

    SciTech Connect

    Depew, C.; Martinez, A.; Collodi, G.; Meloni, R.

    1998-01-01

    Detailed dynamic simulation analysis is a valuable tool that increases the understanding of unit interactions and control system performance in a complex integrated gasification combined-cycle (IGCC) plant. The Sarlux integrated gasification combined cycle (IGCC) plant must simultaneously satisfy electrical power and refinery hydrogen and steam demands (trigeneration gasification). The plant`s gasifier, heat recovery, sulfur removal, hydrogen recovery and steam power generation units are highly integrated and require coordinated control. In this study, dynamic simulation provides insights into the behavior of the process and combined cycle units during normal and upset conditions. The dynamic simulation is used to design a control system that drives the gasifiers to satisfy power, steam and hydrogen demands before a load change or upset is detected by the syngas pressure controller. At the study conclusion, the model will demonstrate how the IGCC plant will respond to the contractual maximum load change rate and process upsets. The study tests the basic process and control system design during the project engineering phase to minimize startup troubleshooting and expensive field changes.

  6. High-Density Plasma Reactors: Simulations for Design

    NASA Technical Reports Server (NTRS)

    Hash, David B.; Meyyappan, Meyya; Arnold, James O. (Technical Monitor)

    1998-01-01

    The development of improved and more efficient plasma reactors is a costly process for the semiconductor industry. Until five years ago, the Industry made most of its advancements through a trial and error approach. More recently, the role of computational modeling in the design process has increased. Both conventional computational fluid dynamics (CFD) techniques like Navier-Stokes solvers as well as particle simulation methods are used to model plasma reactor flowfields. However, since high-density plasma reactors generally operate at low gas pressures on the order of 1 to 10 mTorr, a particle simulation may be necessary because of the failure of CFD techniques to model rarefaction effects. The direct simulation Monte Carlo method is the most widely accepted and employed particle simulation tool and has previously been used to investigate plasma reactor flowfields. A plasma DSMC code is currently under development at NASA Ames Research Center with its foundation as the object-oriented parallel Cornell DSMC code, MONACO. The present investigation is a follow up of a neutral flow investigation of the effects of process parameters as well as reactor design on etch rate and etch rate uniformity. The previous work concentrated on silicon etch of a chlorine flow in a configuration typical of electron cyclotron resonance (ECR) or helical resonator type reactors. The effects of the plasma on the dissociation chemistry were modeled by making assumptions about the electron temperature and number density. The electrons or ions themselves were not simulated.The present work extends these results by simulating the charged species.The electromagnetic fields are calculated such that power deposition is modeled self-consistently. Electron impact reactions are modeled along with mechanisms for charge exchange. An bipolar diffusion assumption is made whereby electrons remain tied to the ions. However, the velocities of tile electrons are allowed to be modified during collisions

  7. Building interactive simulations in a Web page design program.

    PubMed

    Kootsey, J Mailen; Siriphongs, Daniel; McAuley, Grant

    2004-01-01

    A new Web software architecture, NumberLinX (NLX), has been integrated into a commercial Web design program to produce a drag-and-drop environment for building interactive simulations. NLX is a library of reusable objects written in Java, including input, output, calculation, and control objects. The NLX objects were added to the palette of available objects in the Web design program to be selected and dropped on a page. Inserting an object in a Web page is accomplished by adding a template block of HTML code to the page file. HTML parameters in the block must be set to user-supplied values, so the HTML code is generated dynamically, based on user entries in a popup form. Implementing the object inspector for each object permits the user to edit object attributes in a form window. Except for model definition, the combination of the NLX architecture and the Web design program permits construction of interactive simulation pages without writing or inspecting code. PMID:17271495

  8. Design, modeling and simulation of MEMS-based silicon Microneedles

    NASA Astrophysics Data System (ADS)

    Amin, F.; Ahmed, S.

    2013-06-01

    The advancement in semiconductor process engineering and nano-scale fabrication technology has made it convenient to transport specific biological fluid into or out of human skin with minimum discomfort. Fluid transdermal delivery systems such as Microneedle arrays are one such emerging and exciting Micro-Electro Mechanical System (MEMS) application which could lead to a total painless fluid delivery into skin with controllability and desirable yield. In this study, we aimed to revisit the problem with modeling, design and simulations carried out for MEMS based silicon hollow out of plane microneedle arrays for biomedical applications particularly for transdermal drug delivery. An approximate 200 μm length of microneedle with 40 μm diameter of lumen has been successfully shown formed by isotropic and anisotropic etching techniques using MEMS Pro design tool. These microneedles are arranged in size of 2 × 4 matrix array with center to center spacing of 750 μm. Furthermore, comparisons for fluid flow characteristics through these microneedle channels have been modeled with and without the contribution of the gravitational forces using mathematical models derived from Bernoulli Equation. Physical Process simulations have also been performed on TCAD SILVACO to optimize the design of these microneedles aligned with the standard Si-Fabrication lines.

  9. Integrated predictive modelling simulations of burning plasma experiment designs

    NASA Astrophysics Data System (ADS)

    Bateman, Glenn; Onjun, Thawatchai; Kritz, Arnold H.

    2003-11-01

    Models for the height of the pedestal at the edge of H-mode plasmas (Onjun T et al 2002 Phys. Plasmas 9 5018) are used together with the Multi-Mode core transport model (Bateman G et al 1998 Phys. Plasmas 5 1793) in the BALDUR integrated predictive modelling code to predict the performance of the ITER (Aymar A et al 2002 Plasma Phys. Control. Fusion 44 519), FIRE (Meade D M et al 2001 Fusion Technol. 39 336), and IGNITOR (Coppi B et al 2001 Nucl. Fusion 41 1253) fusion reactor designs. The simulation protocol used in this paper is tested by comparing predicted temperature and density profiles against experimental data from 33 H-mode discharges in the JET (Rebut P H et al 1985 Nucl. Fusion 25 1011) and DIII-D (Luxon J L et al 1985 Fusion Technol. 8 441) tokamaks. The sensitivities of the predictions are evaluated for the burning plasma experimental designs by using variations of the pedestal temperature model that are one standard deviation above and below the standard model. Simulations of the fusion reactor designs are carried out for scans in which the plasma density and auxiliary heating power are varied.

  10. Building interactive simulations in a Web page design program.

    PubMed

    Kootsey, J Mailen; Siriphongs, Daniel; McAuley, Grant

    2004-01-01

    A new Web software architecture, NumberLinX (NLX), has been integrated into a commercial Web design program to produce a drag-and-drop environment for building interactive simulations. NLX is a library of reusable objects written in Java, including input, output, calculation, and control objects. The NLX objects were added to the palette of available objects in the Web design program to be selected and dropped on a page. Inserting an object in a Web page is accomplished by adding a template block of HTML code to the page file. HTML parameters in the block must be set to user-supplied values, so the HTML code is generated dynamically, based on user entries in a popup form. Implementing the object inspector for each object permits the user to edit object attributes in a form window. Except for model definition, the combination of the NLX architecture and the Web design program permits construction of interactive simulation pages without writing or inspecting code.

  11. Design of virtual SCADA simulation system for pressurized water reactor

    NASA Astrophysics Data System (ADS)

    Wijaksono, Umar; Abdullah, Ade Gafar; Hakim, Dadang Lukman

    2016-02-01

    The Virtual SCADA system is a software-based Human-Machine Interface that can visualize the process of a plant. This paper described the results of the virtual SCADA system design that aims to recognize the principle of the Nuclear Power Plant type Pressurized Water Reactor. This simulation uses technical data of the Nuclear Power Plant Unit Olkiluoto 3 in Finland. This device was developed using Wonderware Intouch, which is equipped with manual books for each component, animation links, alarm systems, real time and historical trending, and security system. The results showed that in general this device can demonstrate clearly the principles of energy flow and energy conversion processes in Pressurized Water Reactors. This virtual SCADA simulation system can be used as instructional media to recognize the principle of Pressurized Water Reactor.

  12. Design and verification of a cloud field optical simulator

    NASA Technical Reports Server (NTRS)

    Davis, J. M.; Cox, S. K.; Mckee, T. B.

    1983-01-01

    A concept and an apparatus designed to investigate the reflected and transmitted distributions of light from optically thick clouds is presented. The Cloud Field Optical Simulator (CFOS) is a laboratory device which utilizes an array of incandescent lamps as a source, simulated clouds made from cotton or styrofoam as targets, and an array of silicon photodiodes as detectors. The device allows virtually any source-target-detector geometry to be examined. Similitude between real clouds and their CFOS cotton or styrofoam counterparts is established by relying on a linear relationship between optical depth and the ratio of reflected to transmitted light for a semiinfinite layer. Comparisons of principal plane radiances observed by the CFOS with Monte Carlo computations for a water cloud at 0.7 micron show excellent agreement. Initial applications of the CFOS are discussed.

  13. Design and simulation of uncooled microbolometer using coventorware

    NASA Astrophysics Data System (ADS)

    Arora, Suryansh; Paras, Neha; Gurjar, Anil; Narwal, Rakesh; Prasad, B.; Kumar, Dinesh

    2016-04-01

    Recently, a lot of attention has been paid to infrared imaging using uncooled microbolometer detectors, primarily because of their low cost, and wide military and civilian applications like disaster rescue, night vision, homing and tracking, ecology and weather forecasting, target acquisition, predictive inspection and maintenance, surveillance, remote temperature sensing and medical diagnostic and treatment. The present work demonstrates the design and simulation of uncooled microbolometer detector using Coventorware tool. Geometrical optimization has been done to minimize the pixel size up to 18×18 µm. Simulated values for Different parameters like Thermal conductance, Time constant and change in temperature calculated for the structure are 1.2 × 10-7W/K, 4.44ms and 3.5K.

  14. Design and verification of a cloud field optical simulator

    NASA Technical Reports Server (NTRS)

    Davis, J. M.; Cox, S. K.; Mckee, T. B.

    1982-01-01

    A concept and an apparatus designed to investigate the reflected and transmitted distributions of light from optically thick clouds is presented. The Cloud Field Optical Simulator (CFOS) is a laboratory device which utilizes an array of incandescent lamps as a source, simulated clouds made from cotton or styrofoam as targets, and an array of silicon photodiodes as detectors. The device allows virtually any source-target-detector geometry to be examined. Similitude between real clouds and their CFOS cotton or styrofoam counterparts is established by relying on a linear relationship between optical depth and the ratio of reflected to transmitted light for a semi-infinite layer. Comparisons of principal plane radiances observed by the CFOS with Monte Carlo computations for a water cloud at 0.7 microns show excellent agreement.

  15. Beam Dynamics Design and Simulation in Ion Linear Accelerators (

    2006-08-01

    Orginally, the ray tracing code TRACK has been developed to fulfill the many special requirements for the Rare Isotope Accelerator Facility known as RIA. Since no available beam-dynamics code met all the necessary requirements, modifications to the code TRACK were introduced to allow end-to-end (from the ion souce to the production target) simulations of the RIA machine, TRACK is a general beam-dynamics code and can be applied for the design, commissioning and operation of modernmore » ion linear accelerators and beam transport systems.« less

  16. Design analysis tracking and data relay satellite simulation system

    NASA Technical Reports Server (NTRS)

    1974-01-01

    The design and development of the equipment necessary to simulate the S-band multiple access link between user spacecraft, the Tracking and Data Relay Satellite, and a ground control terminal are discussed. The core of the S-band multiple access concept is the use of an Adaptive Ground Implemented Phased Array. The array contains thirty channels and provides the multiplexing and demultiplexing equipment required to demonstrate the ground implemented beam forming feature. The system provided will make it possible to demonstrate the performance of a desired user and ten interfering sources attempting to pass data through the multiple access system.

  17. Designing artificial enzymes from scratch: Experimental study and mesoscale simulation

    NASA Astrophysics Data System (ADS)

    Komarov, Pavel V.; Zaborina, Olga E.; Klimova, Tamara P.; Lozinsky, Vladimir I.; Khalatur, Pavel G.; Khokhlov, Alexey R.

    2016-09-01

    We present a new concept for designing biomimetic analogs of enzymatic proteins; these analogs are based on the synthetic protein-like copolymers. α-Chymotrypsin is used as a prototype of the artificial catalyst. Our experimental study shows that in the course of free radical copolymerization of hydrophobic and hydrophilic monomers the target globular nanostructures of a "core-shell" morphology appear in a selective solvent. Using a mesoscale computer simulation, we show that the protein-like globules can have a large number of catalytic centers located at the hydrophobic core/hydrophilic shell interface.

  18. Beam Dynamics Design and Simulation in Ion Linear Accelerators (

    SciTech Connect

    Ostroumov, Peter N.; Asseev, Vladislav N.; Mustapha, and Brahim

    2006-08-01

    Orginally, the ray tracing code TRACK has been developed to fulfill the many special requirements for the Rare Isotope Accelerator Facility known as RIA. Since no available beam-dynamics code met all the necessary requirements, modifications to the code TRACK were introduced to allow end-to-end (from the ion souce to the production target) simulations of the RIA machine, TRACK is a general beam-dynamics code and can be applied for the design, commissioning and operation of modern ion linear accelerators and beam transport systems.

  19. Integrated Simulation Design Challenges to Support TPS Repair Operations

    NASA Technical Reports Server (NTRS)

    Quiocho, Leslie J.; Crues, Edwin Z.; Huynh, An; Nguyen, Hung T.; MacLean, John

    2006-01-01

    )ntegrated Shuttle, SRMS, ISS (with active ACS) in the orbital environment, and (5) dual-arm SRMS/SSRMS dynamics topology. Integrated simulation V&V run suites were created and correlated to verification runs from subsystem simulations, in order to establish the validity of the results. This paper discusses the simulation design challenges encountered while developing simulation capabilities to mirror the ORM operations. The paper also describes the incremental build approach that was utilized, starting with the subsystem simulation elements and integration into increasing more complex simulations until the resulting ORM worksite dynamics simulation had been assembled. Furthermore, the paper presents an overall integrated simulation V&V methodology based upon a subsystem level testing, integrated comparisons, and phased checkout.

  20. RAS Mutations and Oncogenesis: Not all RAS Mutations are Created Equally

    PubMed Central

    Miller, Mark Steven; Miller, Lance D.

    2012-01-01

    Mutation in RAS proteins is one of the most common genetic alterations observed in human and experimentally induced rodent cancers. In vivo, oncogenic mutations have been shown to occur at exons 12, 13, and 61, resulting in any 1 of 19 possible point mutations in a given tumor for a specific RAS isoform. While some studies have suggested a possible role of different mutant alleles in determining tumor severity and phenotype, no general consensus has emerged on the oncogenicity of different mutant alleles in tumor formation and progression. Part of this may be due to a lack of a single, signature pathway that shows significant alterations between different mutations. Rather, it is likely that subtle differences in the activation, or lack thereof, of downstream effectors by different RAS mutant alleles may determine the eventual outcome in terms of tumor phenotype. This paper reviews our current understanding of the potential role of different RAS mutations on tumorigenesis, highlights studies in model cell culture and in vivo systems, and discusses the potential of expression array and computational network modeling to dissect out differences in activated RAS genes in conferring a transforming phenotype. PMID:22303394

  1. A novel solution for LED wall lamp design and simulation

    NASA Astrophysics Data System (ADS)

    Ge, Rui; Hong, Weibin; Li, Kuangqi; Liang, Pengxiang; Zhao, Fuli

    2014-11-01

    The model of the wall washer lamp and the practical illumination application have been established with a new design of the lens to meet the uniform illumination demand for wall washer lamp based on the Lambertian light sources. Our secondary optical design of freeform surface lens to LED wall washer lamp based on the conservation law of energy and Snell's law can improve the lighting effects as a uniform illumination. With the relationship between the surface of the lens and the surface of the target, a great number of discrete points of the freeform profile curve were obtained through the iterative method. After importing the data into our modeling program, the optical entity was obtained. Finally, to verify the feasibility of the algorithm, the model was simulated by specialized software, with both the LED Lambertian point source and LED panel source model.

  2. VISRAD, 3-D Target Design and Radiation Simulation Code

    NASA Astrophysics Data System (ADS)

    Golovkina, Viktoriya; Macfarlane, Joseph; Golovkin, Igor; Kulkarni, Subodh

    2014-10-01

    The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, LMJ, Z, and PLX. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e.g., that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. We will discuss recent improvements to the software package and plans for future developments.

  3. VISRAD, 3-D Target Design and Radiation Simulation Code

    NASA Astrophysics Data System (ADS)

    Li, Yingjie; Macfarlane, Joseph; Golovkin, Igor

    2015-11-01

    The 3-D view factor code VISRAD is widely used in designing HEDP experiments at major laser and pulsed-power facilities, including NIF, OMEGA, OMEGA-EP, ORION, LMJ, Z, and PLX. It simulates target designs by generating a 3-D grid of surface elements, utilizing a variety of 3-D primitives and surface removal algorithms, and can be used to compute the radiation flux throughout the surface element grid by computing element-to-element view factors and solving power balance equations. Target set-up and beam pointing are facilitated by allowing users to specify positions and angular orientations using a variety of coordinates systems (e.g., that of any laser beam, target component, or diagnostic port). Analytic modeling for laser beam spatial profiles for OMEGA DPPs and NIF CPPs is used to compute laser intensity profiles throughout the grid of surface elements. We will discuss recent improvements to the software package and plans for future developments.

  4. Numerical simulations supporting the process design of ring rolling processes

    NASA Astrophysics Data System (ADS)

    Jenkouk, V.; Hirt, G.; Seitz, J.

    2013-05-01

    In conventional Finite Element Analysis (FEA) of radial-axial ring rolling (RAR) the motions of all tools are usually defined prior to simulation in the preprocessing step. However, the real process holds up to 8 degrees of freedom (DOF) that are controlled by industrial control systems according to actual sensor values and preselected control strategies. Since the histories of the motions are unknown before the experiment and are dependent on sensor data, the conventional FEA cannot represent the process before experiment. In order to enable the usage of FEA in the process design stage, this approach integrates the industrially applied control algorithms of the real process including all relevant sensors and actuators into the FE model of ring rolling. Additionally, the process design of a novel process 'the axial profiling', in which a profiled roll is used for rolling axially profiled rings, is supported by FEA. Using this approach suitable control strategies can be tested in virtual environment before processing.

  5. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts.

    PubMed

    Irani, K; Xia, Y; Zweier, J L; Sollott, S J; Der, C J; Fearon, E R; Sundaresan, M; Finkel, T; Goldschmidt-Clermont, P J

    1997-03-14

    NIH 3T3 fibroblasts stably transformed with a constitutively active isoform of p21(Ras), H-RasV12 (v-H-Ras or EJ-Ras), produced large amounts of the reactive oxygen species superoxide (.O2-). .O2- production was suppressed by the expression of dominant negative isoforms of Ras or Rac1, as well as by treatment with a farnesyltransferase inhibitor or with diphenylene iodonium, a flavoprotein inhibitor. The mitogenic activity of cells expressing H-RasV12 was inhibited by treatment with the chemical antioxidant N-acetyl-L-cysteine. Mitogen-activated protein kinase (MAPK) activity was decreased and c-Jun N-terminal kinase (JNK) was not activated in H-RasV12-transformed cells. Thus, H-RasV12-induced transformation can lead to the production of .O2- through one or more pathways involving a flavoprotein and Rac1. The implication of a reactive oxygen species, probably .O2-, as a mediator of Ras-induced cell cycle progression independent of MAPK and JNK suggests a possible mechanism for the effects of antioxidants against Ras-induced cellular transformation.

  6. An innovative ski-boot: design, numerical simulations and testing.

    PubMed

    Corazza, Stefano; Cobelli, Claudio

    2005-09-01

    The present work is concerned with the design of an innovative ski-boot. In order to optimize ergonomics and biomechanical behavior of the ski-boot it is important to take into account the orientation of the leg with respect to the ground. The SGS system (Stance Geometry System) developed in this work allows the skier to adjust for posture in the frontal plane by rotating the sole of the boot about the antero-posterior axis (ski-boot is then locked in the desired position before skiing). A simplified model of the effect of ski-boot deformation on skiing behavior is used to evaluate the minimal stiffness the system must have. An experimental analysis on the ski slopes was carried out to provide ski-boot deformations and loading data in different skiing conditions, to be used in numerical simulations. Finite Elements Method (FEM) simulations were performed for optimal design of the joint between ski-boot and sole. The active loads and local ski-boot deformations during small- and large-radius turns were experimentally determined and used to validate a FEM model of the ski-boot. The model was used to optimize the design for maximum stiffness and to demonstrate the efficacy of virtual design supported by proper experimental data. Mean loads up to 164% body weight were measured on the outer ski during turning. The new SGS design system allows the adjustment of lateral stance before using the ski-boot, optimizing the ski-boot stiffness through FEM analysis. Innovative aspects of this work included not only the stance geometry system ski-boot but also the setup of a virtual design environment that was validated by experimental evidence. An entire dataset describing loads during skiing has been obtained. The optimized SGS ski-boot increases intrinsic knee stability due to proper adjustment of lateral stance, guaranteeing appropriate stiffness of the ski-boot system. Key PointsLoad acting during different phases of active skiing have been investigated in both qualitative

  7. An Innovative Ski-Boot: Design, Numerical Simulations and Testing

    PubMed Central

    Corazza, Stefano; Cobelli, Claudio

    2005-01-01

    The present work is concerned with the design of an innovative ski-boot. In order to optimize ergonomics and biomechanical behavior of the ski-boot it is important to take into account the orientation of the leg with respect to the ground. The SGS system (Stance Geometry System) developed in this work allows the skier to adjust for posture in the frontal plane by rotating the sole of the boot about the antero-posterior axis (ski-boot is then locked in the desired position before skiing). A simplified model of the effect of ski-boot deformation on skiing behavior is used to evaluate the minimal stiffness the system must have. An experimental analysis on the ski slopes was carried out to provide ski-boot deformations and loading data in different skiing conditions, to be used in numerical simulations. Finite Elements Method (FEM) simulations were performed for optimal design of the joint between ski-boot and sole. The active loads and local ski-boot deformations during small- and large-radius turns were experimentally determined and used to validate a FEM model of the ski-boot. The model was used to optimize the design for maximum stiffness and to demonstrate the efficacy of virtual design supported by proper experimental data. Mean loads up to 164% body weight were measured on the outer ski during turning. The new SGS design system allows the adjustment of lateral stance before using the ski-boot, optimizing the ski-boot stiffness through FEM analysis. Innovative aspects of this work included not only the stance geometry system ski-boot but also the setup of a virtual design environment that was validated by experimental evidence. An entire dataset describing loads during skiing has been obtained. The optimized SGS ski-boot increases intrinsic knee stability due to proper adjustment of lateral stance, guaranteeing appropriate stiffness of the ski-boot system. Key Points Load acting during different phases of active skiing have been investigated in both qualitative

  8. Regulation of Ras Proteins by Reactive Nitrogen Species†

    PubMed Central

    Davis, Michael F.; Vigil, Dom; Campbell, Sharon L.

    2012-01-01

    Ras GTPases have been a subject of intense investigation since the early-80’s, when single point mutations in Ras were shown to cause deregulated cell growth control. Subsequently, Ras was identified as the most prevalent oncogene found in human cancer. Ras proteins regulate a host of pathways involved in cell growth, differentiation, and apoptosis by cycling between inactive GDP-bound and active GTP-bound states. Regulation of Ras activity is controlled by cellular factors that alter guanine nucleotide cycling. Oncogenic mutations prevent protein regulatory factors from down-regulating Ras activity, thereby maintaining Ras in a chronically activated state. The central dogma in the field is that protein modulatory factors are the primary regulators of Ras activity. Since the mid-90’s, however, evidence has accumulated that small molecule reactive nitrogen species (RNS) can also influence Ras guanine nucleotide cycling. Herein, we review the basic chemistry behind RNS formation and discuss the mechanism through which various RNS enhance nucleotide exchange in Ras proteins. In addition, we present studies that demonstrate the physiological relevance of RNS-mediated Ras activation within the context of immune system function, brain function, and cancer development. We also highlight future directions and experimental methods that may enhance our ability to detect RNS-mediated activation in cell cultures and in vivo. The development of such methods may ultimately pave new directions for detecting and elucidating how Ras proteins are regulated by redox species, as well as for targeting redox-activated Ras in cancer and other disease states. PMID:21616138

  9. Simulation of Wind Profile Perturbations for Launch Vehicle Design

    NASA Technical Reports Server (NTRS)

    Adelfang, S. I.

    2004-01-01

    Ideally, a statistically representative sample of measured high-resolution wind profiles with wavelengths as small as tens of meters is required in design studies to establish aerodynamic load indicator dispersions and vehicle control system capability. At most potential launch sites, high- resolution wind profiles may not exist. Representative samples of Rawinsonde wind profiles to altitudes of 30 km are more likely to be available from the extensive network of measurement sites established for routine sampling in support of weather observing and forecasting activity. Such a sample, large enough to be statistically representative of relatively large wavelength perturbations, would be inadequate for launch vehicle design assessments because the Rawinsonde system accurately measures wind perturbations with wavelengths no smaller than 2000 m (1000 m altitude increment). The Kennedy Space Center (KSC) Jimsphere wind profiles (150/month and seasonal 2 and 3.5-hr pairs) are the only adequate samples of high resolution profiles approx. 150 to 300 m effective resolution, but over-sampled at 25 m intervals) that have been used extensively for launch vehicle design assessments. Therefore, a simulation process has been developed for enhancement of measured low-resolution Rawinsonde profiles that would be applicable in preliminary launch vehicle design studies at launch sites other than KSC.

  10. Integrating Multibody Simulation and CFD: toward Complex Multidisciplinary Design Optimization

    NASA Astrophysics Data System (ADS)

    Pieri, Stefano; Poloni, Carlo; Mühlmeier, Martin

    This paper describes the use of integrated multidisciplinary analysis and optimization of a race car model on a predefined circuit. The objective is the definition of the most efficient geometric configuration that can guarantee the lowest lap time. In order to carry out this study it has been necessary to interface the design optimization software modeFRONTIER with the following softwares: CATIA v5, a three dimensional CAD software, used for the definition of the parametric geometry; A.D.A.M.S./Motorsport, a multi-body dynamic simulation software; IcemCFD, a mesh generator, for the automatic generation of the CFD grid; CFX, a Navier-Stokes code, for the fluid-dynamic forces prediction. The process integration gives the possibility to compute, for each geometrical configuration, a set of aerodynamic coefficients that are then used in the multiboby simulation for the computation of the lap time. Finally an automatic optimization procedure is started and the lap-time minimized. The whole process is executed on a Linux cluster running CFD simulations in parallel.

  11. The LHCb Simulation Application, Gauss: Design, Evolution and Experience

    NASA Astrophysics Data System (ADS)

    Clemencic, M.; Corti, G.; Easo, S.; Jones, C. R.; Miglioranzi, S.; Pappagallo, M.; Robbe, P.; LHCb Collaboration

    2011-12-01

    The LHCb simulation application, Gauss, is based on the Gaudi framework and on experiment basic components such as the Event Model and Detector Description. Gauss also depends on external libraries for the generation of the primary events (PYTHIA 6, EvtGen, etc.) and on GEANT4 for particle transport in the experimental setup. The application supports the production of different types of events from minimum bias to B physics signals and particle guns. It is used for purely generator-level studies as well as full simulations. Gauss is used both directly by users and in massive central productions on the grid. The design and implementation of the application and its evolution due to evolving requirements will be described as in the case of the recently adopted Python-based configuration or the possibility of taking into account detectors conditions via a Simulation Conditions database. The challenge of supporting at the same time the flexibililty needed for the different tasks for which it is used, from evaluation of physics reach to background modeling, together with the stability and reliabilty of the code will also be described.

  12. A design of camera simulator for photoelectric image acquisition system

    NASA Astrophysics Data System (ADS)

    Cai, Guanghui; Liu, Wen; Zhang, Xin

    2015-02-01

    In the process of developing the photoelectric image acquisition equipment, it needs to verify the function and performance. In order to make the photoelectric device recall the image data formerly in the process of debugging and testing, a design scheme of the camera simulator is presented. In this system, with FPGA as the control core, the image data is saved in NAND flash trough USB2.0 bus. Due to the access rate of the NAND, flash is too slow to meet the requirement of the sytsem, to fix the problem, the pipeline technique and the High-Band-Buses technique are applied in the design to improve the storage rate. It reads image data out from flash in the control logic of FPGA and output separately from three different interface of Camera Link, LVDS and PAL, which can provide image data for photoelectric image acquisition equipment's debugging and algorithm validation. However, because the standard of PAL image resolution is 720*576, the resolution is different between PAL image and input image, so the image can be output after the resolution conversion. The experimental results demonstrate that the camera simulator outputs three format image sequence correctly, which can be captured and displayed by frame gather. And the three-format image data can meet test requirements of the most equipment, shorten debugging time and improve the test efficiency.

  13. Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies

    PubMed Central

    Chen, Zhao; Liu, Feiyang; Zhang, Jianming; Sattler, Martin; Nelson, Erik; Cowens, Kristen; Christie, Amanda L.; Mitsiades, Constantine; Wong, Kwok-Kin; Liu, Qingsong; Gray, Nathanael; Griffin, James D.

    2015-01-01

    Direct targeting of RAS, which is frequently mutated, has proven to be challenging, and inhibition of individual downstream RAS mediators has resulted in limited clinical efficacy. We designed a chemical screen to identify compounds capable of potentiating mTOR inhibition in mutant RAS-positive leukemia, and identified a Wee1 inhibitor. Synergy was observed in both mutant NRAS- and mutant KRAS-positive acute myelogenous leukemia (AML) cell lines and primary patient samples. The observed synergy enhanced dephosphorylation of AKT, 4E-BP1 and S6K, and correlated with increased apoptosis. The specificity of Wee1 as the target of MK-1775 was validated by Wee1 knockdown (KD), as well as partial reversal of drug combination-induced apoptosis by a CDK1 inhibitor. Importantly, we also extended our findings to other mutant RAS-expressing malignancies, including mutant NRAS-positive melanoma, and mutant KRAS-positive colorectal cancer, pancreatic cancer, and lung cancer. We observed favorable responses with combined Wee1/mTOR inhibition in human cancer cell lines from multiple malignancies, and inhibition of tumor growth in in vivo models of mutant KRAS lung cancer and leukemia. The present study introduces for the first time Wee1 inhibition combined with mTOR inhibition as a novel therapeutic strategy to the selective treatment of mutant RAS-positive leukemia and other mutant RAS-expressing malignancies. PMID:24791855

  14. TLN-4601, a novel anticancer agent, inhibits Ras signaling post Ras prenylation and before MEK activation.

    PubMed

    Boufaied, Nadia; Wioland, My-Anh; Falardeau, Pierre; Gourdeau, Henriette

    2010-06-01

    TLN-4601 is a structurally novel farnesylated dibenzodiazepinone discovered through DECIPHER, Thallion's proprietary drug discovery platform. The compound was shown to have a broad cytotoxic activity (low micromol/l) when tested in the NCI 60 tumor cell line panel and has shown in-vivo antitumor activity in several xenograft models. Related to its farnesylated moiety, the effect of TLN-4601 on Ras mitogen-activated protein kinase signaling was assessed. Downstream Ras signaling events, Raf-1, MEK, and ERK1/2 phosphorylation in MCF7 cells were evaluated by western blot analysis. TLN-4601 prevented epidermal growth factor-induced phosphorylation of Raf-1, MEK, and ERK1/2. This effect was time-dependent and dose-dependent with complete inhibition of protein phosphorylation within 4-6 h at 10 micromol/l. The inhibition of Ras signaling was not mediated by the inhibition of protein prenylation, documented by the lack of effect TLN-4601 on the prenylation of HDJ2 (specific substrate of farnesyltransferase), RAP1A (specific substrate of geranylgeranyl transferase-1), or Ras. As TLN-4601 did not inhibit EGFR, Raf-1, MEK or ERK1/2 kinase activities, the inhibitory effect of TLN-4601 on Ras signaling is not mediated by direct kinase inhibition. Using an Elk-1 trans-activation reporter assay, we found that TLN-4601 inhibits the MEK/ERK pathway at the level of Raf-1. Interestingly, TLN-4601 induces Raf-1 proteasomal-dependent degradation. These data indicate that TLN-4601 may inhibit the Ras-mitogen-activated protein kinase-signaling pathway by depleting the Raf-1 protein.

  15. Design of the biosonar simulator for dolphin's clicks waveform reproduction

    NASA Astrophysics Data System (ADS)

    Ishii, Ken; Akamatsu, Tomonari; Hatakeyama, Yoshimi

    1992-03-01

    The emitted clicks of Dall's porpoises consist of a pulse train of burst signals with an ultrasonic carrier frequency. The authors have designed a biosonar simulator to reproduce the waveforms associated with a dolphin's clicks underwater. The total reproduction system consists of a click signal acquisition block, a waveform analysis block, a memory unit, a click simulator, and a underwater, ultrasonic wave transmitter. In operation, data stored in an EPROM (Erasable Programmable Read Only Memory) are read out sequentially by a fast clock and converted to analog output signals. Then an ultrasonic power amplifier reproduces these signals through a transmitter. The click signal replaying block is referred to as the BSS (Biosonar Simulator). This is what simulates the clicks. The details of the BSS are described in this report. A unit waveform is defined. The waveform is divided into a burst period and a waiting period. Clicks are a sequence based on a unit waveform, and digital data are sequentially read out from an EPROM of waveform data. The basic parameters of the BSS are as follows: (1) reading clock, 100 ns to 25.4 microseconds; (2) number of reading clock, 34 to 1024 times; (3) counter clock in a waiting period, 100 ns to 25.4 microseconds; (4) number of counter clock, zero to 16,777,215 times; (5) number of burst/waiting repetition cycle, one to 128 times; and (6) transmission level adjustment by a programmable attenuator, zero to 86.5 dB. These basic functions enable the BSS to replay clicks of Dall's porpoise precisely.

  16. Overexpressed galectin-3 in pancreatic cancer induces cell proliferation and invasion by binding Ras and activating Ras signaling.

    PubMed

    Song, Shumei; Ji, Baoan; Ramachandran, Vijaya; Wang, Huamin; Hafley, Margarete; Logsdon, Craig; Bresalier, Robert S

    2012-01-01

    Pancreatic cancer (PDAC) is a lethal disease with a five-year survival of 3-5%. Mutations in K-Ras are found in nearly all cases, but K-Ras mutations alone are not sufficient for the development of PDAC. Additional factors contribute to activation of Ras signaling and lead to tumor formation. Galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in PDAC. We therefore investigated the functional role of Gal-3 in pancreatic cancer progression and its relationship to Ras signaling. Expression of Gal-3 was determined by immunohistochemistry, Q-PCR and immunoblot. Functional studies were performed using pancreatic cell lines genetically engineered to express high or low levels of Gal-3. Ras activity was examined by Raf pull-down assays. Co-immunoprecipitation and immunofluorescence were used to assess protein-protein interactions. In this study, we demonstrate that Gal-3 was highly up-regulated in human tumors and in a mutant K-Ras mouse model of PDAC. Down-regulation of Gal-3 by lentivirus shRNA decreased PDAC cell proliferation and invasion in vitro and reduced tumor volume and size in an orthotopic mouse model. Gal-3 bound Ras and maintained Ras activity; down-regulation of Gal-3 decreased Ras activity as well as Ras down-stream signaling including phosphorylation of ERK and AKT and Ral A activity. Transfection of Gal-3 cDNA into PDAC cells with low-level Gal-3 augmented Ras activity and its down-stream signaling. These results suggest that Gal-3 contributes to pancreatic cancer progression, in part, by binding Ras and activating Ras signaling. Gal-3 may therefore be a potential novel target for this deadly disease. PMID:22900040

  17. Application of Simulated Annealing and Related Algorithms to TWTA Design

    NASA Technical Reports Server (NTRS)

    Radke, Eric M.

    2004-01-01

    Simulated Annealing (SA) is a stochastic optimization algorithm used to search for global minima in complex design surfaces where exhaustive searches are not computationally feasible. The algorithm is derived by simulating the annealing process, whereby a solid is heated to a liquid state and then cooled slowly to reach thermodynamic equilibrium at each temperature. The idea is that atoms in the solid continually bond and re-bond at various quantum energy levels, and with sufficient cooling time they will rearrange at the minimum energy state to form a perfect crystal. The distribution of energy levels is given by the Boltzmann distribution: as temperature drops, the probability of the presence of high-energy bonds decreases. In searching for an optimal design, local minima and discontinuities are often present in a design surface. SA presents a distinct advantage over other optimization algorithms in its ability to escape from these local minima. Just as high-energy atomic configurations are visited in the actual annealing process in order to eventually reach the minimum energy state, in SA highly non-optimal configurations are visited in order to find otherwise inaccessible global minima. The SA algorithm produces a Markov chain of points in the design space at each temperature, with a monotonically decreasing temperature. A random point is started upon, and the objective function is evaluated at that point. A stochastic perturbation is then made to the parameters of the point to arrive at a proposed new point in the design space, at which the objection function is evaluated as well. If the change in objective function values (Delta)E is negative, the proposed new point is accepted. If (Delta)E is positive, the proposed new point is accepted according to the Metropolis criterion: rho((Delta)f) = exp((-Delta)E/T), where T is the temperature for the current Markov chain. The process then repeats for the remainder of the Markov chain, after which the temperature is

  18. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis.

    PubMed

    Lazarov, Mirella; Kubo, Yoshiaki; Cai, Ti; Dajee, Maya; Tarutani, Masahito; Lin, Qun; Fang, Min; Tao, Shiying; Green, Cheryl L; Khavari, Paul A

    2002-10-01

    Ras acts with other proteins to induce neoplasia. By itself, however, strong Ras signaling can suppress proliferation of normal cells. In primary epidermal cells, we found that oncogenic Ras transiently decreases cyclin-dependent kinase (CDK) 4 expression in association with cell cycle arrest in G1 phase. CDK4 co-expression circumvents Ras growth suppression and induces invasive human neoplasia resembling squamous cell carcinoma. Tumorigenesis is dependent on CDK4 kinase function, with cyclin D1 required but not sufficient for this process. In facilitating escape from G1 growth restraints, Ras and CDK4 alter the composition of cyclin D and cyclin E complexes and promote resistance to growth inhibition by INK4 cyclin-dependent kinase inhibitors. These data identify a new role for oncogenic Ras in CDK4 regulation and highlight the functional importance of CDK4 suppression in preventing uncontrolled growth.

  19. Simulation design of a wearable see-through retinal projector.

    PubMed

    Sun, Wen-Shing; Tien, Chuen-Lin; Chiang, Yen-Chen; Pan, Jui-Wen

    2015-05-10

    This study proposes a new simulation design for a wearable see-through retinal projector combined with a compact camera. The see-through retinal projector is composed of an illumination system and eyepiece system. In this eyeglass-mounted design, all the information is projected directly into the user's eyes using a see-through retinal projector. The retinal projector forms a 20 in. (50.8 cm) upright virtual image located 2 m in front of the human eye, and the illumination system provides uniform illumination for liquid crystal on silicon (LCoS) panels. Moreover, an RGB LED array is used as the light source to generate color images with color sequences. The compact camera has a lens with an aperture of F/2.8, a half field-of-view (FOV) of 30°, and 2 million pixels. This optical system design with the combination of a see-through retinal projector and a compact camera has a volume of about 5.83 cm(3) and a weight of 6.02 g. PMID:25967506

  20. Dimerize RACK1 upon transformation with oncogenic ras

    SciTech Connect

    Chu, L.-Y.; Chen, Y.-H.; Chuang, N.-N. . E-mail: zonnc@sinica.edu.tw

    2005-05-06

    From our previous studies, we learned that syndecan-2/p120-GAP complex provided docking site for Src to prosecute tyrosine kinase activity upon transformation with oncogenic ras. And, RACK1 protein was reactive with syndecan-2 to keep Src inactivated, but not when Ras was overexpressed. In the present study, we characterized the reaction between RACK1 protein and Ras. RACK1 was isolated from BALB/3T3 cells transfected with plasmids pcDNA3.1-[S-ras(Q{sub 61}K)] of shrimp Penaeus japonicus and RACK1 was revealed to react with GTP-K{sub B}-Ras(Q{sub 61}K), not GDP-K{sub B}-Ras(Q{sub 61}K). This selective interaction between RACK1 and GTP-K{sub B}-Ras(Q{sub 61}K) was further confirmed with RACK1 of human placenta and mouse RACK1-encoded fusion protein. We found that RACK1 was dimerized upon reaction with GTP-K{sub B}-Ras(Q{sub 61}K), as well as with 14-3-3{beta} and geranylgeranyl pyrophosphate, as revealed by phosphorylation with Src tyrosine kinase. We reported the complex of RACK1/GTP-K{sub B}-Ras(Q{sub 61}K) reacted selectively with p120-GAP. This interaction was sufficient to dissemble RACK1 into monomers, a preferred form to compete for the binding of syndecan-2. These data indicate that the reaction of GTP-K{sub B}-Ras(Q{sub 61}K) with RACK1 in dimers may operate a mechanism to deplete RACK1 from reaction with syndecan-2 upon transformation by oncogenic ras and the RACK1/GTP-Ras complex may provide a route to react with p120-GAP and recycle monomeric RACK1 to syndecan-2.

  1. Complex effects of Ras proto-oncogenes in tumorigenesis.

    PubMed

    Diaz, Roberto; Lopez-Barcons, Lluis; Ahn, Daniel; Garcia-Espana, Antonio; Yoon, Andrew; Matthews, Jeremy; Mangues, Ramon; Perez-Soler, Roman; Pellicer, Angel

    2004-04-01

    Ras proteins have been found mutated in about one-third of human tumors. In vitro, Ras has been shown to regulate distinct and contradictory effects, such as cellular proliferation and apoptosis. Nonetheless, the effects that the wild-type protein elicits in tumorigenesis are poorly understood. Depending on the type of tissue, Ras proto-oncogenes appear to either promote or inhibit the tumor phenotype. In this report, we treated wild-type and N-ras knockout mice with 3-methylcholanthrene (MCA) to induce fibrosarcomas and found that MCA is more carcinogenic in wild-type mice than in knockout mice. After injecting different doses of a tumorigenic cell line, the wild-type mice exhibited a shorter latency of tumor development than the knockouts, indicating that there are N-ras-dependent differences in the stromal cells. Likewise, we have analyzed B-cell lymphomas induced by either N-methylnitrosourea or by the N-ras oncogene in mice that over-express the N-ras proto-oncogene and found that the over-expression of wild-type N-ras is able to increase the incidence of these lymphomas. Considered together, our results indicate that Ras proto-oncogenes can enhance or inhibit the malignant phenotype in vivo in different systems.

  2. Activation of ras oncogenes preceding the onset of neoplasia

    SciTech Connect

    Kumar, R.; Barbacid, M. ); Sukumar, S. )

    1990-06-01

    The identification of ras oncogenes in human and animal cancers including precancerous lesions indicates that these genes participate in the early stages of neoplastic development. Yet, these observations do not define the timing of ras oncogene activation in the multistep process of carcinogenesis. To ascertain the timing of ras oncogene activation, an animal model system was devised that involves the induction of mammary carcinomas in rats exposed at birth to the carcinogen nitrosomethylurea. High-resolution restriction fragment length polymorphism analysis of polymerase chain reaction-amplified ras sequences revealed the presence of both H-ras and K-ras oncogenes in normal mammary glands 2 weeks after carcinogen treatment and at least 2 months before the onset of neoplasia. These ras oncogenes can remain latent within the mammary gland until exposure to estrogens, demonstrating that activation of ras oncogenes can precede the onset of neoplasia and suggesting that normal physiological proliferative processes such as estrogen-induced mammary gland development may lead to neoplasia if the targeted cells harbor latent ras oncogenes.

  3. Activation of a human c-K-ras oncogene.

    PubMed Central

    Yamamoto, F; Perucho, M

    1984-01-01

    The human lung carcinomas PR310 and PR371 contain activated c-K-ras oncogenes. The oncogene of PR371 was found to present a mutation at codon 12 of the first coding exon which substitutes cysteine for glycine in the encoded p21 protein. We report here that the transforming gene of PR310 tumor contains a mutation in the second coding exon. An A----T transversion at codon 61 results in the incorporation of histidine instead of glutamine in the c-K-ras gene product. By constructing c-K-ras/c-H-ras chimeric genes we show that this point mutation is sufficient to confer transforming potential to ras genes, and that a hybrid ras gene coding for a protein mutant at both codons 12 and 61 is also capable of transforming NIH3T3 cells. The relative transforming potency of p21 proteins encoded by ras genes mutant at codons 12, 61 or both has been analyzed. Our studies also show that the coding exons of ras genes, including the fourth, can be interchanged and the chimeric p21 ras proteins retain their oncogenic ability in normal rodent established cell lines. PMID:6096811

  4. Colossal Tooling Design: 3D Simulation for Ergonomic Analysis

    NASA Technical Reports Server (NTRS)

    Hunter, Steve L.; Dischinger, Charles; Thomas, Robert E.; Babai, Majid

    2003-01-01

    The application of high-level 3D simulation software to the design phase of colossal mandrel tooling for composite aerospace fuel tanks was accomplished to discover and resolve safety and human engineering problems. The analyses were conducted to determine safety, ergonomic and human engineering aspects of the disassembly process of the fuel tank composite shell mandrel. Three-dimensional graphics high-level software, incorporating various ergonomic analysis algorithms, was utilized to determine if the process was within safety and health boundaries for the workers carrying out these tasks. In addition, the graphical software was extremely helpful in the identification of material handling equipment and devices for the mandrel tooling assembly/disassembly process.

  5. Simulation Assisted Risk Assessment Applied to Launch Vehicle Conceptual Design

    NASA Technical Reports Server (NTRS)

    Mathias, Donovan L.; Go, Susie; Gee, Ken; Lawrence, Scott

    2008-01-01

    A simulation-based risk assessment approach is presented and is applied to the analysis of abort during the ascent phase of a space exploration mission. The approach utilizes groupings of launch vehicle failures, referred to as failure bins, which are mapped to corresponding failure environments. Physical models are used to characterize the failure environments in terms of the risk due to blast overpressure, resulting debris field, and the thermal radiation due to a fireball. The resulting risk to the crew is dynamically modeled by combining the likelihood of each failure, the severity of the failure environments as a function of initiator and time of the failure, the robustness of the crew module, and the warning time available due to early detection. The approach is shown to support the launch vehicle design process by characterizing the risk drivers and identifying regions where failure detection would significantly reduce the risk to the crew.

  6. Designing Crop Simulation Web Service with Service Oriented Architecture Principle

    NASA Astrophysics Data System (ADS)

    Chinnachodteeranun, R.; Hung, N. D.; Honda, K.

    2015-12-01

    Crop simulation models are efficient tools for simulating crop growth processes and yield. Running crop models requires data from various sources as well as time-consuming data processing, such as data quality checking and data formatting, before those data can be inputted to the model. It makes the use of crop modeling limited only to crop modelers. We aim to make running crop models convenient for various users so that the utilization of crop models will be expanded, which will directly improve agricultural applications. As the first step, we had developed a prototype that runs DSSAT on Web called as Tomorrow's Rice (v. 1). It predicts rice yields based on a planting date, rice's variety and soil characteristics using DSSAT crop model. A user only needs to select a planting location on the Web GUI then the system queried historical weather data from available sources and expected yield is returned. Currently, we are working on weather data connection via Sensor Observation Service (SOS) interface defined by Open Geospatial Consortium (OGC). Weather data can be automatically connected to a weather generator for generating weather scenarios for running the crop model. In order to expand these services further, we are designing a web service framework consisting of layers of web services to support compositions and executions for running crop simulations. This framework allows a third party application to call and cascade each service as it needs for data preparation and running DSSAT model using a dynamic web service mechanism. The framework has a module to manage data format conversion, which means users do not need to spend their time curating the data inputs. Dynamic linking of data sources and services are implemented using the Service Component Architecture (SCA). This agriculture web service platform demonstrates interoperability of weather data using SOS interface, convenient connections between weather data sources and weather generator, and connecting

  7. Conceptual Design and Simulation of Forced Convection Micro Heat Spreaders

    NASA Astrophysics Data System (ADS)

    Sert, Cuneyt; Warburton, Tim; Beskok, Ali

    1999-11-01

    The micro heat spreader (MHS) is a closed loop single-phase microfluidic system for efficient dissipation of large, concentrated heat loads. The MHS connects two flow expansion chambers through a micro-channel. The bottom surfaces of the expansion chambers consist of electrostatically actuated micro-membranes. A continuous pumping action for the coolant fluid is generated by driving the membranes with a phase difference of π. Heat generated by the source located just above the micro-channel is rapidly conducted to the fluid due to the small micro-channel height. While the hot fluid is pumped towards the exit of the micro-channel, sudden expansion of the geometry in to the mixing chamber promotes flow separation and mixing of the exiting hot fluid with the colder fluid in the chamber. The pumping direction then reverses, and the procedure is repeated cyclically. The concept testing of the MHS is obtained by an h/p finite element simulation package Nektar, based on an arbitrary Lagrangian Eulerian formulation for solution of the Navier-Stokes and the heat transport equations. The simulations performed for water at Re=6 indicated a thermal energy removal rate of 60 W/cm^2, with a maximum temperature difference of 10 K on the MHS surface. This heat flux is an order of magnitude higher than that dissipated by the micro-heat-pipes used in electronic cooling. The proposed microfluidic design also allows closed-loop control strategies for efficient dissipation of time varying thermal loads.

  8. Designing a prosthesis to simulate the elastic properties of skin.

    PubMed

    Bellamy, K E; Waters, M G J

    2005-01-01

    The materials which are currently used to make maxillofacial prostheses are far from ideal and require considerable improvement with respect to their ability to mimic the properties of skin. To this aim, a novel three-layered maxillofacial prosthesis has been designed consisting of a silicone rubber base layer, an inner gel layer and an outer polymeric coating (to simulate the elastic properties of skin). The aim of the work in this study was to develop the inner silicone gel layer which displays similar properties to facial skin. Through the use of unique linear extensometry testing, in vivo measurements for the Area under the Curve (AUC), Hysteresis (viscoelastic behaviour), Fmax (maximum force), F30 and F60 (force after 30 and 60 seconds) were obtained from the facial skin of 15 volunteers. The results were used as a basis for developing silicone gel formulations for the inner layer, to closely resemble those of facial skin. Gels were made by the addition of both low and high molecular weight unreactive silicone fluids and were further tested for compression, water absorption and dehydration. Testing showed that a gel has been produced that closely simulates the elastic properties of skin when bonded to a base silicone rubber layer. Further testing will need to deduce whether these properties will be affected by the addition of the outer polymeric layer.

  9. Variational data assimilation system "INM RAS - Black Sea"

    NASA Astrophysics Data System (ADS)

    Parmuzin, Eugene; Agoshkov, Valery; Assovskiy, Maksim; Giniatulin, Sergey; Zakharova, Natalia; Kuimov, Grigory; Fomin, Vladimir

    2013-04-01

    Development of Informational-Computational Systems (ICS) for Data Assimilation Procedures is one of multidisciplinary problems. To study and solve these problems one needs to apply modern results from different disciplines and recent developments in: mathematical modeling; theory of adjoint equations and optimal control; inverse problems; numerical methods theory; numerical algebra and scientific computing. The problems discussed above are studied in the Institute of Numerical Mathematics of the Russian Academy of Science (INM RAS) in ICS for Personal Computers (PC). Special problems and questions arise while effective ICS versions for PC are being developed. These problems and questions can be solved with applying modern methods of numerical mathematics and by solving "parallelism problem" using OpenMP technology and special linear algebra packages. In this work the results on the ICS development for PC-ICS "INM RAS - Black Sea" are presented. In the work the following problems and questions are discussed: practical problems that can be studied by ICS; parallelism problems and their solutions with applying of OpenMP technology and the linear algebra packages used in ICS "INM - Black Sea"; Interface of ICS. The results of ICS "INM RAS - Black Sea" testing are presented. Efficiency of technologies and methods applied are discussed. The work was supported by RFBR, grants No. 13-01-00753, 13-05-00715 and by The Ministry of education and science of Russian Federation, project 8291, project 11.519.11.1005 References: [1] V.I. Agoshkov, M.V. Assovskii, S.A. Lebedev, Numerical simulation of Black Sea hydrothermodynamics taking into account tide-forming forces. Russ. J. Numer. Anal. Math. Modelling (2012) 27, No.1, 5-31 [2] E.I. Parmuzin, V.I. Agoshkov, Numerical solution of the variational assimilation problem for sea surface temperature in the model of the Black Sea dynamics. Russ. J. Numer. Anal. Math. Modelling (2012) 27, No.1, 69-94 [3] V.B. Zalesny, N.A. Diansky, V

  10. The IAA RAS Correlator First Results

    NASA Technical Reports Server (NTRS)

    Surkis, Igor; Melnikov, Alexey; Shantyr, Violet; Zimovsky, Vladimir

    2010-01-01

    In 2009 the national Russian VLBI observations were processed by the new correlator ARC (Astrometric Radiointerferometric Correlator). The ARC is a VSI-H correlator and equipped with Mark 5B playback terminals. During 2009 ARC was used to process a series of VLBI sessions, observed on stations Svetloe, Zelenchukskaya, and Badary. NGS files were formed, and EOP parameters were obtained by IAA RAS Analysis Center. The accuracies of the pole coordinates and UT1-UTC were 1-2 mas and 0.07-0.1 ms, respectively.

  11. Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation.

    PubMed

    Winter, Jon J G; Anderson, Malcolm; Blades, Kevin; Brassington, Claire; Breeze, Alexander L; Chresta, Christine; Embrey, Kevin; Fairley, Gary; Faulder, Paul; Finlay, M Raymond V; Kettle, Jason G; Nowak, Thorsten; Overman, Ross; Patel, S Joe; Perkins, Paula; Spadola, Loredana; Tart, Jonathan; Tucker, Julie A; Wrigley, Gail

    2015-03-12

    Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPase-activating protein-catalyzed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilizing or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilization hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf and is effective at inhibiting the exchange of labeled GDP in both mutant (G12C and G12V) and wild type Ras.

  12. Performance of McRAS-AC in the GEOS-5 AGCM: aerosol-cloud-microphysics, precipitation, cloud radiative effects, and circulation

    NASA Astrophysics Data System (ADS)

    Sud, Y. C.; Lee, D.; Oreopoulos, L.; Barahona, D.; Nenes, A.; Suarez, M. J.

    2013-01-01

    A revised version of the Microphysics of clouds with Relaxed Arakawa-Schubert and Aerosol-Cloud interaction scheme (McRAS-AC) including, among others, a new ice nucleation parameterization, is implemented in the GEOS-5 AGCM. Various fields from a 10-yr-long integration of the AGCM with McRAS-AC are compared with their counterparts from an integration of the baseline GEOS-5 AGCM, as well as satellite observations. Generally McRAS-AC simulations have smaller biases in cloud fields and cloud radiative effects over most of the regions of the Earth than the baseline GEOS-5 AGCM. Two systematic biases are identified in the McRAS-AC runs: one is underestimation of cloud particle numbers around 40° S-60° S, and one is overestimate of cloud water path during the Northern Hemisphere summer over the Gulf Stream and North Pacific. Sensitivity tests show that these biases potentially originate from biases in the aerosol input. The first bias is largely eliminated in a test run using 50% smaller radius of sea-salt aerosol particles, while the second bias is substantially reduced when interactive aerosol chemistry is turned on. The main weakness of McRAS-AC is the dearth of low-level marine stratus clouds, a probable outcome of lack of explicit dry-convection in the cloud scheme. Nevertheless, McRAS-AC largely simulates realistic clouds and their optical properties that can be improved further with better aerosol input. An assessment using the COSP simulator in a 1-yr integration provides additional perspectives for understanding cloud optical property differences between the baseline and McRAS-AC simulations and biases against satellite data. Overall, McRAS-AC physically couples aerosols, the microphysics and macrophysics of clouds, and their radiative effects and thereby has better potential to be a valuable tool for climate modeling research.

  13. Design and simulation of microspectrometer based on torsional MEMS grating

    NASA Astrophysics Data System (ADS)

    Yan, Bin; Yuan, Weizheng; Sun, Ruikang; Qiao, Dayong; Yu, Yiting; Li, Taiping

    2010-10-01

    Micro-opto-electro-mechanical systems (MOEMS) has prominent advantages over conventional optical devices, such as smaller, lighter, more stable, lower cost and power consumption. It has been widely applied in the last few years. This paper presents a micro spectrometer based on torsional MEMS grating with micromachining process. As a diffractive component in the micro spectrometer, the torsional MEMS grating is actuated by electrostatic force to scan the spectrum. In contrast to common linear detector arrays with stationary diffraction grating and non-fixed grating rotated by stepper motor to scan spectrum used in most micro spectrometer, MEMS-based spectrometer is dynamically controllable, and has no mechanical moving parts with small size. ZEMAX is used for design, optimization, and simulation analysis of the micro spectrometer with multi-configurations in the cross Czerny-Turner optical system. The results indicate that torsional MEMS grating operates at a torsion angle of +/-3 degree, the spectrometer can scan spectral range of 800-1600nm in NIR (near infrared), spectral resolution is around 10 nm, and the whole spectrometer has a volume of 80mm×55mm×30mm. The study provides an initial theoretical foundation for the further development and design.

  14. Isochronous (CW) Non-Scaling FFAGs: Design and Simulation

    NASA Astrophysics Data System (ADS)

    Johnstone, C.; Berz, M.; Makino, K.; Snopok, P.

    2010-11-01

    The drive for higher beam power, high duty cycle, and reliable beams at reasonable cost has focused international attention and design effort on fixed field accelerators, notably Fixed-Field Alternating Gradient accelerators (FFAGs). High-intensity GeV proton drivers encounter duty cycle and space-charge limits in the synchrotron and machine size concerns in the weaker-focusing cyclotrons. A 10-20 MW proton driver is challenging, if even technically feasible, with conventional accelerators—with the possible exception of a SRF linac, which has a large associated cost and footprint. Recently, the concept of isochronous orbits has been explored and developed for nonscaling FFAGs using powerful new methodologies in FFAG accelerator design and simulation. The property of isochronous orbits enables the simplicity of fixed RF and, by tailoring a nonlinear radial field profile, the FFAG can remain isochronous beyond the energy reach of cyclotrons, well into the relativistic regime. With isochronous orbits, the machine proposed here has the high average current advantage and duty cycle of the cyclotron in combination with the strong focusing, smaller losses, and energy variability that are more typical of the synchrotron. This paper reports on these new advances in FFAG accelerator technology and presents advanced modeling tools for fixed-field accelerators unique to the code COSY INFINITY.

  15. K-Ras promotes the non-small lung cancer cells survival by cooperating with sirtuin 1 and p27 under ROS stimulation.

    PubMed

    Cheng, Dezhi; Zhao, Liang; Xu, Yunsheng; Ou, Rongying; Li, Gang; Yang, Han; Li, Wenfeng

    2015-09-01

    Cigarette smoking might lead to lung cancer. However, the related signaling pathways at molecular level remained unknown until now. In this study, we studied the signaling processes associated between tobacco exposure and lung cancer. First, we detected and validated pathway-specific gene expression at bronchial epithelium. These proteins reflected the activation of signaling pathways relevant to tobacco exposure, including ATM, BCL2, GPX1, K-Ras, IKBKB, and SIRT1. Tobacco smoking was simulated via reactive oxygen species (ROS) pathway. ROS not only arrested cell cycle at G1/S stage but also increased expressions of Sirt1 and p27. Further studies showed that the expression of p27 was dependent on ERK1/2 activation, and p27 itself could halt cell cycle by inhibiting the activation of CDKs. Moreover, activation of K-Ras, the key regulator of Ras/ERK pathway, was tightly regulated by enzyme activity of Sirt1. Deacetylation of K-Ras by Sirt1 increased the transformation of Ras-GTP to Ras-GDP, promoting the activation of downstream of ERK1/2. In reverse, Ras/ERK pathway could also regulate Sirt1 transcription. In conclusion, inhibition of Sirt1 may be an effective strategy for the prevention of tumor progression in high-risk patients or as a therapeutic strategy in established tumors. PMID:25894374

  16. Tornado missile simulation and design methodology. Volume 1: simulation methodology, design applications, and TORMIS computer code. Final report

    SciTech Connect

    Twisdale, L.A.; Dunn, W.L.

    1981-08-01

    A probabilistic methodology has been developed to predict the probabilities of tornado-propelled missiles impacting and damaging nuclear power plant structures. Mathematical models of each event in the tornado missile hazard have been developed and sequenced to form an integrated, time-history simulation methodology. The models are data based where feasible. The data include documented records of tornado occurrence, field observations of missile transport, results of wind tunnel experiments, and missile impact tests. Probabilistic Monte Carlo techniques are used to estimate the risk probabilities. The methodology has been encoded in the TORMIS computer code to facilitate numerical analysis and plant-specific tornado missile probability assessments. Sensitivity analyses have been performed on both the individual models and the integrated methodology, and risk has been assessed for a hypothetical nuclear power plant design case study.

  17. Design tradeoffs in the development of the advanced multispectral simulation test acceptance resource (AMSTAR) HWIL facilities

    NASA Astrophysics Data System (ADS)

    LeSueur, Kenneth G.; Almendinger, Frank J.

    2007-04-01

    The Army's Advanced Multispectral Simulation Test Acceptance Resource (AMSTAR) is a suite of missile Hardware-In-the-Loop (HWIL) simulation / test capabilities designed to support testing from concept through production. This paper presents the design tradeoffs that were conducted in the development of the AMSTAR sensor stimulators and the flight motion simulators. The AMSTAR facility design includes systems to stimulate each of the Millimeter Wave (MMW), Infrared (IR), and Semi-Active Laser (SAL) sensors. The flight motion simulator (FMS) performance was key to the success of the simulation but required many concessions to accommodate the design considerations for the tri-mode stimulation systems.

  18. Ras chaperones: new targets for cancer and immunotherapy.

    PubMed

    Kloog, Yoel; Elad-Sfadia, Galit; Haklai, Roni; Mor, Adam

    2013-01-01

    The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid (FTS, Salirasib®) interferes with Ras membrane interactions that are crucial for Ras-dependent signaling and cellular transformation. FTS had been successfully evaluated in clinical trials of cancer patients. Interestingly, its effect is mediated by targeting Ras chaperones that serve as key coordinators for Ras proper folding and delivery, thus offering a novel target for cancer therapy. The development of new FTS analogs has revealed that the specific modifications to the FTS carboxyl group by esterification and amidation yielded compounds with improved growth inhibitory activity. When FTS was combined with additional therapeutic agents its activity toward Ras was significantly augmented. FTS should be tested not only in cancer but also for genetic diseases associated with abnormal Ras signaling, as well as for various inflammatory and autoimmune disturbances, where Ras plays a major role. We conclude that FTS has a great potential both as a safe anticancer drug and as a promising immune modulator agent. PMID:25033809

  19. H-Ras regulation of TRAIL death receptor mediated apoptosis

    PubMed Central

    Chen, Jun-Jie; Bozza, William P.; Di, Xu; Zhang, Yaqin; Hallett, William; Zhang, Baolin

    2014-01-01

    TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through the death receptors (DRs) 4 and/or 5 expressed on the cell surface. Multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL and agonistic antibodies to DR4 or DR5. However, their therapeutic potential is limited by the high frequency of cancer resistance. Here we provide evidence demonstrating the role of H-Ras in TRAIL receptor mediated apoptosis. By analyzing the genome wide mRNA expression data of the NCI60 cancer cell lines, we found that H-Ras expression was consistently upregulated in TRAIL-resistant cell lines. By contrast, no correlation was found between TRAIL sensitivity and K-Ras expression levels or their mutational profiles. Notably, H-Ras upregulation associated with a surface deficiency of TRAIL death receptors. Selective inhibition of H-Ras activity in TRAIL-resistant cells restored the surface expression of both DR4 and DR5 without changing their total protein levels. The resulting cells became highly susceptible to both TRAIL and agonistic DR5 antibody, whereas K-Ras inhibition had little or no effect on TRAIL-induced apoptosis, indicating H-Ras plays a distinct role in the regulation of TRAIL death receptors. Further studies are warranted to determine the therapeutic potential of H-Ras-specific inhibitors in combination with TRAIL receptor agonists. PMID:25026275

  20. Design studies for the transmission simulator method of experimental dynamic substructuring.

    SciTech Connect

    Mayes, Randall Lee; Arviso, Michael

    2010-05-01

    In recent years, a successful method for generating experimental dynamic substructures has been developed using an instrumented fixture, the transmission simulator. The transmission simulator method solves many of the problems associated with experimental substructuring. These solutions effectively address: (1) rotation and moment estimation at connection points; (2) providing substructure Ritz vectors that adequately span the connection motion space; and (3) adequately addressing multiple and continuous attachment locations. However, the transmission simulator method may fail if the transmission simulator is poorly designed. Four areas of the design addressed here are: (1) designating response sensor locations; (2) designating force input locations; (3) physical design of the transmission simulator; and (4) modal test design. In addition to the transmission simulator design investigations, a review of the theory with an example problem is presented.

  1. Comparison of the Effects of RAS vs. Kain-Fritsch Convective Schemes on Katrina Forecasts with GEOS-5

    NASA Technical Reports Server (NTRS)

    Miller, Timothy L.; Cohen, Charles; Paxton, Jessica; Robertson, F. R. (Pete)

    2009-01-01

    Global forecasts were made with the 0.25-degree latitude version of GEOS-5, with the RAS scheme and with the Kain-Fritsch scheme. Examination was made of the Katrina (2005) hurricane simulation. Replacement of the RAS convective scheme with the K-F scheme results in a much more vigorous Katrina, closer to reality. Still, the result is not as vigorous as reality. In terms of wind maximum, the gap was closed by 50%. The result seems to be due to the RAS scheme drying out the boundary layer, thus hampering the grid-scale secondary circulation and attending cyclone development. The RAS case never developed a full warm core, whereas the K-F case did. Not shown here: The K-F scheme also resulted in a more vigorous storm than when GEOS-5 is run with no convective parameterization. Also not shown: An experiment in which the RAS firing level was moved up by 3 model levels resulted in a stronger, warm-core storm, though not as strong as the K-F case. Effects on storm track were noticed, but not studied.

  2. Use of computational fluid dynamics simulations for design of a pretreatment screw conveyor reactor.

    PubMed

    Berson, R Eric; Hanley, Thomas R

    2005-01-01

    Computational fluid dynamics simulations were employed to compare performance of various designs of a pretreatment screw conveyor reactor. The reactor consisted of a vertical screw used to create cross flow between the upward conveying solids and the downward flow of acid. Simulations were performed with the original screw design and a modified design in which the upper flights of the screw were removed. Results of the simulations show visually that the modified design provided favorable plug flow behavior within the reactor. Pressure drop across the length of the reactor without the upper screws in place was predicted by the simulations to be 5 vs 40 kPa for the original design.

  3. Endogenous K-ras signaling in erythroid differentiation.

    PubMed

    Zhang, Jing; Lodish, Harvey F

    2007-08-15

    K-ras is one of the most frequently mutated genes in virtually all types of human cancers. Using mouse fetal liver erythroid progenitors as a model system, we studied the role of endogenous K-ras signaling in erythroid differentiation. When oncogenic K-ras is expressed from its endogenous promoter, it hyperactivates cytokine-dependent signaling pathways and results in a partial block in erythroid differentiation. In erythroid progenitors deficient in K-ras, cytokine-dependent Akt activation is greatly reduced, leading to delays in erythroid differentiation. Thus, both loss- and gain-of-Kras functions affect erythroid differentiation through modulation of cytokine signaling. These results support the notion that in human cancer patients oncogenic Ras signaling might be controlled by antagonizing essential cytokines.

  4. Regional scale flood modeling using NEXRAD rainfall, GIS, and HEC-HMS/RAS: a case study for the San Antonio River Basin Summer 2002 storm event.

    PubMed

    Knebl, M R; Yang, Z-L; Hutchison, K; Maidment, D R

    2005-06-01

    This paper develops a framework for regional scale flood modeling that integrates NEXRAD Level III rainfall, GIS, and a hydrological model (HEC-HMS/RAS). The San Antonio River Basin (about 4000 square miles, 10,000 km2) in Central Texas, USA, is the domain of the study because it is a region subject to frequent occurrences of severe flash flooding. A major flood in the summer of 2002 is chosen as a case to examine the modeling framework. The model consists of a rainfall-runoff model (HEC-HMS) that converts precipitation excess to overland flow and channel runoff, as well as a hydraulic model (HEC-RAS) that models unsteady state flow through the river channel network based on the HEC-HMS-derived hydrographs. HEC-HMS is run on a 4 x 4 km grid in the domain, a resolution consistent with the resolution of NEXRAD rainfall taken from the local river authority. Watershed parameters are calibrated manually to produce a good simulation of discharge at 12 subbasins. With the calibrated discharge, HEC-RAS is capable of producing floodplain polygons that are comparable to the satellite imagery. The modeling framework presented in this study incorporates a portion of the recently developed GIS tool named Map to Map that has been created on a local scale and extends it to a regional scale. The results of this research will benefit future modeling efforts by providing a tool for hydrological forecasts of flooding on a regional scale. While designed for the San Antonio River Basin, this regional scale model may be used as a prototype for model applications in other areas of the country.

  5. Effects of Thinking Style on Design Strategies: Using Bridge Construction Simulation Programs

    ERIC Educational Resources Information Center

    Sun, Chuen-Tsai; Wang, Dai-Yi; Chang, Yu-Yeh

    2013-01-01

    Computer simulation users can freely control operational factors and simulation results, repeat processes, make changes, and learn from simulation environment feedback. The focus of this paper is on simulation-based design tools and their effects on student learning processes in a group of 101 Taiwanese senior high school students. Participants…

  6. Interactive Graphics Simulator: Design, Development, and Effectiveness/Cost Evaluation. Final Report.

    ERIC Educational Resources Information Center

    Pieper, William J.; And Others

    This study was initiated to design, develop, implement, and evaluate a videodisc-based simulator system, the Interactive Graphics Simulator (IGS) for 6883 Converter Flight Control Test Station training at Lowry Air Force Base, Colorado. The simulator provided a means for performing task analysis online, developing simulations from the task…

  7. NICMOS cold-well displacement monitor: a portable Hubble simulator

    NASA Astrophysics Data System (ADS)

    Mentzell, John E.; McIntosh, Malcolm B.; Schwenker, John P.; Thompson, Rodger I.

    1998-08-01

    The anomalous motion of the near IR camera and multi-object spectrometer (NICMOS) detector arrays was originally discovered and characterized during ground optical testing, in a large, high fidelity Hubble Space Telescope (HST) simulator. To monitor the state of the cryo-mechanical system, as NICMOS traveled among several testing sties, a portable stimulus was needed. The cold-well displacement monitor (CDM) was quickly assembled from a very simple design. The 'cheaper, better, faster' approach proved to be a winner here. Off-the-shelf optics, a simplified interface to the instrument, and a limited set of requirements were used. After calibration against the large refractive aberration simulator/Hubble opto-mechanical simulator (RAS/HOMS), the CDM gave results of similar accuracy to RAS/HOMS. It became the primary tool for the difficult job of managing the NICMOS cryogen system up through launch.

  8. Heat-load simulator for heat sink design

    NASA Technical Reports Server (NTRS)

    Dunleavy, A. M.; Vaughn, T. J.

    1968-01-01

    Heat-load simulator is fabricated from 1/4-inch aluminum plate with a contact surface equal in dimensions and configuration to those of the electronic installation. The method controls thermal output to simulate actual electronic component thermal output.

  9. Algorithm design for a gun simulator based on image processing

    NASA Astrophysics Data System (ADS)

    Liu, Yu; Wei, Ping; Ke, Jun

    2015-08-01

    In this paper, an algorithm is designed for shooting games under strong background light. Six LEDs are uniformly distributed on the edge of a game machine screen. They are located at the four corners and in the middle of the top and the bottom edges. Three LEDs are enlightened in the odd frames, and the other three are enlightened in the even frames. A simulator is furnished with one camera, which is used to obtain the image of the LEDs by applying inter-frame difference between the even and odd frames. In the resulting images, six LED are six bright spots. To obtain the LEDs' coordinates rapidly, we proposed a method based on the area of the bright spots. After calibrating the camera based on a pinhole model, four equations can be found using the relationship between the image coordinate system and the world coordinate system with perspective transformation. The center point of the image of LEDs is supposed to be at the virtual shooting point. The perspective transformation matrix is applied to the coordinate of the center point. Then we can obtain the virtual shooting point's coordinate in the world coordinate system. When a game player shoots a target about two meters away, using the method discussed in this paper, the calculated coordinate error is less than ten mm. We can obtain 65 coordinate results per second, which meets the requirement of a real-time system. It proves the algorithm is reliable and effective.

  10. Ras activation and symmetry breaking during Dictyostelium chemotaxis.

    PubMed

    Kortholt, Arjan; Keizer-Gunnink, Ineke; Kataria, Rama; Van Haastert, Peter J M

    2013-10-01

    Central to chemotaxis is the molecular mechanism by which a shallow spatial gradient of chemoattractant induces symmetry breaking of activated signaling molecules. Previously, we have used Dictyostelium mutants to investigate the minimal requirements for chemotaxis, and identified a basal signaling module providing activation of Ras and F-actin at the leading edge. Here, we show that Ras activation after application of a pipette releasing the chemoattractant cAMP has three phases, each depending on specific guanine-nucleotide-exchange factors (GEFs). Initially a transient activation of Ras occurs at the entire cell boundary, which is proportional to the local cAMP concentrations and therefore slightly stronger at the front than in the rear of the cell. This transient Ras activation is present in gα2 (gpbB)-null cells but not in gβ (gpbA)-null cells, suggesting that Gβγ mediates the initial activation of Ras. The second phase is symmetry breaking: Ras is activated only at the side of the cell closest to the pipette. Symmetry breaking absolutely requires Gα2 and Gβγ, but not the cytoskeleton or four cAMP-induced signaling pathways, those dependent on phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3], cGMP, TorC2 and PLA2. As cells move in the gradient, the crescent of activated Ras in the front half of the cell becomes confined to a small area at the utmost front of the cell. Confinement of Ras activation leads to cell polarization, and depends on cGMP formation, myosin and F-actin. The experiments show that activation, symmetry breaking and confinement of Ras during Dictyostelium chemotaxis uses different G-protein subunits and a multitude of Ras GEFs and GTPase-activating proteins (GAPs).

  11. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding

    PubMed Central

    Ting, Pamela Y.; Johnson, Christian W.; Fang, Cong; Cao, Xiaoqing; Graeber, Thomas G.; Mattos, Carla; Colicelli, John

    2015-01-01

    RAS proteins are signal transduction gatekeepers that mediate cell growth, survival, and differentiation through interactions with multiple effector proteins. The RAS effector RAS- and RAB-interacting protein 1 (RIN1) activates its own downstream effectors, the small GTPase RAB5 and the tyrosine kinase Abelson tyrosine-protein kinase (ABL), to modulate endocytosis and cytoskeleton remodeling. To identify ABL substrates downstream of RAS-to-RIN1 signaling, we examined human HEK293T cells overexpressing components of this pathway. Proteomic analysis revealed several novel phosphotyrosine peptides, including Harvey rat sarcoma oncogene (HRAS)-pTyr137. Here we report that ABL phosphorylates tyrosine 137 of H-, K-, and NRAS. Increased RIN1 levels enhanced HRAS-Tyr137 phosphorylation by nearly 5-fold, suggesting that RAS-stimulated RIN1 can drive ABL-mediated RAS modification in a feedback circuit. Tyr137 is well conserved among RAS orthologs and is part of a transprotein H-bond network. Crystal structures of HRASY137F and HRASY137E revealed conformation changes radiating from the mutated residue. Although consistent with Tyr137 participation in allosteric control of HRAS function, the mutations did not alter intrinsic GTP hydrolysis rates in vitro. HRAS-Tyr137 phosphorylation enhanced HRAS signaling capacity in cells, however, as reflected by a 4-fold increase in the association of phosphorylated HRASG12V with its effector protein RAF proto-oncogene serine/threonine protein kinase 1 (RAF1). These data suggest that RAS phosphorylation at Tyr137 allosterically alters protein conformation and effector binding, providing a mechanism for effector-initiated modulation of RAS signaling.—Ting, P. Y., Johnson, C. W., Fang, C., Cao, X., Graeber, T. G., Mattos, C., Colicelli, J. Tyrosine phosphorylation of RAS by ABL allosterically enhances effector binding. PMID:25999467

  12. RAS Synthetic Lethal Screens Revisited: Still Seeking the Elusive Prize?

    PubMed

    Downward, Julian

    2015-04-15

    The RAS genes are critical oncogenic drivers activated by point mutation in some 20% of human malignancies. However, no pharmacologic approaches to targeting RAS proteins directly have yet succeeded, leading to suggestions that these proteins may be "undruggable." This has led to two alternative indirect approaches to targeting RAS function in cancer. One has been to target RAS signaling pathways downstream at tractable enzymes such as kinases, particularly in combination. The other, which is the focus of this review, has been to seek targets that are essential in cells bearing an activated RAS oncogene, but not those without. This synthetic lethal approach, while rooted in ideas from invertebrate genetics, has been inspired most strongly by the successful use of PARP inhibitors, such as olaparib, in the clinic to treat BRCA defective cancers. Several large-scale screens have been carried out using RNA interference-mediated expression silencing to find genes that are uniquely essential to RAS-mutant but not wild-type cells. These screens have been notable for the low degree of overlap between their results, with the possible exception of proteasome components, and have yet to lead to successful new clinical approaches to the treatment of RAS-mutant cancers. Possible reasons for these disappointing results are discussed here, along with a reevaluation of the approaches taken. On the basis of experience to date, RAS synthetic lethality has so far fallen some way short of its original promise and remains unproven as an approach to finding effective new ways of tackling RAS-mutant cancers. Clin Cancer Res; 21(8); 1802-9. ©2015 AACR. See all articles in this CCR Focus section, "Targeting RAS-Driven Cancers." PMID:25878361

  13. Regulation of collagen I gene expression by ras.

    PubMed Central

    Slack, J L; Parker, M I; Robinson, V R; Bornstein, P

    1992-01-01

    Although transformation of rodent fibroblasts can lead to dramatic changes in expression of extracellular matrix genes, the molecular basis and physiological significance of these changes remain poorly understood. In this study, we have investigated the mechanism(s) by which ras affects expression of the genes encoding type I collagen. Levels of both alpha 1(I) and alpha 2(I) collagen mRNAs were markedly reduced in Rat 1 fibroblasts overexpressing either the N-rasLys-61 or the Ha-rasVal-12 oncogene. In fibroblasts conditionally transformed with N-rasLys-61, alpha 1(I) transcript levels began to decline within 8 h of ras induction and reached 1 to 5% of control levels after 96 h. In contrast, overexpression of normal ras p21 had no effect on alpha 1(I) or alpha 2(I) mRNA levels. Nuclear run-on experiments demonstrated that the transcription rates of both the alpha 1(I) and alpha 2(I) genes were significantly reduced in ras-transformed cells compared with those in parental cells. In addition, the alpha 1(I) transcript was less stable in transformed cells. Chimeric plasmids containing up to 3.6 kb of alpha 1(I) 5'-flanking DNA and up to 2.3 kb of the 3'-flanking region were expressed at equivalent levels in both normal and ras-transformed fibroblasts. However, a cosmid clone containing the entire mouse alpha 1(I) gene, including 3.7 kb of 5'- and 4 kb of 3'-flanking DNA, was expressed at reduced levels in fibroblasts overexpressing oncogenic ras. We conclude that oncogenic ras regulates the type I collagen genes at both transcriptional and posttranscriptional levels and that this effect, at least for the alpha 1(I) gene, may be mediated by sequences located either within the body of the gene itself or in the distal 3'-flanking region. Images PMID:1406656

  14. Purpose and Learning Benefits of Simulations: A Design and Development Perspective.

    ERIC Educational Resources Information Center

    Goosen, Kenneth R.; Jensen, Ron; Wells, Robert

    2001-01-01

    Considers the role of the simulation designer in the development of business enterprise simulations used in collegiate business education. Topics include the designer's knowledge domain; conflicting business administration theories in accounting, finance, economics, marketing, production, and income tax; and other designer issues. (LRW)

  15. Gas-grain simulation experiment module conceptual design and gas-grain simulation facility breadboard development

    NASA Technical Reports Server (NTRS)

    Zamel, James M.; Petach, Michael; Gat, Nahum; Kropp, Jack; Luong, Christina; Wolff, Michael

    1993-01-01

    This report delineates the Option portion of the Phase A Gas-Grain Simulation Facility study. The conceptual design of a Gas-Grain Simulation Experiment Module (GGSEM) for Space Shuttle Middeck is discussed. In addition, a laboratory breadboard was developed during this study to develop a key function for the GGSEM and the GGSF, specifically, a solid particle cloud generating device. The breadboard design and test results are discussed and recommendations for further studies are included. The GGSEM is intended to fly on board a low earth orbit (LEO), manned platform. It will be used to perform a subset of the experiments planned for the GGSF for Space Station Freedom, as it can partially accommodate a number of the science experiments. The outcome of the experiments performed will provide an increased understanding of the operational requirements for the GGSF. The GGSEM will also act as a platform to accomplish technology development and proof-of-principle experiments for GGSF hardware, and to verify concepts and designs of hardware for GGSF. The GGSEM will allow assembled subsystems to be tested to verify facility level operation. The technology development that can be accommodated by the GGSEM includes: GGSF sample generation techniques, GGSF on-line diagnostics techniques, sample collection techniques, performance of various types of sensors for environmental monitoring, and some off-line diagnostics. Advantages and disadvantages of several LEO platforms available for GGSEM applications are identified and discussed. Several of the anticipated GGSF experiments require the deagglomeration and dispensing of dry solid particles into an experiment chamber. During the GGSF Phase A study, various techniques and devices available for the solid particle aerosol generator were reviewed. As a result of this review, solid particle deagglomeration and dispensing were identified as key undeveloped technologies in the GGSF design. A laboratory breadboard version of a solid

  16. Rapidly Re-Configurable Flight Simulator Tools for Crew Vehicle Integration Research and Design

    NASA Technical Reports Server (NTRS)

    Pritchett, Amy R.

    2002-01-01

    While simulation is a valuable research and design tool, the time and difficulty required to create new simulations (or re-use existing simulations) often limits their application. This report describes the design of the software architecture for the Reconfigurable Flight Simulator (RFS), which provides a robust simulation framework that allows the simulator to fulfill multiple research and development goals. The core of the architecture provides the interface standards for simulation components, registers and initializes components, and handles the communication between simulation components. The simulation components are each a pre-compiled library 'plugin' module. This modularity allows independent development and sharing of individual simulation components. Additional interfaces can be provided through the use of Object Data/Method Extensions (OD/ME). RFS provides a programmable run-time environment for real-time access and manipulation, and has networking capabilities using the High Level Architecture (HLA).

  17. Rapidly Re-Configurable Flight Simulator Tools for Crew Vehicle Integration Research and Design

    NASA Technical Reports Server (NTRS)

    Schutte, Paul C.; Trujillo, Anna; Pritchett, Amy R.

    2000-01-01

    While simulation is a valuable research and design tool, the time and difficulty required to create new simulations (or re-use existing simulations) often limits their application. This report describes the design of the software architecture for the Reconfigurable Flight Simulator (RFS), which provides a robust simulation framework that allows the simulator to fulfill multiple research and development goals. The core of the architecture provides the interface standards for simulation components, registers and initializes components, and handles the communication between simulation components. The simulation components are each a pre-compiled library 'plug-in' module. This modularity allows independent development and sharing of individual simulation components. Additional interfaces can be provided through the use of Object Data/Method Extensions (OD/ME). RFS provides a programmable run-time environment for real-time access and manipulation, and has networking capabilities using the High Level Architecture (HLA).

  18. RasGRP3 regulates the migration of glioma cells via interaction with Arp3

    PubMed Central

    Lee, Hae Kyung; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Poisson, Laila M.; Blumberg, Peter M.; Brodie, Chaya

    2015-01-01

    Glioblastoma (GBM), the most aggressive primary brain tumors, are highly infiltrative. Although GBM express high Ras activity and Ras proteins have been implicated in gliomagenesis, Ras-activating mutations are not frequent in these tumors. RasGRP3, an important signaling protein responsive to diacylglycerol (DAG), increases Ras activation. Here, we examined the expression and functions of RasGRP3 in GBM and glioma cells. RasGRP3 expression was upregulated in GBM specimens and glioma stem cells compared with normal brains and neural stem cells, respectively. RasGRP3 activated Ras and Rap1 in glioma cells and increased cell migration and invasion partially via Ras activation. Using pull-down assay and mass spectroscopy we identified the actin-related protein, Arp3, as a novel interacting protein of RasGRP3. The interaction of RasGRP3 and Arp3 was validated by immunofluorescence staining and co-immunoprecipitation, and PMA, which activates RasGRP3 and induces its translocation to the peri-nuclear region, increased the association of Arp3 and RasGRP3. Arp3 was upregulated in GBM, regulated cell spreading and migration and its silencing partially decreased these effects of RasGRP3 in glioma cells. In summary, RasGRP3 acts as an important integrating signaling protein of the DAG and Ras signaling pathways and actin polymerization and represents an important therapeutic target in GBM. PMID:25682201

  19. RasGRF1 regulates the hypothalamic-pituitary-adrenal axis specifically in early-adolescent female mice.

    PubMed

    Uzturk, Belkis Gizem; Jin, Shan-Xue; Rubin, Beverly; Bartolome, Christopher; Feig, Larry A

    2015-10-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 min/day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after one, three and five exposures is magnified approximately threefold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females.

  20. RasGRF1 Regulates the Hypothalamic-Pituitary-Adrenal Axis Specifically in Early-Adolescent Female Mice

    PubMed Central

    Uzturk, Belkis Gizem; Jin, Shan-xue; Rubin, Beverly; Bartolome, Christopher; Feig, Larry A.

    2015-01-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 minutes a day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after 1, 3, and 5 exposures is magnified ~3-fold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females. PMID:26246084

  1. Designing Better Scaffolding in Teaching Complex Systems with Graphical Simulations

    NASA Astrophysics Data System (ADS)

    Li, Na

    Complex systems are an important topic in science education today, but they are usually difficult for secondary-level students to learn. Although graphic simulations have many advantages in teaching complex systems, scaffolding is a critical factor for effective learning. This dissertation study was conducted around two complementary research questions on scaffolding: (1) How can we chunk and sequence learning activities in teaching complex systems? (2) How can we help students make connections among system levels across learning activities (level bridging)? With a sample of 123 seventh-graders, this study employed a 3x2 experimental design that factored sequencing methods (independent variable 1; three levels) with level-bridging scaffolding (independent variable 2; two levels) and compared the effectiveness of each combination. The study measured two dependent variables: (1) knowledge integration (i.e., integrating and connecting content-specific normative concepts and providing coherent scientific explanations); (2) understanding of the deep causal structure (i.e., being able to grasp and transfer the causal knowledge of a complex system). The study used a computer-based simulation environment as the research platform to teach the ideal gas law as a system. The ideal gas law is an emergent chemical system that has three levels: (1) experiential macro level (EM) (e.g., an aerosol can explodes when it is thrown into the fire); (2) abstract macro level (AM) (i.e., the relationships among temperature, pressure and volume); (3) micro level (Mi) (i.e., molecular activity). The sequencing methods of these levels were manipulated by changing the order in which they were delivered with three possibilities: (1) EM-AM-Mi; (2) Mi-AM-EM; (3) AM-Mi-EM. The level-bridging scaffolding variable was manipulated on two aspects: (1) inserting inter-level questions among learning activities; (2) two simulations dynamically linked in the final learning activity. Addressing the first

  2. Improving the Aircraft Design Process Using Web-Based Modeling and Simulation

    NASA Technical Reports Server (NTRS)

    Reed, John A.; Follen, Gregory J.; Afjeh, Abdollah A.; Follen, Gregory J. (Technical Monitor)

    2000-01-01

    Designing and developing new aircraft systems is time-consuming and expensive. Computational simulation is a promising means for reducing design cycle times, but requires a flexible software environment capable of integrating advanced multidisciplinary and multifidelity analysis methods, dynamically managing data across heterogeneous computing platforms, and distributing computationally complex tasks. Web-based simulation, with its emphasis on collaborative composition of simulation models, distributed heterogeneous execution, and dynamic multimedia documentation, has the potential to meet these requirements. This paper outlines the current aircraft design process, highlighting its problems and complexities, and presents our vision of an aircraft design process using Web-based modeling and simulation.

  3. Improving the Aircraft Design Process Using Web-based Modeling and Simulation

    NASA Technical Reports Server (NTRS)

    Reed, John A.; Follen, Gregory J.; Afjeh, Abdollah A.

    2003-01-01

    Designing and developing new aircraft systems is time-consuming and expensive. Computational simulation is a promising means for reducing design cycle times, but requires a flexible software environment capable of integrating advanced multidisciplinary and muitifidelity analysis methods, dynamically managing data across heterogeneous computing platforms, and distributing computationally complex tasks. Web-based simulation, with its emphasis on collaborative composition of simulation models, distributed heterogeneous execution, and dynamic multimedia documentation, has the potential to meet these requirements. This paper outlines the current aircraft design process, highlighting its problems and complexities, and presents our vision of an aircraft design process using Web-based modeling and simulation.

  4. OPTIMIZATION OF THE HYSPEC DESIGN USING MONTE CARLO SIMULATIONS.

    SciTech Connect

    GHOSH, V.J.; HAGEN, M.E.; LEONHARDT, W.J.; ZALIZNYAK, I.; SHAPIRO, S.M.; PASSELL, L.

    2005-04-25

    HYSPEC is a direct geometry spectrometer to be installed at the SNS [1] on beamline 14B where it will view a cryogenic coupled hydrogen moderator, The ''hybrid'' design combines time-of-flight spectroscopy with focusing Bragg optics to provide a high monochromatic flux on small single crystal samples, with a very low background at an extended detector bank. The instrument is optimized for an incident energy range of 3-90meV. It will have a medium energy resolution (2-10%) and will provide a flux on sample of the order of 10{sup 6}-10{sup 7} neutrons/s-cm{sup 2}. The spectrometer will be located in a satellite building outside the SNS experimental hall at the end of a 35m curved supermirror guide. A straight-slotted Fermi chopper will be used to monochromate the neutron beam and to determine the burst width. The 15cm high, 4cm wide beam will be focused onto a 2cm by 2cm area at the sample position using Bragg reflection from one of two crystal arrays. For unpolarized neutron studies these will be Highly Oriented Pyrolitic graphite crystals while for polarized neutron studies these will be replaced with Heusler alloy crystals. These focusing crystal arrays will be placed in a drum shield similar to those used for triple axis spectrometers. Hyspec will have a movable detector bank housing 160 position sensitive detectors. This detector bank will pivot about the sample axis. It will have a radius of 4.5m, a horizontal range of 60{sup o}, and a vertical range of {+-} 7.5{sup o}. In order to reduce background at the detector bank both a curved guide and a T0 chopper will be used. A bank of 20 supermirror bender polarization analyzers [2] will be used to spatially separate the polarized neutrons in the scattered beam so that both scattered neutron spin states can be measured simultaneously. The results of Monte Carlo simulations performed to optimize the instrument design will be discussed.

  5. Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis

    PubMed Central

    Bunda, Severa; Burrell, Kelly; Heir, Pardeep; Zeng, Lifan; Alamsahebpour, Amir; Kano, Yoshihito; Raught, Brian; Zhang, Zhong-Yin; Zadeh, Gelareh; Ohh, Michael

    2015-01-01

    Ras is phosphorylated on a conserved tyrosine at position 32 within the switch I region via Src kinase. This phosphorylation inhibits the binding of effector Raf while promoting the engagement of GTPase-activating protein (GAP) and GTP hydrolysis. Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling. In comparison to normal astrocytes, SHP2 activity is elevated in astrocytes isolated from glioblastoma multiforme (GBM)-prone H-Ras(12V) knock-in mice as well as in glioma cell lines and patient-derived GBM specimens exhibiting hyperactive Ras. Pharmacologic inhibition of SHP2 activity attenuates cell proliferation, soft-agar colony formation and orthotopic GBM growth in NOD/SCID mice and decelerates the progression of low-grade astrocytoma to GBM in a spontaneous transgenic glioma mouse model. These results identify SHP2 as a direct activator of Ras and a potential therapeutic target for cancers driven by a previously ‘undruggable' oncogenic or hyperactive Ras. PMID:26617336

  6. Rapid Modeling, Assembly and Simulation in Design Optimization

    NASA Technical Reports Server (NTRS)

    Housner, Jerry

    1997-01-01

    A new capability for design is reviewed. This capability provides for rapid assembly of detail finite element models early in the design process where costs are most effectively impacted. This creates an engineering environment which enables comprehensive analysis and design optimization early in the design process. Graphical interactive computing makes it possible for the engineer to interact with the design while performing comprehensive design studies. This rapid assembly capability is enabled by the use of Interface Technology, to couple independently created models which can be archived and made accessible to the designer. Results are presented to demonstrate the capability.

  7. RAS Synthetic Lethal Screens Revisited: Still Seeking the Elusive Prize?

    PubMed Central

    Downward, Julian

    2015-01-01

    The RAS genes are critical oncogenic drivers activated by point mutation in some 20% of human malignancies. However, no pharmacological approaches to targeting RAS proteins directly have yet succeeded, leading to suggestions that these proteins may be “undruggable.” This has led to two alternative indirect approaches to targeting RAS function in cancer. One has been to target RAS signaling pathways downstream at tractable enzymes such as kinases, particularly in combination. The other, which is the focus of this review, has been to seek targets that are essential in cells bearing an activated RAS oncogene, but not those without. This synthetic lethal approach, while rooted in ideas from invertebrate genetics, has been inspired most strongly by the successful use of PARP inhibitors, such as olaparib, in the clinic to treat BRCA defective cancers. Several large-scale screens have been carried out using RNA interference-mediated expression silencing to find genes that are uniquely essential to RAS mutant but not wild type cells. These screens have been notable for the low degree of overlap between their results, with the possible exception of proteasome components, and have yet to lead to successful new clinical approaches to the treatment of RAS mutant cancers. Possible reasons for these disappointing results are discussed here, along with a re-evaluation of the approaches taken. Based on experience to date, RAS synthetic lethality has so far fallen some way short of its original promise and remains unproven as an approach to finding effective new ways of tackling RAS mutant cancers. PMID:25878361

  8. GTP-dependent association of Raf-1 with Ha-Ras: identification of Raf as a target downstream of Ras in mammalian cells.

    PubMed Central

    Koide, H; Satoh, T; Nakafuku, M; Kaziro, Y

    1993-01-01

    Ras is involved in signal transduction of various factors for growth, differentiation, and oncogenesis. Recent studies have revealed several proteins that function upstream and downstream of the Ras signaling pathway. However, its immediate downstream target molecular has not yet been identified. In an effort to identify the Ras-associated downstream proteins, we added recombinant Ha-Ras in a GTP-bound form to cell-free lysates and used several antibodies against Ras to immunoprecipitate Ras complexes. We found that a serine/threonine kinase, Raf-1, was coimmunoprecipitated with Ha-Ras by two anti-Ras antibodies (LA069 and Y13-238), whereas a neutralizing antibody against Ras (Y13-259) could not precipitate Raf-1. The coimmunoprecipitation was observed with a complex of Ras and guanosine 5'-[gamma- thio]triphosphate but not with a complex of Ras and guanosine 5'-[beta-thio]diphosphate. The GTP-dependent association of Ha-Ras with Raf-1 was observed with lysates of various types of cultured cells, including NIH 3T3, pheochromocytoma (PC) 12, Ba/F3, and Jurkat T cells, and also with crude extracts from rat brain. Furthermore, Raf-1 was precipitated with a transforming Ha-Ras mutant ([Val12]Ras) and wild-type Ha-Ras but not with an effector-region mutant ([Leu35,ARg37]Ras) that lacks transforming activity. These results indicate that Ras.GTP physically associates with Raf either directly or through other component(s) and strongly suggest that Raf functions in close downstream proximity to Ras in mammalian cells. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8378348

  9. Serum-dependent transcriptional networks identify distinct functional roles for H-Ras and N-Ras during initial stages of the cell cycle

    PubMed Central

    2009-01-01

    Background Using oligonucleotide microarrays, we compared transcriptional profiles corresponding to the initial cell cycle stages of mouse fibroblasts lacking the small GTPases H-Ras and/or N-Ras with those of matching, wild-type controls. Results Serum-starved wild-type and knockout ras fibroblasts had very similar transcriptional profiles, indicating that H-Ras and N-Ras do not significantly control transcriptional responses to serum deprivation stress. In contrast, genomic disruption of H-ras or N-ras, individually or in combination, determined specific differential gene expression profiles in response to post-starvation stimulation with serum for 1 hour (G0/G1 transition) or 8 hours (mid-G1 progression). The absence of N-Ras caused significantly higher changes than the absence of H-Ras in the wave of transcriptional activation linked to G0/G1 transition. In contrast, the absence of H-Ras affected the profile of the transcriptional wave detected during G1 progression more strongly than did the absence of N-Ras. H-Ras was predominantly functionally associated with growth and proliferation, whereas N-Ras had a closer link to the regulation of development, the cell cycle, immunomodulation and apoptosis. Mechanistic analysis indicated that extracellular signal-regulated kinase (ERK)-dependent activation of signal transducer and activator of transcription 1 (Stat1) mediates the regulatory effect of N-Ras on defense and immunity, whereas the pro-apoptotic effects of N-Ras are mediated through ERK and p38 mitogen-activated protein kinase signaling. Conclusions Our observations confirm the notion of an absolute requirement for different peaks of Ras activity during the initial stages of the cell cycle and document the functional specificity of H-Ras and N-Ras during those processes. PMID:19895680

  10. A Study of Educational Simulations Part II--Interface Design

    ERIC Educational Resources Information Center

    Adams, W.; Reid, S.; LeMaster, R.; McKagan, S.; Perkins, K.; Dubson, M.; Wieman, C.

    2008-01-01

    Interactive computer simulations with complex representations and sophisticated graphics are a relatively new addition to the classroom, and research in this area is limited. We have conducted over 200 individual student interviews during which the students described what they were thinking as they interacted with simulations. These interviews…

  11. An Integrated Design and Development System for Graphics Simulation.

    ERIC Educational Resources Information Center

    Richardson, J. Jeffrey

    In the training of maintenance and operations technicians, three enhancements to a basic, straightforward, fixed-sequence simulation system can be useful. The primary advantage of the resultant system is that the principal object of simulation is the task to be performed, which includes both the planning knowledge and the equipment actions…

  12. Canonical RTK-Ras-ERK signaling and related alternative pathways

    PubMed Central

    Sundaram, Meera V.

    2013-01-01

    Receptor Tyrosine Kinase (RTK)-Ras-Extracellular signal-regulated kinase (ERK) signaling pathways control many aspects of C. elegans development and behavior. Studies in C. elegans helped elucidate the basic framework of the RTK-Ras-ERK pathway and continue to provide insights into its complex regulation, its biological roles, how it elicits cell-type appropriate responses, and how it interacts with other signaling pathways to do so. C. elegans studies have also revealed biological contexts in which alternative RTK- or Ras-dependent pathways are used instead of the canonical pathway. PMID:23908058

  13. PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes.

    PubMed

    Anta, B; Pérez-Rodríguez, A; Castro, J; García-Domínguez, C A; Ibiza, S; Martínez, N; Durá, L M; Hernández, S; Gragera, T; Peña-Jiménez, D; Yunta, M; Zarich, N; Crespo, P; Serrador, J M; Santos, E; Muñoz, A; Oliva, J L; Rojas-Cabañeros, J M

    2016-01-01

    The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment. PMID:27468687

  14. PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

    PubMed Central

    Anta, B; Pérez-Rodríguez, A; Castro, J; García- Domínguez, C A; Ibiza, S; Martínez, N; Durá, L M; Hernández, S; Gragera, T; Peña-Jiménez, D; Yunta, M; Zarich, N; Crespo, P; Serrador, J M; Santos, E; Muñoz, A; Oliva, J L; Rojas-Cabañeros, J M

    2016-01-01

    The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment. PMID:27468687

  15. PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes.

    PubMed

    Anta, B; Pérez-Rodríguez, A; Castro, J; García-Domínguez, C A; Ibiza, S; Martínez, N; Durá, L M; Hernández, S; Gragera, T; Peña-Jiménez, D; Yunta, M; Zarich, N; Crespo, P; Serrador, J M; Santos, E; Muñoz, A; Oliva, J L; Rojas-Cabañeros, J M

    2016-07-28

    The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment.

  16. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy

    PubMed Central

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S.; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J.; Lipskaia, Larissa; Chemaly, Elie R.

    2015-01-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. PMID:26260012

  17. Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy.

    PubMed

    Ramos-Kuri, Manuel; Rapti, Kleopatra; Mehel, Hind; Zhang, Shihong; Dhandapany, Perundurai S; Liang, Lifan; García-Carrancá, Alejandro; Bobe, Regis; Fischmeister, Rodolphe; Adnot, Serge; Lebeche, Djamel; Hajjar, Roger J; Lipskaia, Larissa; Chemaly, Elie R

    2015-11-01

    The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic cardiac hypertrophy. In isolated adult cardiomyocytes after 2 weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy.

  18. Identification and characterization of rain, a novel Ras-interacting protein with a unique subcellular localization.

    PubMed

    Mitin, Natalia Y; Ramocki, Melissa B; Zullo, Alfred J; Der, Channing J; Konieczny, Stephen F; Taparowsky, Elizabeth J

    2004-05-21

    The Ras small GTPase functions as a signaling node and is activated by extracellular stimuli. Upon activation, Ras interacts with a spectrum of functionally diverse downstream effectors and stimulates multiple cytoplasmic signaling cascades that regulate cellular proliferation, differentiation, and apoptosis. In addition to the association of Ras with the plasma membrane, recent studies have established an association of Ras with Golgi membranes. Whereas the effectors of signal transduction by activated, plasma membrane-localized Ras are well characterized, very little is known about the effectors used by Golgi-localized Ras. In this study, we report the identification of a novel Ras-interacting protein, Rain, that may serve as an effector for endomembrane-associated Ras. Rain does not share significant sequence similarity with any known mammalian proteins, but contains a Ras-associating domain that is found in RalGDS, AF-6, and other characterized Ras effectors. Rain interacts with Ras in a GTP-dependent manner in vitro and in vivo, requires an intact Ras core effector-binding domain for this interaction, and thus fits the definition of a Ras effector. Unlike other Ras effectors, however, Rain is localized to perinuclear, juxta-Golgi vesicles in intact cells and is recruited to the Golgi by activated Ras. Finally, we found that Rain cooperates with activated Raf and causes synergistic transformation of NIH3T3 cells. Taken together, these observations support a role for Rain as a novel protein that can serve as an effector of endomembrane-localized Ras.

  19. The Statistical Power of the Cluster Randomized Block Design with Matched Pairs--A Simulation Study

    ERIC Educational Resources Information Center

    Dong, Nianbo; Lipsey, Mark

    2010-01-01

    This study uses simulation techniques to examine the statistical power of the group- randomized design and the matched-pair (MP) randomized block design under various parameter combinations. Both nearest neighbor matching and random matching are used for the MP design. The power of each design for any parameter combination was calculated from…

  20. Challenges in Integrating a Complex Systems Computer Simulation in Class: An Educational Design Research

    ERIC Educational Resources Information Center

    Loke, Swee-Kin; Al-Sallami, Hesham S.; Wright, Daniel F. B.; McDonald, Jenny; Jadhav, Sheetal; Duffull, Stephen B.

    2012-01-01

    Complex systems are typically difficult for students to understand and computer simulations offer a promising way forward. However, integrating such simulations into conventional classes presents numerous challenges. Framed within an educational design research, we studied the use of an in-house built simulation of the coagulation network in four…

  1. Simulation design: A Teaching Technique for Political Science

    ERIC Educational Resources Information Center

    Deiner, John T.

    1974-01-01

    Goals, course structure, physical and technical problems, the running of a simulation and evaluation of students are described for a game representing the political system of Argentina in a university comparative government course. (Author/KM)

  2. Optical design of a high-power LED-based solar simulator

    NASA Astrophysics Data System (ADS)

    Toro-Betancur, Veronica; Velásquez-López, Alejandro; Velásquez, David; Acevedo-Gómez, David

    2016-04-01

    The optical design of a High-Power LED based Solar Simulator was made in order to reach the AM1.5G spectrum standards. An optical model of the light emitted by the LEDs was made and used for spectral intensities calculations and the light intensity uniformity was optimized. A class AAA solar simulator was designed using a hexagonal LED distribution.

  3. The Use of Simulation for the Design and Analysis of Thermophotovoltaic Networks

    SciTech Connect

    JE Oppenlander; JL Vell; WS Gaes; DM Siganporia; LR Danielson; MW Dashiell

    2004-07-20

    Simulation has provided valuable quantification of the fundamental behavior of thermophotovoltaic cell networks. The results of simulation studies have supported the design and fabrication of small-scale demonstration networks and are expected to guide assembly of large-scale systems. This paper describes the methodology and software simulator developed to address issues in thermophotovoltaic (TPV) networking, including failure analysis, electrical network design, and nonuniform illumination. Results from simulation studies are given illustrating their application to the design and fabrication of small-scale TPV arrays.

  4. Data Systems Dynamic Simulation - A total system for data system design assessments and trade studies

    NASA Technical Reports Server (NTRS)

    Hooper, J. W.; Rowe, D. W.

    1978-01-01

    Data Systems Dynamic Simulation is a simulation system designed to reduce cost and time and increase the confidence and comprehensiveness of Data Systems Simulation. It is designed to simulate large data processing and communications systems from end-to-end or by subsystem. Those features relevant to system timing, control, sizing, personnel support activities, cost and external influences are modeled. Emphasis is placed on ease of use, comprehensive system performance measures, and extensive post simulation analysis capability. The system has been used to support trade studies of the NASA data system needs in the 1985 to 1990 time frame.

  5. The F-92 RELIANT: Air transport system design simulation

    NASA Technical Reports Server (NTRS)

    1992-01-01

    The design proposal of a semester long design project by group 'F' for AE 441 is addressed. In formulating this design, the driving philosophy was not just to fulfill the mission requirements (discussed in chapter two), but to do so in a creative manner - this explains the unconventional aircraft design, named the F-92 RELIANT. Although unconventional, and perhaps more expensive to produce, the design has distinct advantages which could only be attained through such a creative design. Major components of the F-92 Reliant include: (1) unobstructed cargo bay, 1024 cu. in. capability; (2) loading ramp; (3) dual wing configuration; and (4) polyhedral wing configuration. These design components either originated or evolved to create an aircraft that would most effectively meet the goals of cargo transportation in AeroWorld at minimum cost.

  6. Chemical biology tools for regulating RAS signaling complexity in space and time.

    PubMed

    van Hattum, Hilde; Waldmann, Herbert

    2014-09-18

    Rat sarcoma (RAS) family members are small GTPases that control a number of signaling pathways important for normal cellular proliferation. Therefore, it is no surprise that a significant portion of human tumors express constitutively active mutated RAS proteins, which leads to deregulation of RAS signaling pathways, resulting in pathological perturbations of cell growth and death. Although the molecular details of RAS signaling cascades are well understood, there is still a largely unmet need for small molecule probes to control RAS signaling in space and time. More broadly, given the prevalence of mutated RAS in cancer, the need to translate the insights obtained from using small molecule probes into clinically useful drugs is also significant. In this review, we introduce RAS proteins and the signaling pathways they are involved in, and discuss some of the innovative chemical biology approaches to regulate RAS signaling, which include the exploitation of newly identified binding pockets, covalent inhibitors for mutated RAS, and RAS localization impairment.

  7. The arginine finger of RasGAP helps Gln-61 align the nucleophilic water in GAP-stimulated hydrolysis of GTP.

    PubMed

    Resat, H; Straatsma, T P; Dixon, D A; Miller, J H

    2001-05-22

    The Ras family of GTPases is a collection of molecular switches that link receptors on the plasma membrane to signaling pathways that regulate cell proliferation and differentiation. The accessory GTPase-activating proteins (GAPs) negatively regulate the cell signaling by increasing the slow intrinsic GTP to GDP hydrolysis rate of Ras. Mutants of Ras are found in 25-30% of human tumors. The most dramatic property of these mutants is their insensitivity to the negative regulatory action of GAPs. All known oncogenic mutants of Ras map to a small subset of amino acids. Gln-61 is particularly important because virtually all mutations of this residue eliminate sensitivity to GAPs. Despite its obvious importance for carcinogenesis, the role of Gln-61 in the GAP-stimulated GTPase activity of Ras has remained a mystery. Our molecular dynamics simulations of the p21ras-p120GAP-GTP complex suggest that the local structure around the catalytic region can be different from that revealed by the x-ray crystal structure. We find that the carbonyl oxygen on the backbone of the arginine finger supplied in trans by p120GAP (Arg-789) interacts with a water molecule in the active site that is forming a bridge between the NH(2) group of the Gln-61 and the gamma-phosphate of GTP. Thus, Arg-789 may play a dual role in generating the nucleophile as well as stabilizing the transition state for PO bond cleavage. PMID:11371635

  8. Women and the RAS: 100 years of Fellowship

    NASA Astrophysics Data System (ADS)

    Bailey, Mandy

    2016-02-01

    In January 1916, the RAS elected its first women Fellows. Mandy Bailey looks back at the social and scientific circumstances of this step towards equality, introducing a year of articles celebrating the centenary.

  9. Chaperone-mediated specificity in Ras and Rap signaling.

    PubMed

    Azoulay-Alfaguter, Inbar; Strazza, Marianne; Mor, Adam

    2015-01-01

    Ras and Rap proteins are closely related small guanosine triphosphatase (GTPases) that share similar effector-binding domains but operate in a very different signaling networks; Ras has a dominant role in cell proliferation, while Rap mediates cell adhesion. Ras and Rap proteins are regulated by several shared processes such as post-translational modification, phosphorylation, activation by guanine exchange factors and inhibition by GTPase-activating proteins. Sub-cellular localization and trafficking of these proteins to and from the plasma membrane are additional important regulatory features that impact small GTPases function. Despite its importance, the trafficking mechanisms of Ras and Rap proteins are not completely understood. Chaperone proteins play a critical role in trafficking of GTPases and will be the focus of the discussion in this work. We will review several aspects of chaperone biology focusing on specificity toward particular members of the small GTPase family. Understanding this specificity should provide key insights into drug development targeting individual small GTPases.

  10. Interferon-β Signaling Contributes to Ras Transformation

    PubMed Central

    Tsai, Yu-Chen; Pestka, Sidney; Wang, Lu-Hai; Runnels, Loren W.; Wan, Shan; Lyu, Yi Lisa; Liu, Leroy F.

    2011-01-01

    Increasing evidence has pointed to activated type I interferon signaling in tumors. However, the molecular basis for such activation and its role in tumorigenesis remain unclear. In the current studies, we report that activation of type I interferon (IFN) signaling in tumor cells is primarily due to elevated secretion of the type I interferon, IFN-β. Studies in oncogene-transformed cells suggest that oncogenes such as Ras and Src can activate IFN-β signaling. Significantly, elevated IFN-β signaling in Ras-transformed mammary epithelial MCF-10A cells was shown to contribute to Ras transformation as evidenced by morphological changes, anchorage-independent growth, and migratory properties. Our results demonstrate for the first time that the type I IFN, IFN-β, contributes to Ras transformation and support the notion that oncogene-induced cytokines play important roles in oncogene transformation. PMID:21897875

  11. The RASopathies: Developmental syndromes of Ras/MAPK pathway dysregulation

    PubMed Central

    Tidyman, William E.; Rauen, Katherine A.

    2009-01-01

    The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of the cell cycle, differentiation, growth and cell senescence, all of which are critical to normal development. It is therefore not surprising that its dysregulation has profound effects on development. A class of developmental disorders, the “RASopathies”, is caused by germline mutations in genes that encode protein components of the Ras/MAPK pathway. The vast majority of these mutations result in increased signal transduction down the Ras/MAPK pathway, but usually to a lesser extent than somatic mutations associated with oncogenesis. Each syndrome exhibits unique phenotypic features, however, since they all cause dysregulation of the Ras/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes, including characteristic facial features, cardiac defects, cutaneous abnormalities, neurocognitive delay and a predisposition to malignancies. Here we review the clinical and underlying molecular basis for each of these syndromes. PMID:19467855

  12. Advancing lighting and daylighting simulation: The transition from analysis to design aid tools

    SciTech Connect

    Hitchcock, R.J.

    1995-05-01

    This paper explores three significant software development requirements for making the transition from stand-alone lighting simulation/analysis tools to simulation-based design aid tools. These requirements include specialized lighting simulation engines, facilitated methods for creating detailed simulatable building descriptions, an automated techniques for providing lighting design guidance. Initial computer implementations meant to address each of these requirements are discussed to further elaborate these requirements and to illustrate work-in-progress.

  13. Conceptual Design of Simulation Models in an Early Development Phase of Lunar Spacecraft Simulator Using SMP2 Standard

    NASA Astrophysics Data System (ADS)

    Lee, Hoon Hee; Koo, Cheol Hea; Moon, Sung Tae; Han, Sang Hyuck; Ju, Gwang Hyeok

    2013-08-01

    The conceptual study for Korean lunar orbiter/lander prototype has been performed in Korea Aerospace Research Institute (KARI). Across diverse space programs around European countries, a variety of simulation application has been developed using SMP2 (Simulation Modelling Platform) standard related to portability and reuse of simulation models by various model users. KARI has not only first-hand experience of a development of SMP compatible simulation environment but also an ongoing study to apply the SMP2 development process of simulation model to a simulator development project for lunar missions. KARI has tried to extend the coverage of the development domain based on SMP2 standard across the whole simulation model life-cycle from software design to its validation through a lunar exploration project. Figure. 1 shows a snapshot from a visualization tool for the simulation of lunar lander motion. In reality, a demonstrator prototype on the right-hand side of image was made and tested in 2012. In an early phase of simulator development prior to a kick-off start in the near future, targeted hardware to be modelled has been investigated and indentified at the end of 2012. The architectural breakdown of the lunar simulator at system level was performed and the architecture with a hierarchical tree of models from the system to parts at lower level has been established. Finally, SMP Documents such as Catalogue, Assembly, Schedule and so on were converted using a XML(eXtensible Mark-up Language) converter. To obtain benefits of the suggested approaches and design mechanisms in SMP2 standard as far as possible, the object-oriented and component-based design concepts were strictly chosen throughout a whole model development process.

  14. PRG3 induces Ras-dependent oncogenic cooperation in gliomas

    PubMed Central

    Yakubov, Eduard; Chen, Daishi; Broggini, Thomas; Sehm, Tina; Majernik, Gökce Hatipoglu; Hock, Stefan W.; Schwarz, Marc; Engelhorn, Tobias; Doerfler, Arnd; Buchfelder, Michael; Eyupoglu, Ilker Y.; Savaskan, Nicolai E.

    2016-01-01

    Malignant gliomas are one of the most devastating cancers in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and disturbed gene expression levels conferring selective growth advantage. Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas. We have identified perturbed PRG3 levels in human malignant brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. Further, imbalanced PRG3 levels in gliomas foster Ras-driven oncogenic amplification with increased proliferation and cell migration although angiogenesis was unaffected. Hence, PRG3 interacts with RasGEF1 (RasGRF1/CDC25), undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 (PRG3ΔCT) inhibits Ras. Moreover PRG3 silencing makes gliomas resistant to Ras inhibition. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome. Thus, our data show that the interference with PRG3 homeostasis amplifies oncogenic properties and foster the malignancy potential in gliomas. PMID:27058420

  15. Calmodulin modulates H-Ras mediated Raf-1 activation.

    PubMed

    Moretó, Jemina; Lladó, Anna; Vidal-Quadras, Maite; Calvo, Maria; Pol, Albert; Enrich, Carlos; Tebar, Francesc

    2008-06-01

    We have previously demonstrated that, in COS-1 cells, inhibition of calmodulin increases Ras-GTP levels although it decreases Raf-1 activity and consequently MAPK. The present study analyzes the role of calmodulin in the regulation of Raf-1. First we show, using FRET microscopy, that inhibition of Raf-1 was not a consequence of a decreased interaction between H-Ras and Raf-1. Besides, the analysis of the phosphorylation state of Raf-1 showed that calmodulin, through downstream PI3K, is essential to ensure the Ser338-Raf-1 phosphorylation, critical for Raf-1 activation. We also show that the expression of a dominant negative mutant of PI3K impairs the calmodulin-mediated Raf-1 activation; in addition, both calmodulin and PI3K inhibitors decrease phospho-Ser338 and Raf-1 activity from upstream active H-Ras (H-RasG12V) and this effect is dependent on endocytosis. Importantly, in H-Ras depleted COS-1 cells, calmodulin does not modulate MAPK activation. Altogether, the results suggest that calmodulin regulation of MAPK in COS-1 cells relies upon H-Ras control of Raf-1 activity and involves PI3K.

  16. Plk2 Raps up Ras to subdue synapses

    PubMed Central

    Lee, Kea Joo; Hoe, Hyang-Sook

    2011-01-01

    We recently identified the activity-inducible protein kinase Plk2 as a novel overseer of the balance between Ras and Rap small GTPases. Plk2 achieves a profound level of regulatory control by interacting with and phosphorylating at least four Ras and Rap guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Combined, these actions result in synergistic suppression of Ras and hyperstimulation of Rap signaling. Perturbation of Plk2 function abolished homeostatic adaptation of synapses to enhanced activity and impaired behavioral adaptation in various learning tasks, indicating that this regulation was critical for maintaining appropriate Ras/Rap levels. These studies provide insights into the highly cooperative nature of Ras and Rap regulation in neurons. However, different GEF and GAP substrates of Plk2 also controlled specific aspects of dendritic spine morphology, illustrating the ability of individual GAPs/GEFs to assemble microdomains of Ras and Rap signaling that respond to different stimuli and couple to distinct output pathways. PMID:21776418

  17. Design and development of an unconstrained dynamic knee simulator.

    PubMed

    McLean, C A; Ahmed, A M

    1993-05-01

    A dynamic knee simulator has been developed to allow in-vitro investigation of the mechanical response of the joint corresponding to dynamic functional activities, e.g., walking. In the simulator, the controlled inputs are the time-histories of three parameters of a given dynamic activity: the flexion angle, and the flexion/extension moment and tibial axial force components of the foot-to-floor reaction. A combination of stepping motors and electro-hydraulic actuators is used to apply to a knee specimen, simultaneously and independently, the specified load and/or displacement inputs while allowing unconstrained relative motion between the joint members. Satisfactory performance of the simulator has been established for walking gait conditions based on measurements on three fresh-frozen specimens.

  18. An intelligent simulation environment for control system design

    SciTech Connect

    Robinson, J.T.

    1989-01-01

    The Oak Ridge National Laboratory is currently assisting in the development of advanced control systems for the next generation of nuclear power plants. This paper presents a prototype interactive and intelligent simulation environment being developed to support this effort. The environment combines tools from the field of Artificial Intelligence; in particular object-oriented programming, a LISP programming environment, and a direct manipulation user interface; with traditional numerical methods for simulating combined continuous/discrete processes. The resulting environment is highly interactive and easy to use. Models may be created and modified quickly through a window oriented direct manipulation interface. Models may be modified at any time, even as the simulation is running, and the results observed immediately via real-time graphics. 8 refs., 3 figs.

  19. Resistance of R-Ras knockout mice to skin tumour induction

    PubMed Central

    May, Ulrike; Prince, Stuart; Vähätupa, Maria; Laitinen, Anni M.; Nieminen, Katriina; Uusitalo-Järvinen, Hannele; Järvinen, Tero A. H.

    2015-01-01

    The R-ras gene encodes a small GTPase that is a member of the Ras family. Despite close sequence similarities, R-Ras is functionally distinct from the prototypic Ras proteins; no transformative activity and no activating mutations of R-Ras in human malignancies have been reported for it. R-Ras activity appears inhibitory towards tumour proliferation and invasion, and to promote cellular quiescence. Contrary to this, using mice with a deletion of the R-ras gene, we found that R-Ras facilitates DMBA/TPA-induced skin tumour induction. The tumours appeared in wild-type (WT) mice on average 6 weeks earlier than in R-Ras knockout (R-Ras KO) mice. WT mice developed almost 6 times more tumours than R-Ras KO mice. Despite strong R-Ras protein expression in the dermal blood vessels, no R-Ras could be detected in the epidermis from where the tumours arose. The DMBA/TPA skin tumourigenesis-model is highly dependent upon inflammation, and we found a greatly attenuated skin inflammatory response to DMBA/TPA-treatment in the R-Ras KO mice in the context of leukocyte infiltration and proinflammatory cytokine expression. Thus, these data suggest that despite its characterised role in promoting cellular quiescence, R-Ras is pro-tumourigenic in the DMBA/TPA tumour model and important for the inflammatory response to DMBA/TPA treatment. PMID:26133397

  20. K-Ras4B phosphorylation at Ser181 is inhibited by calmodulin and modulates K-Ras activity and function.

    PubMed

    Alvarez-Moya, B; López-Alcalá, C; Drosten, M; Bachs, O; Agell, N

    2010-11-01

    Fine tuning of Ras activity is widely known as a mechanism to induce different cellular responses. Recently, we have shown that calmodulin (CaM) binds to K-Ras and that K-Ras phosphorylation inhibits its interaction with CaM. In this study we report that CaM inhibits K-Ras phosphorylation at Ser181 by protein kinase C (PKC) in vivo, and this is a mechanism to modulate K-Ras activity and signaling. Although CaM inhibition increased the activation of endogenous K-Ras, PKC inhibition decreased its activation status. We demonstrate that K-Ras phosphorylation decreased susceptibility to p120GAP activity. Accordingly, we also observed that non-phosphorylable K-Ras mutant exhibits a less sustained activation profile and do not efficiently activate AKT at low growth factor doses compared with wild-type K-Ras. It is interesting that the physiological responses induced by K-Ras are affected by this phosphorylation; when K-Ras cannot be phosphorylated it exhibits a remarkably decreased ability to stimulate proliferation in non-saturated serum conditions. Finally, we demonstrate that phosphorylation also regulates oncogenic K-Ras functions, as focus formation capacity, mobility and apoptosis resistance upon adriamycin treatment of cells expressing oncogenic K-Ras that cannot be phosphorylated are highly compromised. Moreover, at low serum concentration proliferation and survival is practically inhibited when cells cannot phosphorylate oncogenic K-Ras. In this condition, K-Ras phosphorylation is essential to ensure a proper activation of mitogen-activated protein kinase and PI3K/AKT pathways. In summary, our findings suggest that the interplay between CaM interaction and PKC phosphorylation is essential to regulate non-oncogenic and oncogenic K-Ras activity and functionality.

  1. Case Studies in Computer Adaptive Test Design through Simulation.

    ERIC Educational Resources Information Center

    Eignor, Daniel R.; And Others

    The extensive computer simulation work done in developing the computer adaptive versions of the Graduate Record Examinations (GRE) Board General Test and the College Board Admissions Testing Program (ATP) Scholastic Aptitude Test (SAT) is described in this report. Both the GRE General and SAT computer adaptive tests (CATs), which are fixed length…

  2. Designing Simulations for Athletic Training Students through Interprofessional Teaching Collaboration

    ERIC Educational Resources Information Center

    Tivener, Kristin Ann; Gloe, Donna Sue

    2015-01-01

    Context: While multidisciplinary team approaches to education and practice have been promoted for decades, literature on collaborative efforts in athletic training and nursing remains sparse. Objective: The goal of this article is to provide an example of an interprofessional teaching collaboration in which a simulation scenario was developed…

  3. Design and implementation of the Interactive Communications Simulator (ICS)

    NASA Astrophysics Data System (ADS)

    Modestino, J. W.; Matis, K. R.; Jung, K. Y.; Vickers, A. L.

    1981-04-01

    This report describes the development and capabilities of a fairly comprehensive system for the digital simulation of a wide variety of point-to-point digital communication systems. This system is called the Interactive Communications Simulator (ICS). The ICS is a flexible, graphics oriented, high speed, and highly interactive hardware/software system consisting of a PDP 11-40 minicomputer acting as host to a fast peripheral array processor, the Floating Point Systems AP-120B. Its modeling structure is the classical breakout of the various generic signal processing functions in any communication link, from source to sink. The signal processing functions are predominantly modeled in terms of their complex envelope representations for uniformity, ease, and accuracy of analyses. It is fully supported by an extensive graphics support package and many powerful analysis subroutines, to facilitate user-interactions, analyses, and output displays. The modeling and simulation tasks are optimally partitioned between the PDP 11/40 host and the AP-120B peripheral array processor to ensure ease-of-use and highly efficient manipulations. The ICS also features realistic channel models, in addition to the analytically expedient Additive White Gaussian Noise (AWGN) channel, so that the performance and behavior of all modeled transceiver functions can be more exactly assessed and specified. All simulation modules are written in the AP Assembly Language, and the system software, graphics support package and analysis subroutines are written in DEC FORTRAN IV.

  4. Knowledge-Driven Design of Virtual Patient Simulations

    ERIC Educational Resources Information Center

    Vergara, Victor; Caudell, Thomas; Goldsmith, Timothy; Panaiotis; Alverson, Dale

    2009-01-01

    Virtual worlds provide unique opportunities for instructors to promote, study, and evaluate student learning and comprehension. In this article, Victor Vergara, Thomas Caudell, Timothy Goldsmith, Panaiotis, and Dale Alverson explore the advantages of using virtual reality environments to create simulations for medical students. Virtual simulations…

  5. Designing Better Scaffolding in Teaching Complex Systems with Graphical Simulations

    ERIC Educational Resources Information Center

    Li, Na

    2013-01-01

    Complex systems are an important topic in science education today, but they are usually difficult for secondary-level students to learn. Although graphic simulations have many advantages in teaching complex systems, scaffolding is a critical factor for effective learning. This dissertation study was conducted around two complementary research…

  6. A DISCUS EMP simulator design for long narrow buried objects

    SciTech Connect

    van Lint, V.A.J.; Berger, R.A.; Crevier, W.; Dancz, J.; Naff, T.; Pettus, E.; Stettner, R.

    1982-12-01

    A Distributed Source Conducting Medium Underground System (DISCUS) Simulator concept to provide both fast rise time and late time EMP excitation is presented. An early time module has been constructed and tested. Calculations of the electric and magnetic fields for this single prototype are compared with experimental measurements.

  7. Aiding Design of Wave Energy Converters via Computational Simulations

    NASA Astrophysics Data System (ADS)

    Jebeli Aqdam, Hejar; Ahmadi, Babak; Raessi, Mehdi; Tootkaboni, Mazdak

    2015-11-01

    With the increasing interest in renewable energy sources, wave energy converters will continue to gain attention as a viable alternative to current electricity production methods. It is therefore crucial to develop computational tools for the design and analysis of wave energy converters. A successful design requires balance between the design performance and cost. Here an analytical solution is used for the approximate analysis of interactions between a flap-type wave energy converter (WEC) and waves. The method is verified using other flow solvers and experimental test cases. Then the model is used in conjunction with a powerful heuristic optimization engine, Charged System Search (CSS) to explore the WEC design space. CSS is inspired by charged particles behavior. It searches the design space by considering candidate answers as charged particles and moving them based on the Coulomb's laws of electrostatics and Newton's laws of motion to find the global optimum. Finally the impacts of changes in different design parameters on the power takeout of the superior WEC designs are investigated. National Science Foundation, CBET-1236462.

  8. High-Alpha Research Vehicle (HARV) longitudinal controller: Design, analyses, and simulation resultss

    NASA Technical Reports Server (NTRS)

    Ostroff, Aaron J.; Hoffler, Keith D.; Proffitt, Melissa S.; Brown, Philip W.; Phillips, Michael R.; Rivers, Robert A.; Messina, Michael D.; Carzoo, Susan W.; Bacon, Barton J.; Foster, John F.

    1994-01-01

    This paper describes the design, analysis, and nonlinear simulation results (batch and piloted) for a longitudinal controller which is scheduled to be flight-tested on the High-Alpha Research Vehicle (HARV). The HARV is an F-18 airplane modified for and equipped with multi-axis thrust vectoring. The paper includes a description of the facilities, a detailed review of the feedback controller design, linear analysis results of the feedback controller, a description of the feed-forward controller design, nonlinear batch simulation results, and piloted simulation results. Batch simulation results include maximum pitch stick agility responses, angle of attack alpha captures, and alpha regulation for full lateral stick rolls at several alpha's. Piloted simulation results include task descriptions for several types of maneuvers, task guidelines, the corresponding Cooper-Harper ratings from three test pilots, and some pilot comments. The ratings show that desirable criteria are achieved for almost all of the piloted simulation tasks.

  9. A virtual simulator designed for collision prevention in proton therapy

    SciTech Connect

    Jung, Hyunuk; Kum, Oyeon; Han, Youngyih Park, Hee Chul; Kim, Jin Sung; Choi, Doo Ho

    2015-10-15

    Purpose: In proton therapy, collisions between the patient and nozzle potentially occur because of the large nozzle structure and efforts to minimize the air gap. Thus, software was developed to predict such collisions between the nozzle and patient using treatment virtual simulation. Methods: Three-dimensional (3D) modeling of a gantry inner-floor, nozzle, and robotic-couch was performed using SolidWorks based on the manufacturer’s machine data. To obtain patient body information, a 3D-scanner was utilized right before CT scanning. Using the acquired images, a 3D-image of the patient’s body contour was reconstructed. The accuracy of the image was confirmed against the CT image of a humanoid phantom. The machine components and the virtual patient were combined on the treatment-room coordinate system, resulting in a virtual simulator. The simulator simulated the motion of its components such as rotation and translation of the gantry, nozzle, and couch in real scale. A collision, if any, was examined both in static and dynamic modes. The static mode assessed collisions only at fixed positions of the machine’s components, while the dynamic mode operated any time a component was in motion. A collision was identified if any voxels of two components, e.g., the nozzle and the patient or couch, overlapped when calculating volume locations. The event and collision point were visualized, and collision volumes were reported. Results: All components were successfully assembled, and the motions were accurately controlled. The 3D-shape of the phantom agreed with CT images within a deviation of 2 mm. Collision situations were simulated within minutes, and the results were displayed and reported. Conclusions: The developed software will be useful in improving patient safety and clinical efficiency of proton therapy.

  10. High Altitude Venus Operations Concept Trajectory Design, Modeling and Simulation

    NASA Technical Reports Server (NTRS)

    Lugo, Rafael A.; Ozoroski, Thomas A.; Van Norman, John W.; Arney, Dale C.; Dec, John A.; Jones, Christopher A.; Zumwalt, Carlie H.

    2015-01-01

    A trajectory design and analysis that describes aerocapture, entry, descent, and inflation of manned and unmanned High Altitude Venus Operation Concept (HAVOC) lighter-than-air missions is presented. Mission motivation, concept of operations, and notional entry vehicle designs are presented. The initial trajectory design space is analyzed and discussed before investigating specific trajectories that are deemed representative of a feasible Venus mission. Under the project assumptions, while the high-mass crewed mission will require further research into aerodynamic decelerator technology, it was determined that the unmanned robotic mission is feasible using current technology.

  11. Regulation of an H-ras-related transcript by parathyroid hormone in rat osteosarcoma cells

    NASA Technical Reports Server (NTRS)

    Scott, D. K.; Weaver, W. R.; Clohisy, J. C.; Brakenhoff, K. D.; Kahn, A. J.; Partridge, N. C.

    1992-01-01

    The rat osteosarcoma cell line UMR 106-01 is a commonly used model system for the study of osteoblast function. However, it also expresses a phenotype characteristic of transformed cells. To test whether the latter could be accounted for by aberrant oncogene expression, we probed Northern blots of UMR and other osteoblastic cells with a panel of oncogene probes. These blots, when probed with a cDNA specific for v-H-ras, revealed a 7.0-kilobase (kb) H-ras-related transcript (designated HRRT) in UMR 106-01 cells that was not expressed in other osteoblastic cells. Osteoblast-enriched calvarial cells expressed the typical 1.1-kb H-ras mRNA, which was absent in UMR cells. Additionally, Western blots of lysates of UMR cells documented the presence of three proteins immunologically related to H-rasp21. To determine whether HRRT represented a recombinant retrovirus product, Northern blots were probed with a cDNA specific for the highly conserved gag-pol region of Moloney murine leukemia virus. These blots showed parallel cross-reactivity with an apparently identical transcript of 7.0 kb. The 7.0-kb transcripts detected by both v-H-ras and gag-pol probes declined to the same extent after treatment with concentrations of PTH known to inhibit proliferation of these cells. PTH regulated the abundance of HRRT in a time- and dose-dependent manner, with greatest repression of the transcript after 8 h of treatment with 10(-8) M PTH. The decrease in HRRT could not be completely accounted for by changes in transcriptional activity, as determined by nuclear run-on assays.(ABSTRACT TRUNCATED AT 250 WORDS).

  12. A methodology towards virtualisation-based high performance simulation platform supporting multidisciplinary design of complex products

    NASA Astrophysics Data System (ADS)

    Ren, Lei; Zhang, Lin; Tao, Fei; (Luke) Zhang, Xiaolong; Luo, Yongliang; Zhang, Yabin

    2012-08-01

    Multidisciplinary design of complex products leads to an increasing demand for high performance simulation (HPS) platforms. One great challenge is how to achieve high efficient utilisation of large-scale simulation resources in distributed and heterogeneous environments. This article reports a virtualisation-based methodology to realise a HPS platform. This research is driven by the issues concerning large-scale simulation resources deployment and complex simulation environment construction, efficient and transparent utilisation of fine-grained simulation resources and high reliable simulation with fault tolerance. A framework of virtualisation-based simulation platform (VSIM) is first proposed. Then the article investigates and discusses key approaches in VSIM, including simulation resources modelling, a method to automatically deploying simulation resources for dynamic construction of system environment, and a live migration mechanism in case of faults in run-time simulation. Furthermore, the proposed methodology is applied to a multidisciplinary design system for aircraft virtual prototyping and some experiments are conducted. The experimental results show that the proposed methodology can (1) significantly improve the utilisation of fine-grained simulation resources, (2) result in a great reduction in deployment time and an increased flexibility for simulation environment construction and (3)achieve fault tolerant simulation.

  13. Design and modeling of an on-silicon spiral inductor library using improved EM simulations

    NASA Astrophysics Data System (ADS)

    Goni-Iturri, A.; Khemchandani, S. L.; del Pino, F. J.; Garcia, J.; Gonzalez, B.; Hernandez, A.

    2005-06-01

    This paper deals with the design and modeling of integrated spiral inductors for RF applications by means of a general purpose Electromagnetic (EM) simulator. These tools allow optimizing flexibly the inductor layout structure. The inductor performance can be obtained by using a three-dimensional design tool or a two-dimensional one. Planar 2-D or so called 2.5-Ds simulators are faster and accept complex coil geometries. We have used one of these simulators, the Advanced Design System planar EM simulator, Momentum, from Agilent. The inductor quality factor (Q) is limited, among other phenomena, by the series resistance of the metal traces and the substrate losses. Therefore the simulator requires an accurate set up of the process and simulator parameters and a correct algorithm to model metal thickness to rely on simulation results. In this paper we analyze and compare these different approaches. A high-quality factor inductor library on a 0.35 μm SiGe technology at 5 GHz is also designed in this work using the proper simulator set up. Nine of the inductors have been fabricated and measured to test the simulator reliability. Measurements taken over a frequency range from 500 MHz to 10GHz show a good agreement with 2.5-EM simulations.

  14. Delineation of the Roles Played by RasG and RasC in cAMP-dependent Signal Transduction during the Early Development of Dictyostelium discoideum

    PubMed Central

    Bolourani, Parvin; Spiegelman, George B.

    2006-01-01

    On starvation, the cellular slime mold Dictyostelium discoideum initiates a program of development leading to formation of multicellular structures. The initial cell aggregation requires chemotaxis to cyclic AMP (cAMP) and relay of the cAMP signal by the activation of adenylyl cyclase (ACA), and it has been shown previously that the Ras protein RasC is involved in both processes. Insertional inactivation of the rasG gene resulted in delayed aggregation and a partial inhibition of early gene expression, suggesting that RasG also has a role in early development. Both chemotaxis and ACA activation were reduced in the rasG− cells, but the effect on chemotaxis was more pronounced. When the responses of rasG− cells to cAMP were compared with the responses of rasC− and rasC−rasG− strains, generated in otherwise isogenic backgrounds, these studies revealed that signal transduction through RasG is more important in chemotaxis and early gene expression, but that signal transduction through RasC is more important in ACA activation. Because the loss of either of the two Ras proteins alone did not result in a total loss of signal output down either of the branches of the cAMP signal-response pathway, there appears to be some overlap of function. PMID:16885420

  15. Simian virus 40 large T antigen contains two independent activities that cooperate with a ras oncogene to transform rat embryo fibroblasts.

    PubMed Central

    Cavender, J F; Conn, A; Epler, M; Lacko, H; Tevethia, M J

    1995-01-01

    The simian virus 40 large T antigen immortalizes growing primary cells in culture. In addition, this viral oncoprotein cooperates with an activated ras protein to produce dense foci on monolayers of rat embryo fibroblasts (REF). The relationship between independent immortalization and cooperative transformation with ras has not been defined. Previously, two regions of T antigen were shown to contain immortalization activities. An N-terminal fragment consisting of amino acids 1 to 147 immortalizes rodent cells (L. Sompayrac and K. J. Danna, Virology 181:412-415, 1991). Loss-of-function analysis indicated that immortalization depended on integrity of the T-antigen segments containing amino acids 351 to 450 and 533 to 626 (T. D. Kierstead and M. J. Tevethia, J. Virol. 67:1817-1829, 1993). The experiments described here were directed toward determining whether these same T-antigen regions were sufficient for cooperation with ras. Initially, constructs that produce T antigens containing amino acids 176 to 708 (T176-708) or 1 to 147 were tested in a ras cooperation assay. Both polypeptides cooperated with ras to produce dense foci on monolayers of primary REF. These results showed that T antigen contains two separate ras cooperation activities. In order to determine the N-terminal limit of the ras cooperation activity contained within the T176-708 polypeptide, a series of constructs designed to produce fusion proteins containing T-antigen segments beginning at residues 251, 301, 337, 351, 371, 401, 451, 501, 551, 601, and 651 was generated. Each of these constructs was tested for the capacity to cooperate with ras to produce dense foci on REF monolayers. The results indicated that a polypeptide containing T-antigen amino acids 251 to 708 (T251-708) was sufficient to cooperate with ras, whereas the more extensively truncated products were not. The abilities of the N-terminally truncated T antigens to bind p53 were examined in p53-deficient cells infected with a

  16. Design of the IPIRG-2 simulated seismic forcing function

    SciTech Connect

    Olson, R.; Scott, P.; Wilkowski, G.

    1996-02-01

    A series of pipe system experiments was conducted in IPIRG-2 that used a realistic seismic forcing function. Because the seismic forcing function was more complex than the single-frequency increasing-amplitude sinusoidal forcing function used in the IPIRG-1 pipe system experiments, considerable effort went into designing the function. This report documents the design process for the seismic forcing function used in the IPIRG-2 pipe system experiments.

  17. Advanced Information Technology in Simulation Based Life Cycle Design

    NASA Technical Reports Server (NTRS)

    Renaud, John E.

    2003-01-01

    In this research a Collaborative Optimization (CO) approach for multidisciplinary systems design is used to develop a decision based design framework for non-deterministic optimization. To date CO strategies have been developed for use in application to deterministic systems design problems. In this research the decision based design (DBD) framework proposed by Hazelrigg is modified for use in a collaborative optimization framework. The Hazelrigg framework as originally proposed provides a single level optimization strategy that combines engineering decisions with business decisions in a single level optimization. By transforming this framework for use in collaborative optimization one can decompose the business and engineering decision making processes. In the new multilevel framework of Decision Based Collaborative Optimization (DBCO) the business decisions are made at the system level. These business decisions result in a set of engineering performance targets that disciplinary engineering design teams seek to satisfy as part of subspace optimizations. The Decision Based Collaborative Optimization framework more accurately models the existing relationship between business and engineering in multidisciplinary systems design.

  18. High Sensitivity MEMS Strain Sensor: Design and Simulation

    PubMed Central

    Mohammed, Ahmed A. S.; Moussa, Walied A.; Lou, Edmond

    2008-01-01

    In this article, we report on the new design of a miniaturized strain microsensor. The proposed sensor utilizes the piezoresistive properties of doped single crystal silicon. Employing the Micro Electro Mechanical Systems (MEMS) technology, high sensor sensitivities and resolutions have been achieved. The current sensor design employs different levels of signal amplifications. These amplifications include geometric, material and electronic levels. The sensor and the electronic circuits can be integrated on a single chip, and packaged as a small functional unit. The sensor converts input strain to resistance change, which can be transformed to bridge imbalance voltage. An analog output that demonstrates high sensitivity (0.03mV/με), high absolute resolution (1με) and low power consumption (100μA) with a maximum range of ±4000με has been reported. These performance characteristics have been achieved with high signal stability over a wide temperature range (±50°C), which introduces the proposed MEMS strain sensor as a strong candidate for wireless strain sensing applications under harsh environmental conditions. Moreover, this sensor has been designed, verified and can be easily modified to measure other values such as force, torque…etc. In this work, the sensor design is achieved using Finite Element Method (FEM) with the application of the piezoresistivity theory. This design process and the microfabrication process flow to prototype the design have been presented.

  19. Constraining Particle Variation in Lunar Regolith for Simulant Design

    NASA Technical Reports Server (NTRS)

    Schrader, Christian M.; Rickman, Doug; Stoeser, Douglas; Hoelzer, Hans

    2008-01-01

    Simulants are used by the lunar engineering community to develop and test technologies for In Situ Resource Utilization (ISRU), excavation and drilling, and for mitigation of hazards to machinery and human health. Working with the United States Geological Survey (USGS), other NASA centers, private industry and academia, Marshall Space Flight Center (MSFC) is leading NASA s lunar regolith simulant program. There are two main efforts: simulant production and simulant evaluation. This work requires a highly detailed understanding of regolith particle type, size, and shape distribution, and of bulk density. The project has developed Figure of Merit (FoM) algorithms to quantitatively compare these characteristics between two materials. The FoM can be used to compare two lunar regolith samples, regolith to simulant, or two parcels of simulant. In work presented here, we use the FoM algorithm to examine the variance of particle type in Apollo 16 highlands regolith core and surface samples. For this analysis we have used internally consistent particle type data for the 90-150 m fraction of Apollo core 64001/64002 from station 4, core 60009/60010 from station 10, and surface samples from various Apollo 16 stations. We calculate mean modal compositions for each core and for the group of surface samples and quantitatively compare samples of each group to its mean as a measurement of within-group variance; we also calculate an FoM for every sample against the mean composition of 64001/64002. This gives variation with depth at two locations and between Apollo 16 stations. Of the tested groups, core 60009/60010 has the highest internal variance with an average FoM score of 0.76 and core 64001/64002 has the lowest with an average FoM of 0.92. The surface samples have a low but intermediate internal variance with an average FoM of 0.79. FoM s calculated against the 64001/64002 mean reference composition range from 0.79-0.97 for 64001/64002, from 0.41-0.91 for 60009/60010, and from

  20. Clinical simulation as a boundary object in design of health IT-systems.

    PubMed

    Rasmussen, Stine Loft; Jensen, Sanne; Lyng, Karen Marie

    2013-01-01

    Healthcare organizations are very complex, holding numerous stakeholders with various approaches and goals towards the design of health IT-systems. Some of these differences may be approached by applying the concept of boundary objects in a participatory IT-design process. Traditionally clinical simulation provides the opportunity to evaluate the design and the usage of clinical IT-systems without endangering the patients and interrupting clinical work. In this paper we present how clinical simulation additionally holds the potential to function as a boundary object in the design process. The case points out that clinical simulation provides an opportunity for discussions and mutual learning among the various stakeholders involved in design of standardized electronic clinical documentation templates. The paper presents and discusses the use of clinical simulation in the translation, transfer and transformation of knowledge between various stakeholders in a large healthcare organization. PMID:23941951

  1. Simulation And Design Of A Reflection Magnet For The EAST Neutral Beam System

    SciTech Connect

    Zhen Liangli; Dong Huchun

    2011-09-26

    The simulation and design of a reflection magnet to be installed in the Experimental Advanced Superconducting Tokamak (EAST) neutral beam injection system are reported. A parametric design and simulation for the reflection magnet was carried out. For a deuterium beam with 42 cm as the bending radius, the intensity of reflection magnet field is about 1376 Gs at the energy of 80 keV. In order to determine position of the ion dump and the surface power load, a particle simulation with Monte Carlo was developed to study ion trajectories. In addition, the louver design is introduced.

  2. Hermes CX-7: Air transport system design simulation

    NASA Technical Reports Server (NTRS)

    Amer, Brian; Barter, John; Colucci, Jay; Foley, Caryn; Kockler, James; Rapp, David; Zeiger, Matthew

    1992-01-01

    The Hermes CX-7 has been designed to service the overnight parcel package delivery needs of the cities of Aeroworld as determined in the G-Dome Enterprises market survey. The design optimization centers on the prime goal of servicing the needs of these cities as efficiently and profitably as possible. The greatest factors which affect the design of an aircraft for the mission outlined in the Request for Proposal are cost, construction feasibility and effectiveness of the design. Other influencing factors are given by the constraints of the market, including a maximum takeoff and landing distance of 60 feet, storage capability in a container of size 5 ft. x 3 ft. x 2 ft., cargo packages of 2 inch and 4 inch cubes, and ability to turn with a radius no larger than 60 feet. Safety considerations such as flying at or below Mach one (30 ft/s) and controllability and maintainability of the aircraft must also be designed into the aircraft. Another influential factor is the efficiency of the aircraft which involves optimizations and tradeoffs of such factors as weight, lifting surface sizing, structural redundancy, and material costs.

  3. The Significance of Ras Activity in Pancreatic Cancer Initiation

    PubMed Central

    Logsdon, Craig D.; Lu, Weiqin

    2016-01-01

    The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K-RAS. However, oncogenic K-Rasmt alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Rasmt. Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Rasmt is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Rasmt activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Rasmt. Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Rasmt activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease. PMID:26929740

  4. H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells: a role for MMP-2 in the H-ras-induced invasive phenotype.

    PubMed

    Moon, A; Kim, M S; Kim, T G; Kim, S H; Kim, H E; Chen, Y Q; Kim, H R

    2000-01-15

    Elevated p21ras expression is associated with tumor aggressiveness in breast cancer including the extent of invasion into fat tissues, infiltration into lymphatic vessels and tumor recurrence. In the present study, we have examined the roles of H-ras and N-ras, members of the human ras gene family, in the pathogenesis of breast cancer. We show that H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells (MCF10A) as determined by the Matrigel invasion assay, whereas both H-ras and N-ras induce anchorage-independent growth, as shown by soft agar assay. We examined the effects of H-ras and N-ras activation on the expression of MMP-2 and MMP-9, which can degrade type IV collagen, the major structural collagen of the basement membrane. We show that MMP-2 is efficiently induced by H-ras, whereas MMP-9 induction is more prominent in N-ras-activated MCF10A cells. We also show that H-ras-mediated invasiveness is significantly inhibited when the expression of MMP-2 is down-regulated, using an oligodeoxyribonucleotide complementary to the MMP-2 mRNA, or when MMP-2 activity is blocked by its inhibitor TIMP-2 (tissue inhibitors of matrix metalloproteinase-2). Our results show that the H-ras-induced invasive phenotype is associated more closely with the expression of MMP-2 in human breast epithelial cells, rather than the induction of MMP-9 expression, as shown previously for rat embryonic fibroblasts.

  5. [Research advances of K-ras mutation in the prognosis and targeted therapy of gastric cancer].

    PubMed

    Huang, Y; Wei, J; Liu, B R

    2016-02-01

    K-ras mutations have been described in 30% of human cancers with significantly different mutation frequencies. High K-ras mutation frequency is found in many cancers such as pancreas and lung cancers, whereas, gastric cancer has a relatively low K-ras mutation frequency. In recent years, numerous researches have focused on the K-ras mutation in gastric cancer. This review summarizes the K-ras mutation frequency in gastric cancer, the relationship of K-ras mutation with clinicopathologic features and prognosis of gastric cancer patients, targeted therapy for K-ras mutated gastric cancer, some small-molecular inhibitors of K-ras, and development of targeted therapy drugs for K-ras signaling pathway in gastric cancer.

  6. A role for RalGDS and a novel Ras effector in the Ras-mediated inhibition of skeletal myogenesis.

    PubMed

    Ramocki, M B; White, M A; Konieczny, S F; Taparowsky, E J

    1998-07-10

    Oncogenic Ras inhibits the differentiation of skeletal muscle cells through the activation of multiple downstream signaling pathways, including a Raf-dependent, mitogen-activated or extracellular signal-regulated kinase kinase/mitogen-activated protein kinase (MEK/MAPK)-independent pathway. Here we report that a non-Raf binding Ras effector-loop variant (H-Ras G12V,E37G), which retains interaction with the Ral guanine nucleotide dissociation stimulator (RalGDS), inhibits the conversion of MyoD-expressing C3H10T1/2 mouse fibroblasts to skeletal muscle. We show that H-Ras G12V,E37G, RalGDS, and the membrane-localized RalGDS CAAX protein inhibit the activity of alpha-actin-Luc, a muscle-specific reporter gene containing a necessary E-box and serum response factor (SRF) binding site, while a RalGDS protein defective for Ras interaction has no effect on alpha-actin-Luc transcription. H-Ras G12V,E37G does not activate endogenous MAPK, but does increase SRF-dependent transcription. Interestingly, RalGDS, RalGDS CAAX, and RalA G23V inhibit H-Ras G12V, E37G-induced expression of an SRF-regulated reporter gene, demonstrating that signaling through RalGDS does not duplicate the action of H-Ras G12V,E37G in this system. As additional evidence for this, we show that H-Ras G12V,E37G inhibits the expression of troponin I-Luc, an SRF-independent muscle-specific reporter gene, whereas RalGDS and RalGDS CAAX do not. Although our studies show that signaling through RalGDS can interfere with the expression of reporter genes dependent on SRF activity (including alpha-actin-Luc), our studies also provide strong evidence that an additional signaling molecule(s) activated by H-Ras G12V,E37G is required to achieve the complete inhibition of the myogenic differentiation program.

  7. Cellular and subcellular localization of Ras guanyl nucleotide-releasing protein in the rat hippocampus.

    PubMed

    Pierret, P; Vallée, A; Mechawar, N; Dower, N A; Stone, J C; Richardson, P M; Dunn, R J

    2001-01-01

    Ras guanyl nucleotide-releasing protein (RasGRP) is a recently discovered Ras guanyl nucleotide exchange factor that is expressed in selected regions of the rodent CNS, with high levels of expression in the hippocampus. Biochemical studies suggest that RasGRP can activate the Ras signal pathway in response to changes in diacylglycerol and possibly calcium. To investigate potential sites for RasGRP signaling, we have determined the cellular and subcellular localization of RasGRP protein in adult rat hippocampus, and have also examined the appearance of RasGRP mRNA and protein during hippocampal development. RasGRP immunoreactivity is predominately localized to those neurons participating in the direct cortico-hippocampo-cortical loop. In both hippocampal and entorhinal neurons, RasGRP protein appeared to be localized to both dendrites and somata, but not to axons. Electron microscopy of hippocampal pyramidal cells confirmed RasGRP immunoreactivity in neuronal cell bodies and dendrites, where it appeared to be associated with microtubules. The localization of RasGRP to dendrites suggests a role for this pathway in the regulation of dendritic function. Examination of developing hippocampal structures indicated that RasGRP mRNA and protein appear synchronously during the first 2 weeks of postnatal development as these neurons become fully mature. This result indicates that the RasGRP signal transduction pathway is not required during early hippocampal development, but is a feature of mature neurons during the later stages of development.

  8. Signal integration by lipid-mediated spatial cross talk between Ras nanoclusters.

    PubMed

    Zhou, Yong; Liang, Hong; Rodkey, Travis; Ariotti, Nicholas; Parton, Robert G; Hancock, John F

    2014-03-01

    Lipid-anchored Ras GTPases form transient, spatially segregated nanoclusters on the plasma membrane that are essential for high-fidelity signal transmission. The lipid composition of Ras nanoclusters, however, has not previously been investigated. High-resolution spatial mapping shows that different Ras nanoclusters have distinct lipid compositions, indicating that Ras proteins engage in isoform-selective lipid sorting and accounting for different signal outputs from different Ras isoforms. Phosphatidylserine is a common constituent of all Ras nanoclusters but is only an obligate structural component of K-Ras nanoclusters. Segregation of K-Ras and H-Ras into spatially and compositionally distinct lipid assemblies is exquisitely sensitive to plasma membrane phosphatidylserine levels. Phosphatidylserine spatial organization is also modified by Ras nanocluster formation. In consequence, Ras nanoclusters engage in remote lipid-mediated communication, whereby activated H-Ras disrupts the assembly and operation of spatially segregated K-Ras nanoclusters. Computational modeling and experimentation reveal that complex effects of caveolin and cortical actin on Ras nanoclustering are similarly mediated through regulation of phosphatidylserine spatiotemporal dynamics. We conclude that phosphatidylserine maintains the lateral segregation of diverse lipid-based assemblies on the plasma membrane and that lateral connectivity between spatially remote lipid assemblies offers important previously unexplored opportunities for signal integration and signal processing.

  9. Architectural design and simulation of a virtual memory

    NASA Technical Reports Server (NTRS)

    Kwok, G.; Chu, Y.

    1971-01-01

    Virtual memory is an imaginary main memory with a very large capacity which the programmer has at his disposal. It greatly contributes to the solution of the dynamic storage allocation problem. The architectural design of a virtual memory is presented which implements by hardware the idea of queuing and scheduling the page requests to a paging drum in such a way that the access of the paging drum is increased many times. With the design, an increase of up to 16 times in page transfer rate is achievable when the virtual memory is heavily loaded. This in turn makes feasible a great increase in the system throughput.

  10. Ras-mutant cancer cells display B-Raf binding to Ras that activates extracellular signal-regulated kinase and is inhibited by protein kinase A phosphorylation.

    PubMed

    Li, Yanping; Takahashi, Maho; Stork, Philip J S

    2013-09-20

    The small G protein Ras regulates proliferation through activation of the mitogen-activated protein (MAP) kinase (ERK) cascade. The first step of Ras-dependent activation of ERK signaling is Ras binding to members of the Raf family of MAP kinase kinase kinases, C-Raf and B-Raf. Recently, it has been reported that in melanoma cells harboring oncogenic Ras mutations, B-Raf does not bind to Ras and does not contribute to basal ERK activation. For other types of Ras-mutant tumors, the relative contributions of C-Raf and B-Raf are not known. We examined non-melanoma cancer cell lines containing oncogenic Ras mutations and express both C-Raf and B-Raf isoforms, including the lung cancer cell line H1299 cells. Both B-Raf and C-Raf were constitutively bound to oncogenic Ras and contributed to Ras-dependent ERK activation. Ras binding to B-Raf and C-Raf were both subject to inhibition by the cAMP-dependent protein kinase PKA. cAMP inhibited the growth of H1299 cells and Ras-dependent ERK activation via PKA. PKA inhibited the binding of Ras to both C-Raf and B-Raf through phosphorylations of C-Raf at Ser-259 and B-Raf at Ser-365, respectively. These studies demonstrate that in non-melanocytic Ras-mutant cancer cells, Ras signaling to B-Raf is a significant contributor to ERK activation and that the B-Raf pathway, like that of C-Raf, is a target for inhibition by PKA. We suggest that cAMP and hormones coupled to cAMP may prove useful in dampening the effects of oncogenic Ras in non-melanocytic cancer cells through PKA-dependent actions on B-Raf as well as C-Raf.

  11. Advanced Simulation Technology to Design Etching Process on CMOS Devices

    NASA Astrophysics Data System (ADS)

    Kuboi, Nobuyuki

    2015-09-01

    Prediction and control of plasma-induced damage is needed to mass-produce high performance CMOS devices. In particular, side-wall (SW) etching with low damage is a key process for the next generation of MOSFETs and FinFETs. To predict and control the damage, we have developed a SiN etching simulation technique for CHxFy/Ar/O2 plasma processes using a three-dimensional (3D) voxel model. This model includes new concepts for the gas transportation in the pattern, detailed surface reactions on the SiN reactive layer divided into several thin slabs and C-F polymer layer dependent on the H/N ratio, and use of ``smart voxels''. We successfully predicted the etching properties such as the etch rate, polymer layer thickness, and selectivity for Si, SiO2, and SiN films along with process variations and demonstrated the 3D damage distribution time-dependently during SW etching on MOSFETs and FinFETs. We confirmed that a large amount of Si damage was caused in the source/drain region with the passage of time in spite of the existing SiO2 layer of 15 nm in the over etch step and the Si fin having been directly damaged by a large amount of high energy H during the removal step of the parasitic fin spacer leading to Si fin damage to a depth of 14 to 18 nm. By analyzing the results of these simulations and our previous simulations, we found that it is important to carefully control the dose of high energy H, incident energy of H, polymer layer thickness, and over-etch time considering the effects of the pattern structure, chamber-wall condition, and wafer open area ratio. In collaboration with Masanaga Fukasawa and Tetsuya Tatsumi, Sony Corporation. We thank Mr. T. Shigetoshi and Mr. T. Kinoshita of Sony Corporation for their assistance with the experiments.

  12. Design and validation of inert homemade explosive simulants for X-ray-based inspection systems

    NASA Astrophysics Data System (ADS)

    Faust, Anthony A.; Nacson, Sabatino; Koffler, Bruce; Bourbeau, Éric; Gagne, Louis; Laing, Robin; Anderson, C. J.

    2014-05-01

    Transport Canada (TC), the Canadian Armed Forces, and other public security agencies have an interest in the assessment of the potential utility of advanced explosives detection technologies to aid in the detection and interdiction of commercial grade, military grade, and homemade or improvised explosives (HME or IE). The availability of suitable, non-hazardous, non-toxic, explosive simulants is of concern when assessing the potential utility of such detection systems. Lack of simulants limits the training opportunities, and ultimately the detection probability, of security personnel using these systems. While simulants for commercial and military grade explosives are available for a wide variety of detection technologies, the design and production of materials to simulate improvised explosives has not kept pace with this emerging threat. Funded by TC and the Canadian Safety and Security Program, Defence Research and Development Canada (DRDC), Visiontec Systems, and Optosecurity engaged in an effort to develop inert, non-toxic Xray interrogation simulants for IE materials such as ammonium nitrate, potassium chlorate, and triacetone triperoxide. These simulants were designed to mimic key X-ray interrogation-relevant material properties of real improvised explosives, principally their bulk density and effective atomic number. Different forms of the simulants were produced and tested, simulating the different explosive threat formulations that could be encountered by front line security workers. These simulants comply with safety and stability requirements, and as best as possible match form and homogeneity. This paper outlines the research program, simulant design, and validation.

  13. Unfixing Design Fixation: From Cause to Computer Simulation

    ERIC Educational Resources Information Center

    Dong, Andy; Sarkar, Somwrita

    2011-01-01

    This paper argues that design fixation, in part, entails fixation at the level of meta-representation, the representation of the relation between a representation and its reference. In this paper, we present a mathematical model that mimics the idea of how fixation can occur at the meta-representation level. In this model, new abstract concepts…

  14. LiteVis: Integrated Visualization for Simulation-Based Decision Support in Lighting Design.

    PubMed

    Sorger, Johannes; Ortner, Thomas; Luksch, Christian; Schwärzler, Michael; Gröller, Eduard; Piringer, Harald

    2016-01-01

    State-of-the-art lighting design is based on physically accurate lighting simulations of scenes such as offices. The simulation results support lighting designers in the creation of lighting configurations, which must meet contradicting customer objectives regarding quality and price while conforming to industry standards. However, current tools for lighting design impede rapid feedback cycles. On the one side, they decouple analysis and simulation specification. On the other side, they lack capabilities for a detailed comparison of multiple configurations. The primary contribution of this paper is a design study of LiteVis, a system for efficient decision support in lighting design. LiteVis tightly integrates global illumination-based lighting simulation, a spatial representation of the scene, and non-spatial visualizations of parameters and result indicators. This enables an efficient iterative cycle of simulation parametrization and analysis. Specifically, a novel visualization supports decision making by ranking simulated lighting configurations with regard to a weight-based prioritization of objectives that considers both spatial and non-spatial characteristics. In the spatial domain, novel concepts support a detailed comparison of illumination scenarios. We demonstrate LiteVis using a real-world use case and report qualitative feedback of lighting designers. This feedback indicates that LiteVis successfully supports lighting designers to achieve key tasks more efficiently and with greater certainty. PMID:26529708

  15. Design, development and testing of an ambient lighting simulator for external illumination of a transport simulator cockpit

    NASA Technical Reports Server (NTRS)

    Batson, Vernon M.; Gupton, Lawrence E.

    1990-01-01

    Researchers at the NASA-Langley Research Center several years ago began to examine concepts for a facility which could simulate the full range of lighting conditions encountered in flight. The purpose of this facility was to evaluate advanced technology display devices in a cockpit environment. The Aircraft Cockpit Ambient Lighting Simulation System (ACALSS) has been developed to meet that need. The ACALSS surrounds a wide-body part-task simulator cockpit, the Advanced Display Evaluation Cockpit, and interfaces with a VAX 11/780 computer, which is used to host both a math model of a modern transport aircraft and a solar motion model (which animates a servoed sun simulator). Several concepts were evaluated and an efficient design using an ellipsoid reflector and Fresnel luminaires was selected for implementation.

  16. SKA Weak Lensing II: Simulated Performance and Survey Design Considerations

    NASA Astrophysics Data System (ADS)

    Bonaldi, Anna; Harrison, Ian; Camera, Stefano; Brown, Michael L.

    2016-08-01

    We construct a pipeline for simulating weak lensing cosmology surveys with the Square Kilometre Array (SKA), taking as inputs telescope sensitivity curves; correlated source flux, size and redshift distributions; a simple ionospheric model; source redshift and ellipticity measurement errors. We then use this simulation pipeline to optimise a 2-year weak lensing survey performed with the first deployment of the SKA (SKA1). Our assessments are based on the total signal-to-noise of the recovered shear power spectra, a metric that we find to correlate very well with a standard dark energy figure of merit. We first consider the choice of frequency band, trading off increases in number counts at lower frequencies against poorer resolution; our analysis strongly prefers the higher frequency Band 2 (950-1760 MHz) channel of the SKA-MID telescope to the lower frequency Band 1 (350-1050 MHz). Best results would be obtained by allowing the centre of Band 2 to shift towards lower frequency, around 1.1 GHz. We then move on to consider survey size, finding that an area of 5,000 square degrees is optimal for most SKA1 instrumental configurations. Finally, we forecast the performance of a weak lensing survey with the second deployment of the SKA. The increased survey size (3π steradian) and sensitivity improves both the signal-to-noise and the dark energy metrics by two orders of magnitude.

  17. Unified Simulation and Analysis Framework for Deep Space Navigation Design

    NASA Technical Reports Server (NTRS)

    Anzalone, Evan; Chuang, Jason; Olsen, Carrie

    2013-01-01

    As the technology that enables advanced deep space autonomous navigation continues to develop and the requirements for such capability continues to grow, there is a clear need for a modular expandable simulation framework. This tool's purpose is to address multiple measurement and information sources in order to capture system capability. This is needed to analyze the capability of competing navigation systems as well as to develop system requirements, in order to determine its effect on the sizing of the integrated vehicle. The development for such a framework is built upon Model-Based Systems Engineering techniques to capture the architecture of the navigation system and possible state measurements and observations to feed into the simulation implementation structure. These models also allow a common environment for the capture of an increasingly complex operational architecture, involving multiple spacecraft, ground stations, and communication networks. In order to address these architectural developments, a framework of agent-based modules is implemented to capture the independent operations of individual spacecraft as well as the network interactions amongst spacecraft. This paper describes the development of this framework, and the modeling processes used to capture a deep space navigation system. Additionally, a sample implementation describing a concept of network-based navigation utilizing digitally transmitted data packets is described in detail. This developed package shows the capability of the modeling framework, including its modularity, analysis capabilities, and its unification back to the overall system requirements and definition.

  18. Design and implementation of interactive strap-down inertial navigation simulation system for UAV

    NASA Astrophysics Data System (ADS)

    Cheng, Chuan-qi; Cheng, Xiang; Hao, Xiang-yang; Zhao, Man-dan

    2016-01-01

    Strap-down inertial navigation system (SINS) is widely used in military field, to facilitate the study of SINS algorithms and various coupled navigation algorithms, a simulation system of SINS is designed. Based on modular design, with good portability and expansibility, the system consists of four independent modules: analysis module of motion state, trajectory simulator, IMU simulation module and SINS calculation module. With graphical interface, the system can control every motion state of the trajectory, which is convenient to generate various trajectories efficiently. Using rotation vector attitude algorithm to process simulation data, experiment results show that the attitude, velocity and position error is consistent with the theoretical value, which verifies the rationality of the simulation model and the availability of the simulation system.

  19. Altered expression of Bcl-2, c-Myc, H-Ras, K-Ras, and N-Ras does not influence the course of mycosis fungoides

    PubMed Central

    Maj, Joanna; Jankowska-Konsur, Alina; Plomer-Niezgoda, Ewa; Sadakierska-Chudy, Anna

    2013-01-01

    Introduction Data about genetic alterations in mycosis fungoides (MF) are limited and their significance not fully elucidated. The aim of the study was to explore the expression of various oncogenes in MF and to assess their influence on the disease course. Material and methods Skin biopsies from 27 MF patients (14 with early MF and 13 with advanced disease) and 8 healthy volunteers were analyzed by real-time polymerase chain reaction (PCR) to detect Bcl-2, c-Myc, H-Ras, K-Ras and N-Ras expression. All PCR reactions were performed using an Applied Biosystems 7900HT Fast Real-Time PCR System and interpreted using Sequence Detection Systems software which utilizes the comparative delta Ct method. The level of mRNA was normalized to GAPDH expression. All data were analyzed statistically. Results All evaluated oncogenes were found to be expressed in the skin from healthy controls and MF patients. Bcl-2 (–4.2 ±2.2 vs. –2.2 ±1.1; p = 0.01), H-Ras (–3.0 ±3.3 vs. 0.6 ±2.6; p = 0.01) and N-Ras (–3.6 ±2.0 vs. –1.1 ±2.4; p = 0.03) were expressed at significantly lower levels in MF. No relationships between oncogene expression and disease stage, presence of distant metastases and survival were observed (p > 0.05 for all comparisons). Conclusions The pathogenic role and prognostic significance of analyzed oncogenes in MF seem to be limited and further studies are needed to establish better prognostic factors for patients suffering from MF. PMID:24273576

  20. Inhibition of ras oncogene: a novel approach to antineoplastic therapy.

    PubMed

    Scharovsky, O G; Rozados, V R; Gervasoni, S I; Matar, P

    2000-01-01

    The most frequently detected oncogene alterations, both in animal and human cancers, are the mutations in the ras oncogene family. These oncogenes are mutated or overexpressed in many human tumors, with a high incidence in tumors of the pancreas, thyroid, colon, lung and certain types of leukemia. Ras is a small guanine nucleotide binding protein that transduces biological information from the cell surface to cytoplasmic components within cells. The signal is transduced to the cell nucleus through second messengers, and it ultimately induces cell division. Oncogenic forms of p21(ras) lead to unregulated, sustained signaling through downstream effectors. The ras family of oncogenes is involved in the development of both primary tumors and metastases making it a good therapeutic target. Several therapeutic approaches to cancer have been developed pointing to reducing the altered gene product or to eliminating its biological function: (1) gene therapy with ribozymes, which are able to break down specific RNA sequences, or with antisense oligonucleotides, (2) immunotherapy through passive or active immunization protocols, and (3) inhibition of p21(ras) farnesylation either by inhibition of farnesyl transferase or synthesis inhibition of farnesyl moieties. PMID:10895051

  1. Ras regulation of DNA-methylation and cancer

    SciTech Connect

    Patra, Samir Kumar

    2008-04-01

    Genome wide hypomethylation and regional hypermethylation of cancer cells and tissues remain a paradox, though it has received a convincing confirmation that epigenetic switching systems, including DNA-methylation represent a fundamental regulatory mechanism that has an impact on genome maintenance and gene transcription. Methylated cytosine residues of vertebrate DNA are transmitted by clonal inheritance through the strong preference of DNA methyltransferase, DNMT1, for hemimethylated-DNA. Maintenance of methylation patterns is necessary for normal development of mice, and aberrant methylation patterns are associated with many human tumours. DNMT1 interacts with many proteins during cell cycle progression, including PCNA, p53, EZH2 and HP1. Ras family of GTPases promotes cell proliferation by its oncogenic nature, which transmits signals by multiple pathways in both lipid raft dependent and independent fashion. DNA-methylation-mediated repression of DNA-repair protein O6-methylguanine DNA methyltransferase (MGMT) gene and increased rate of K-Ras mutation at codon for amino acids 12 and 13 have been correlated with a secondary role for Ras-effector homologues (RASSFs) in tumourigenesis. Lines of evidence suggest that DNA-methylation associated repression of tumour suppressors and apoptotic genes and ceaseless proliferation of tumour cells are regulated in part by Ras-signaling. Control of Ras GTPase signaling might reduce the aberrant methylation and accordingly may reduce the risk of cancer development.

  2. Oncogenic Ras influences the expression of multiple lncRNAs.

    PubMed

    Kotake, Yojiro; Naemura, Madoka; Kitagawa, Kyoko; Niida, Hiroyuki; Tsunoda, Toshiyuki; Shirasawa, Senji; Kitagawa, Masatoshi

    2016-08-01

    Recent ultrahigh-density tiling array and large-scale transcriptome analysis have revealed that large numbers of long non-coding RNAs (lncRNAs) are transcribed in mammals. Several lncRNAs have been implicated in transcriptional regulation, organization of nuclear structure, and post-transcriptional processing. However, the regulation of expression of lncRNAs is less well understood. Here, we show that the exogenous and endogenous expression of an oncogenic form of small GTPase Ras (called oncogenic Ras) decrease the expression of lncRNA ANRIL (antisense non-coding RNA in the INK4 locus), which is involved in the regulation of cellular senescence. We also show that forced expression of oncogenic Ras increases the expression of lncRNA PANDA (p21 associated ncRNA DNA damage activated), which is involved in the regulation of apoptosis. Microarray analysis demonstrated that expression of multiple lncRNAs fluctuated by forced expression of oncogenic Ras. These findings indicate that oncogenic Ras regulates the expression of a large number of lncRNAs including functional lncRNAs, such as ANRIL and PANDA.

  3. Design and simulation of a plant control system for a GCFR demonstration plant

    SciTech Connect

    Estrine, E.A.; Greiner, H.G.

    1980-02-01

    A plant control system is being designed for a 300 MW(e) Gas Cooled Fast Breeder Reactor (GCFR) demonstration plant. Control analysis is being performed as an integral part of the plant design process to ensure that control requirements are satisfied as the plant design evolves. Plant models and simulations are being developed to generate information necessary to further define control system requirements for subsequent plant design iterations.

  4. Design and simulation of satellite attitude control system based on Simulink and VR

    NASA Astrophysics Data System (ADS)

    Zhang, Yang; Gan, Qingbo; Kang, Jingshu

    2016-01-01

    In order to research satellite attitude control system design and visual simulation, the simulation framework of satellite dynamics and attitude control using Simulink were established. The design of satellite earth-oriented control system based on quaternion feedback was completed. The 3D scene based on VR was created and models in the scene were driven by simulation data of Simulink. By coordinate transformation. successful observing the scene in inertial coordinate system, orbit coordinate system and body coordinate system. The result shows that application of simulation method of Simulink combined with VR in the design of satellite attitude control system field, has the advantages of high confidence level, hard real-time property, multi-perspective and multi-coordinate system observing the scene, and improves the comprehensibility and accuracy of the design.

  5. The Numerical Propulsion System Simulation: A Multidisciplinary Design System for Aerospace Vehicles

    NASA Technical Reports Server (NTRS)

    Lytle, John K.

    1999-01-01

    Advances in computational technology and in physics-based modeling are making large scale, detailed simulations of complex systems possible within the design environment. For example, the integration of computing, communications, and aerodynamics has reduced the time required to analyze ma or propulsion system components from days and weeks to minutes and hours. This breakthrough has enabled the detailed simulation of major propulsion system components to become a routine part of design process and to provide the designer with critical information about the components early in the design process. This paper describes the development of the Numerical Propulsion System Simulation (NPSS), a multidisciplinary system of analysis tools that is focussed on extending the simulation capability from components to the full system. This will provide the product developer with a "virtual wind tunnel" that will reduce the number of hardware builds and tests required during the development of advanced aerospace propulsion systems.

  6. CALOR89 calorimeter simulations, benchmarking, and design calculations

    SciTech Connect

    Handler, T. ); Panakkal, J.K.; Proudfoot, J. ); Cremaldi, L.; Moore, B.; Reidy, J.J. ); Alsmiller, R.G. Jr.; Fu, P.; Gabriel, T.A. )

    1990-01-01

    Results on CALOR89 benchmarking and design calculations utilizing the CALOR89 programs are presented. The benchmarking is done with respect to the ZEUS and DO calorimeters. The design calculations were done for a variety of absorbers (depleted uranium, lead, and iron) of various thickness for a given scintillator thickness and for a fixed absorber thickness using various thickness for the scintillator. These studies indicate that a compensating calorimeter can be built using lead as the absorber, whereas a purely iron calorimeter would be non-compensating. A depleted uranium calorimeter would possibly be unsuitable if used in a large configuration and a high luminosity machine because of the delayed energy release from capture gammas. 11 refs., 5 figs.

  7. Rainwater catchment system design using simulated future climate data

    NASA Astrophysics Data System (ADS)

    Wallace, Corey D.; Bailey, Ryan T.; Arabi, Mazdak

    2015-10-01

    Rainwater harvesting techniques are used worldwide to augment potable water supply, provide water for small-scale irrigation practices, increase rainwater-use efficiency for sustained crop growth in arid and semi-arid regions, decrease urban stormwater flow volumes, and in general to relieve dependency on urban water resources cycles. A number of methods have been established in recent years to estimate reliability of rainwater catchment systems (RWCS) and thereby properly size the components (roof catchment area, storage tank size) of the system for a given climatic region. These methods typically use historical or stochastically-generated rainfall patterns to quantify system performance and optimally size the system, with the latter accounting for possible rainfall scenarios based on statistical relationships of historical rainfall patterns. To design RWCS systems that can sustainably meet water demand under future climate conditions, this paper introduces a method that employs climatic data from general circulation models (GCMs) to develop a suite of catchment area vs. storage size design curves that capture uncertainty in future climate scenarios. Monthly rainfall data for the 2010-2050 time period is statistically downscaled to daily values using a Markov chain algorithm, with results used only from GCMs that yield rainfall patterns that are statistically consistent with historical rainfall patterns. The process is demonstrated through application to two climatic regions of the Federated States of Micronesia (FSM) in the western Pacific, wherein the majority of the population relies on rainwater harvesting for potable water supply. Through the use of design curves, communities can provide household RWCS that achieve a certain degree of storage reliability. The method described herein can be applied generally to any geographic region. It can be used to first, assess the future performance of existing household systems; and second, to design or modify systems

  8. Identification of a farnesol analog as a Ras function inhibitor using both an in vivo Ras activation sensor and a phenotypic screening approach

    PubMed Central

    Srinivasan, Kamalakkannan; Subramanian, Thangaiah; Spielmann, H. Peter

    2013-01-01

    Mutations in Ras isoforms such as K-Ras, N-Ras, and H-Ras contribute to roughly 85, 15, and 1 % of human cancers, respectively. Proper membrane targeting of these Ras isoforms, a prerequisite for Ras activity, requires farnesylation or geranylgeranylation at the C-terminal CAAX box. We devised an in vivo screening strategy based on monitoring Ras activation and phenotypic physiological outputs for assaying synthetic Ras function inhibitors (RFI). Ras activity was visualized by the trans-location of RBDRaf1-GFP to activated Ras at the plasma membrane. By using this strategy, we screened one synthetic farnesyl substrate analog (AGOH) along with nine putative inhibitors and found that only m-CN-AGOH inhibited Ras activation. Phenotypic analysis of starving cells could be used to monitor polarization, motility, and the inability of these treated cells to aggregate properly during fruiting body formation. Incorporation of AGOH and m-CN-AGOH to cellular proteins was detected by western blot. These screening assays can be incorporated into a high throughput screening format using Dictyostelium discoideum and automated microscopy to determine effective RFIs. These RFI candidates can then be further tested in mammalian systems. PMID:24194124

  9. Muscarinic receptors transform NIH 3T3 cells through a Ras-dependent signalling pathway inhibited by the Ras-GTPase-activating protein SH3 domain.

    PubMed Central

    Mattingly, R R; Sorisky, A; Brann, M R; Macara, I G

    1994-01-01

    Expression of certain subtypes of human muscarinic receptors in NIH 3T3 cells provides an agonist-dependent model of cellular transformation by formation of foci in response to carbachol. Although focus formation correlates with the ability of the muscarinic receptors to activate phospholipase C, the actual mitogenic signal transduction pathway is unknown. Through cotransfection experiments and measurement of the activation state of native and epitope-tagged Ras proteins, the contributions of Ras and Ras GTPase-activating protein (Ras-GAP) to muscarinic receptor-dependent transformation were defined. Transforming muscarinic receptors were able to activate Ras, and such activation was required for transformation because focus formation was inhibited by coexpression of either Ras with a dominant-negative mutation or constructs of Ras-GAP that include the catalytic domain. Coexpression of the N-terminal region of GAP or of its isolated SH3 (Src homology 3) domain, but not its SH2 domain, was also sufficient to suppress muscarinic receptor-dependent focus formation. Point mutations at conserved residues in the Ras-GAP SH3 domain reversed its action, leading to an increase in carbachol-dependent transformation. The inhibitory effect of expression of the Ras-GAP SH3 domain occurs proximal to Ras activation and is selective for the mitogenic pathway activated by carbachol, as cellular transformation by either v-Ras or trkA/nerve growth factor is unaffected. Images PMID:7969134

  10. Some real-time simulation applications to Space Shuttle approach and landing design and test

    NASA Technical Reports Server (NTRS)

    Law, H. G., III; Stegall, H. W.

    1984-01-01

    In the present discussion of the roles played by real time, man-in-the-loop engineering simulation in the development of NASA Space Shuttle approaches and landings, attention is given to the function of the simulator as a design and verification tool. Aspects of the problem posed by Shuttle landings, and the difficulties involved in this problem's quantification, are noted. Recent results of control system studies for pitch axis control, using fixed- and motion-base simulators, are discussed.

  11. Lunar Regolith Characterization for Simulant Design and Evaluation

    NASA Technical Reports Server (NTRS)

    Schrader, Christian M.; Stoeser, Douglas; Rickman, Douglas; Wentworth, Susan J.; Mclemore, Carole; Fikes, John; McKay, David S.

    2009-01-01

    NASA's Marshall Space Flight Center (MSFC), in conjunction with the United States Geological Survey (USGS), is implementing a new data acquisition strategy to support the development and evaluation of lunar regolith simulants. The objective is to characterize the variance in particle composition, size, shape, and bulk density of the lunar regolith. Apollo drive and drill cores are the preferred samples as they allow for investigation of variation with depth, and many proposed operations on the moon will involve excavation of lunar regolith to depths of at least tens of centimeters. Multiple Apollo cores will be sampled multiple times along their vertical axes and analyzed. This will permit statistical statements about variation both within a core, between closely spaced cores, and between distant areas.

  12. Neutron micro-beam design simulation by Monte Carlo

    NASA Astrophysics Data System (ADS)

    Pazirandeh, Ali; Taheri, Ali

    2007-09-01

    Over the last two decades neutron micro-beam has increasingly been developing in view of various applications in molecular activation analysis, micro-radiography in space and aviation and in radiation induced bystander effects in bio-cells. In this paper the structure and simulation of a neutron micro-beam is presented. The collimator for micro-beam is made of a polyethylene cylinder with a small hole along the centerline of the cylinder. The hole is filled with very thin needles in triangular or rectangular arrangement. The neutron source was reactor neutrons or a spontaneous Cf-252 neutron source falling on the top side of the collimator. The outgoing thermal and epithermal neutron fluxes were calculated.

  13. Simulation tools for computer-aided design and numerical investigations of high-power gyrotrons

    NASA Astrophysics Data System (ADS)

    Damyanova, M.; Balabanova, E.; Kern, S.; Illy, S.; Sabchevski, S.; Thumm, M.; Vasileva, E.; Zhelyazkov, I.

    2012-03-01

    Modelling and simulation are essential tools for computer-aided design (CAD), analysis and optimization of high-power gyrotrons used as radiation sources for electron cyclotron resonance heating (ECRH) and current drive (ECCD) of magnetically confined plasmas in the thermonuclear reactor ITER. In this communication, we present the current status of our simulation tools and discuss their further development.

  14. Designing a Virtual Olympic Games Framework by Using Simulation in Web 2.0 Technologies

    ERIC Educational Resources Information Center

    Stoilescu, Dorian

    2013-01-01

    Instructional simulation had major difficulties in the past for offering limited possibilities in practice and learning. This article proposes a link between instructional simulation and Web 2.0 technologies. More exactly, I present the design of the Virtual Olympic Games Framework (VOGF), as a significant demonstration of how interactivity in…

  15. Design and Application of Interactive Simulations in Problem-Solving in University-Level Physics Education

    ERIC Educational Resources Information Center

    Ceberio, Mikel; Almudí, José Manuel; Franco, Ángel

    2016-01-01

    In recent years, interactive computer simulations have been progressively integrated in the teaching of the sciences and have contributed significant improvements in the teaching-learning process. Practicing problem-solving is a key factor in science and engineering education. The aim of this study was to design simulation-based problem-solving…

  16. Design of an Indoor Sonic Boom Simulator at NASA Langley Research Center

    NASA Technical Reports Server (NTRS)

    Klos, Jacob; Sullivan, Brenda M.; Shepherd, Kevin P.

    2008-01-01

    Construction of a simulator to recreate the soundscape inside residential buildings exposed to sonic booms is scheduled to start during the summer of 2008 at NASA Langley Research Center. The new facility should be complete by the end of the year. The design of the simulator allows independent control of several factors that create the indoor soundscape. Variables that will be isolated include such factors as boom duration, overpressure, rise time, spectral shape, level of rattle, level of squeak, source of rattle and squeak, level of vibration and source of vibration. Test subjects inside the simulator will be asked to judge the simulated soundscape, which will represent realistic indoor boom exposure. Ultimately, this simulator will be used to develop a functional relationship between human response and the sound characteristics creating the indoor soundscape. A conceptual design has been developed by NASA personnel, and is currently being vetted through small-scale risk reduction tests that are being performed in-house. The purpose of this document is to introduce the conceptual design, identify how the indoor response will be simulated, briefly outline some of the risk reduction tests that have been completed to vet the design, and discuss the impact of these tests on the simulator design.

  17. Simulation verification techniques study: Simulation self test hardware design and techniques report

    NASA Technical Reports Server (NTRS)

    1974-01-01

    The final results are presented of the hardware verification task. The basic objectives of the various subtasks are reviewed along with the ground rules under which the overall task was conducted and which impacted the approach taken in deriving techniques for hardware self test. The results of the first subtask and the definition of simulation hardware are presented. The hardware definition is based primarily on a brief review of the simulator configurations anticipated for the shuttle training program. The results of the survey of current self test techniques are presented. The data sources that were considered in the search for current techniques are reviewed, and results of the survey are presented in terms of the specific types of tests that are of interest for training simulator applications. Specifically, these types of tests are readiness tests, fault isolation tests and incipient fault detection techniques. The most applicable techniques were structured into software flows that are then referenced in discussions of techniques for specific subsystems.

  18. Simulating Water Markets to Help Design Water Rights Regimes

    NASA Astrophysics Data System (ADS)

    Harou, J. J.; Erfani, T.; Huskova, I.; Binions, O.

    2012-12-01

    In many catchments in England no further licenses are available from the Environmental regulator that provides them. The possibility of trading water between license holders has been recognized as a potentially effective and economically efficient strategy to mitigate increasing scarcity. Although trading licenses has been possible since several years, it very rarely happens (roughly 50 trades in 8 years). Several barriers to trade exist including lack of sufficient and prolonged scarcity, license-holder unwillingness to risk future renewal, likelihood license will be downgraded during a trade, duration of time required for approving a trade, etc. Regulators seek to make policy changes so that their inability to grant new licenses will not harm the local and national economy. What policy changes will most cost-effectively increase trading and allow it to effectively reduce the economic cost of scarcity events? A screening tool that could help evaluate problems and advantages of different regulatory solutions, and that could serve to test, assuming transaction costs can be quantified, their effect on trading under specific conditions would be useful. We propose such a water market simulator that predicts economically efficient pair-wise trade (between willing buyers and sellers) and represents the interaction of trades with natural hydrological flows, engineered infrastructure and a particular regulatory regime. The model emulates license-holders' willingness to engage in short-term trade transactions. In their initial form different 'agents' (license holders) are represented using an economic benefit function of water use which is supplemented by rules to represent behavioral or other characteristics of realistic system behavior. A case study based on the river Ouse basin (UK) is made to test the model. The model simulates the catchment weekly over several years considering reservoirs and pair-wise specific transaction costs. Several regulatory policies are tested

  19. First Step of Glycosylphosphatidylinositol (GPI) Biosynthesis Cross-talks with Ergosterol Biosynthesis and Ras Signaling in Candida albicans*

    PubMed Central

    Yadav, Bhawna; Bhatnagar, Shilpi; Ahmad, Mohammad Faiz; Jain, Priyanka; Pratyusha, Vavilala A.; Kumar, Pravin; Komath, Sneha Sudha

    2014-01-01

    Candida albicans is a leading cause of fungal infections worldwide. It has several glycosylphosphatidylinositol (GPI)-anchored virulence factors. Inhibiting GPI biosynthesis attenuates its virulence. Building on our previous work, we explore the interaction of GPI biosynthesis in C. albicans with ergosterol biosynthesis and hyphal morphogenesis. This study is also the first report of transcriptional co-regulation existing between two subunits of the multisubunit enzyme complex, GPI-N-acetylglucosaminyltransferase (GPI-GnT), involved in the first step of GPI anchor biosynthesis in eukaryotes. Using mutational analysis, we show that the accessory subunits, GPI2 and GPI19, of GPI-GnT exhibit opposite effects on ergosterol biosynthesis and Ras signaling (which determines hyphal morphogenesis). This is because the two subunits negatively regulate one another; GPI19 mutants show up-regulation of GPI2, whereas GPI2 mutants show up-regulation of GPI19. Two different models were examined as follows. First, the two GPI-GnT subunits independently interact with ergosterol biosynthesis and Ras signaling. Second, the two subunits mutually regulate one another and thereby regulate sterol levels and Ras signaling. Analysis of double mutants of these subunits indicates that GPI19 controls ergosterol biosynthesis through ERG11 levels, whereas GPI2 determines the filamentation by cross-talk with Ras1 signaling. Taken together, this suggests that the first step of GPI biosynthesis talks to and regulates two very important pathways in C. albicans. This could have implications for designing new antifungal strategies. PMID:24356967

  20. Analyzing and designing object-oriented missile simulations with concurrency

    NASA Astrophysics Data System (ADS)

    Randorf, Jeffrey Allen

    2000-11-01

    A software object model for the six degree-of-freedom missile modeling domain is presented. As a precursor, a domain analysis of the missile modeling domain was started, based on the Feature-Oriented Domain Analysis (FODA) technique described by the Software Engineering Institute (SEI). It was subsequently determined the FODA methodology is functionally equivalent to the Object Modeling Technique. The analysis used legacy software documentation and code from the ENDOSIM, KDEC, and TFrames 6-DOF modeling tools, including other technical literature. The SEI Object Connection Architecture (OCA) was the template for designing the object model. Three variants of the OCA were considered---a reference structure, a recursive structure, and a reference structure with augmentation for flight vehicle modeling. The reference OCA design option was chosen for maintaining simplicity while not compromising the expressive power of the OMT model. The missile architecture was then analyzed for potential areas of concurrent computing. It was shown how protected objects could be used for data passing between OCA object managers, allowing concurrent access without changing the OCA reference design intent or structure. The implementation language was the 1995 release of Ada. OCA software components were shown how to be expressed as Ada child packages. While acceleration of several low level and other high operations level are possible on proper hardware, there was a 33% degradation of 4th order Runge-Kutta integrator performance of two simultaneous ordinary differential equations using Ada tasking on a single processor machine. The Defense Department's High Level Architecture was introduced and explained in context with the OCA. It was shown the HLA and OCA were not mutually exclusive architectures, but complimentary. HLA was shown as an interoperability solution, with the OCA as an architectural vehicle for software reuse. Further directions for implementing a 6-DOF missile modeling

  1. Improved Space Charge Modeling for Simulation and Design of Photoinjectors

    SciTech Connect

    Robert H. Jackson, Thuc Bui, John Verboncoeur

    2010-04-19

    Photoinjectors in advanced high-energy accelerators reduce beam energy spreads and enhance undulator photon fluxes. Photoinjector design is difficult because of the substantial differences in time and spatial scales. This Phase I program explored an innovative technique, the local Taylor polynomial (LTP) formulation, for improving finite difference analysis of photoinjectors. This included improved weighting techniques, systematic formula for high order interpolation and electric field computation, and improved handling of space charge. The Phase I program demonstrated that the approach was powerful, accurate, and efficient. It handles space charge gradients better than currently available technology.

  2. Design of a high-speed digital processing element for parallel simulation

    NASA Technical Reports Server (NTRS)

    Milner, E. J.; Cwynar, D. S.

    1983-01-01

    A prototype of a custom designed computer to be used as a processing element in a multiprocessor based jet engine simulator is described. The purpose of the custom design was to give the computer the speed and versatility required to simulate a jet engine in real time. Real time simulations are needed for closed loop testing of digital electronic engine controls. The prototype computer has a microcycle time of 133 nanoseconds. This speed was achieved by: prefetching the next instruction while the current one is executing, transporting data using high speed data busses, and using state of the art components such as a very large scale integration (VLSI) multiplier. Included are discussions of processing element requirements, design philosophy, the architecture of the custom designed processing element, the comprehensive instruction set, the diagnostic support software, and the development status of the custom design.

  3. Students as Simulation Designers and Developers--Using Computer Simulations for Teaching Boundary Layer Processes.

    ERIC Educational Resources Information Center

    Johnson, Tristan E.; Clayson, Carol Anne

    As technology developments seek to improve learning, researchers, developers, and educators seek to understand how technological properties impact performance. This paper delineates how a traditional science course is enhanced through the use of simulation projects directed by the students themselves as a means to increase their level of knowledge…

  4. James Webb Space Telescope Optical Simulation Testbed II: design of a three-lens anastigmat telescope simulator

    NASA Astrophysics Data System (ADS)

    Choquet, Élodie; Levecq, Olivier; N'Diaye, Mamadou; Perrin, Marshall D.; Soummer, Rémi

    2014-08-01

    The JamesWebb Space Telescope (JWST) Optical Simulation Testbed (JOST) is a tabletop experiment designed to reproduce the main aspects of wavefront sensing and control (WFS and C) for JWST. To replicate the key optical physics of JWST's three-mirror anastigmat (TMA) design at optical wavelengths we have developed a three-lens anastigmat optical system. This design uses custom lenses (plano-convex, plano-concave, and bi-convex) with fourth-order aspheric terms on powered surfaces to deliver the equivalent image quality and sampling of JWST NIRCam at the WFS and C wavelength (633 nm, versus JWST's 2.12 μm). For active control, in addition to the segmented primary mirror simulator, JOST reproduces the secondary mirror alignment modes with five degrees of freedom. We present the testbed requirements and its optical and optomechanical design. We study the linearity of the main aberration modes (focus, astigmatism, coma) both as a function of field point and level of misalignments of the secondary mirror. We find that the linearity with the transmissive design is similar to what is observed with a traditional TMA design, and will allow us to develop a linear-control alignment strategy based on the multi-field methods planned for JWST.

  5. Characterization and developmental expression of a Drosophila ras oncogene.

    PubMed Central

    Mozer, B; Marlor, R; Parkhurst, S; Corces, V

    1985-01-01

    We cloned a Drosophila melanogaster ras gene (Dmras64B) on the basis of its homology to the ras oncogen from Harvey murine sarcoma virus. This gene mapped at chromosomal position 64B on the left arm of the third chromosome. Sequencing of Dmras64B revealed extensive amino acid homology with the proteins encoded by the human and Saccharomyces cerevisiae ras genes. The coding region of the Drosophila gene is interrupted by two introns located in different positions with respect to its human counterpart. Dmras64B encodes three different RNAs (1.6, 2.1, and 2.6 kilobases long) that are constantly expressed throughout the development of the fly. Images PMID:3921827

  6. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade.

    PubMed Central

    Benn, J; Schneider, R J

    1994-01-01

    Hepatitis B virus produces a small (154-amino acid) transcriptional transactivating protein, HBx, which is required for viral infection and has been implicated in virus-mediated liver oncogenesis. However, the molecular mechanism for HBx activity and its possible influence on cell proliferation have remained obscure. A number of studies suggest that HBx may stimulate transcription by indirectly activating transcription factors, possibly by influencing cell signaling pathways. We now present biochemical evidence that HBx activates Ras and rapidly induces a cytoplasmic signaling cascade linking Ras, Raf, and mitogen-activated protein kinase (MAP kinase), leading to transcriptional transactivation. HBx strongly elevates levels of GTP-bound Ras, activated and phosphorylated Raf, and tyrosine-phosphorylated and activated MAP kinase. Transactivation of transcription factor AP-1 by HBx is blocked by inhibition of Ras or Raf activities but not by inhibition of Ca(2+)- and diacylglycerol-dependent protein kinase C. HBx was also found to stimulate DNA synthesis in serum-starved cells. The hepatitis B virus HBx protein therefore stimulates Ras-GTP complex formation and promotes downstream signaling through Raf and MAP kinases, and may influence cell proliferation. Images PMID:7937954

  7. Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation

    PubMed Central

    Sung, Hyeran; Kanchi, Krishna L.; Wang, Xue; Hill, Kristen S.; Messina, Jane L.; Lee, Ji-Hyun; Kim, Youngchul; Dees, Nathan D.; Ding, Li; Teer, Jamie K.; Yang, Shengyu; Sarnaik, Amod A.; Sondak, Vernon K.; Mulé, James J.; Wilson, Richard K.; Weber, Jeffrey S.; Kim, Minjung

    2016-01-01

    Inactivation of Ras GTPase activating proteins (RasGAPs) can activate Ras, increasing the risk for tumor development. Utilizing a melanoma whole genome sequencing (WGS) data from 13 patients, we identified two novel, clustered somatic missense mutations (Y472H and L481F) in RASA1 (RAS p21 protein activator 1, also called p120RasGAP). We have shown that wild type RASA1, but not identified mutants, suppresses soft agar colony formation and tumor growth of BRAF mutated melanoma cell lines via its RasGAP activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. Moreover, R-Ras increased and RASA1 suppressed Ral-A activation among Ras downstream effectors. In addition to mutations, loss of RASA1 expression was frequently observed in metastatic melanoma samples on melanoma tissue microarray (TMA) and a low level of RASA1 mRNA expression was associated with decreased overall survival in melanoma patients with BRAF mutations. Thus, these data support that RASA1 is inactivated by mutation or by suppressed expression in melanoma and that RASA1 plays a tumor suppressive role by inhibiting R-Ras, a previously less appreciated member of the Ras small GTPases. PMID:26993606

  8. Galectin-1 dimers can scaffold Raf-effectors to increase H-ras nanoclustering

    PubMed Central

    Blaževitš, Olga; Mideksa, Yonatan G.; Šolman, Maja; Ligabue, Alessio; Ariotti, Nicholas; Nakhaeizadeh, Hossein; Fansa, Eyad K.; Papageorgiou, Anastassios C.; Wittinghofer, Alfred; Ahmadian, Mohammad R.; Abankwa, Daniel

    2016-01-01

    Galectin-1 (Gal-1) dimers crosslink carbohydrates on cell surface receptors. Carbohydrate-derived inhibitors have been developed for cancer treatment. Intracellularly, Gal-1 was suggested to interact with the farnesylated C-terminus of Ras thus specifically stabilizing GTP-H-ras nanoscale signalling hubs in the membrane, termed nanoclusters. The latter activity may present an alternative mechanism for how overexpressed Gal-1 stimulates tumourigenesis. Here we revise the current model for the interaction of Gal-1 with H-ras. We show that it indirectly forms a complex with GTP-H-ras via a high-affinity interaction with the Ras binding domain (RBD) of Ras effectors. A computationally generated model of the Gal-1/C-Raf-RBD complex is validated by mutational analysis. Both cellular FRET as well as proximity ligation assay experiments confirm interaction of Gal-1 with Raf proteins in mammalian cells. Consistently, interference with H-rasG12V-effector interactions basically abolishes H-ras nanoclustering. In addition, an intact dimer interface of Gal-1 is required for it to positively regulate H-rasG12V nanoclustering, but negatively K-rasG12V nanoclustering. Our findings suggest stacked dimers of H-ras, Raf and Gal-1 as building blocks of GTP-H-ras-nanocluster at high Gal-1 levels. Based on our results the Gal-1/effector interface represents a potential drug target site in diseases with aberrant Ras signalling. PMID:27087647

  9. Synthetic tracked aperture ultrasound imaging: design, simulation, and experimental evaluation.

    PubMed

    Zhang, Haichong K; Cheng, Alexis; Bottenus, Nick; Guo, Xiaoyu; Trahey, Gregg E; Boctor, Emad M

    2016-04-01

    Ultrasonography is a widely used imaging modality to visualize anatomical structures due to its low cost and ease of use; however, it is challenging to acquire acceptable image quality in deep tissue. Synthetic aperture (SA) is a technique used to increase image resolution by synthesizing information from multiple subapertures, but the resolution improvement is limited by the physical size of the array transducer. With a large F-number, it is difficult to achieve high resolution in deep regions without extending the effective aperture size. We propose a method to extend the available aperture size for SA-called synthetic tracked aperture ultrasound (STRATUS) imaging-by sweeping an ultrasound transducer while tracking its orientation and location. Tracking information of the ultrasound probe is used to synthesize the signals received at different positions. Considering the practical implementation, we estimated the effect of tracking and ultrasound calibration error to the quality of the final beamformed image through simulation. In addition, to experimentally validate this approach, a 6 degree-of-freedom robot arm was used as a mechanical tracker to hold an ultrasound transducer and to apply in-plane lateral translational motion. Results indicate that STRATUS imaging with robotic tracking has the potential to improve ultrasound image quality. PMID:27088108

  10. A magnet-based vibrating wire sensor: design and simulation

    NASA Astrophysics Data System (ADS)

    Bourquin, Frédéric; Joly, Michel

    2005-02-01

    Vibrating strings help in measuring relative displacements in a mechanical system. Since the ground natural frequency of a string increases when it is stretched, monitoring the ground frequency yields the current length of the string. Therefore a wire able to vibrate between two anchor points of a system acts as a relative displacement sensor. Excitation is usually achieved by means of an active coil, which is very close to the vibrating iron wire. Vibrating wire sensors (VWS) based on this excitation may prove obtrusive and one is limited to wires of small length. The new VWS takes advantage of distributed passive magnets, which force the wire to vibrate mainly in its fundamental mode. The sensor proves scalable and much less obtrusive when fully embedded, since it can be made flat and very flexible. On the basis of a simplified electromechanical modelling of the measurement process, a suitable distribution of magnets is proposed, which is proved numerically and experimentally to make the measurement robust with respect to mechanical uncertainties. Moreover, numerical simulations suggest measuring not the voltage in the vibrating wire but the current in an auxiliary circuit.

  11. Design distributed simulation platform for vehicle management system

    NASA Astrophysics Data System (ADS)

    Wen, Zhaodong; Wang, Zhanlin; Qiu, Lihua

    2006-11-01

    Next generation military aircraft requires the airborne management system high performance. General modules, data integration, high speed data bus and so on are needed to share and manage information of the subsystems efficiently. The subsystems include flight control system, propulsion system, hydraulic power system, environmental control system, fuel management system, electrical power system and so on. The unattached or mixed architecture is changed to integrated architecture. That means the whole airborne system is regarded into one system to manage. So the physical devices are distributed but the system information is integrated and shared. The process function of each subsystem are integrated (including general process modules, dynamic reconfiguration), furthermore, the sensors and the signal processing functions are shared. On the other hand, it is a foundation for power shared. Establish a distributed vehicle management system using 1553B bus and distributed processors which can provide a validation platform for the research of airborne system integrated management. This paper establishes the Vehicle Management System (VMS) simulation platform. Discuss the software and hardware configuration and analyze the communication and fault-tolerant method.

  12. Design, Simulation and Fabrication of Triaxial MEMS High Shock Accelerometer.

    PubMed

    Zhang, Zhenhai; Shi, Zhiguo; Yang, Zhan; Xie, Zhihong; Zhang, Donghong; Cai, De; Li, Kejie; Shen, Yajing

    2015-04-01

    On the basis of analyzing the disadvantage of other structural accelerometer, three-axis high g MEMS piezoresistive accelerometer was put forward in order to apply to the high-shock test field. The accelerometer's structure and working principle were discussed in details. The simulation results show that three-axis high shock MEMS accelerometer can bear high shock. After bearing high shock impact in high-shock shooting test, three-axis high shock MEMS accelerometer can obtain the intact metrical information of the penetration process and still guarantee the accurate precision of measurement in high shock load range, so we can not only analyze the law of stress wave spreading and the penetration rule of the penetration process of the body of the missile, but also furnish the testing technology of the burst point controlling. The accelerometer has far-ranging application in recording the typical data that projectile penetrating hard target and furnish both technology guarantees for penetration rule and defend engineering.

  13. Conversion of microalgae to jet fuel: process design and simulation.

    PubMed

    Wang, Hui-Yuan; Bluck, David; Van Wie, Bernard J

    2014-09-01

    Microalgae's aquatic, non-edible, highly genetically modifiable nature and fast growth rate are considered ideal for biomass conversion to liquid fuels providing promise for future shortages in fossil fuels and for reducing greenhouse gas and pollutant emissions from combustion. We demonstrate adaptability of PRO/II software by simulating a microalgae photo-bio-reactor and thermolysis with fixed conversion isothermal reactors adding a heat exchanger for thermolysis. We model a cooling tower and gas floatation with zero-duty flash drums adding solids removal for floatation. Properties data are from PRO/II's thermodynamic data manager. Hydrotreating is analyzed within PRO/II's case study option, made subject to Jet B fuel constraints, and we determine an optimal 6.8% bioleum bypass ratio, 230°C hydrotreater temperature, and 20:1 bottoms to overhead distillation ratio. Process economic feasibility occurs if cheap CO2, H2O and nutrient resources are available, along with solar energy and energy from byproduct combustion, and hydrotreater H2 from product reforming. PMID:24997379

  14. Conversion of microalgae to jet fuel: process design and simulation.

    PubMed

    Wang, Hui-Yuan; Bluck, David; Van Wie, Bernard J

    2014-09-01

    Microalgae's aquatic, non-edible, highly genetically modifiable nature and fast growth rate are considered ideal for biomass conversion to liquid fuels providing promise for future shortages in fossil fuels and for reducing greenhouse gas and pollutant emissions from combustion. We demonstrate adaptability of PRO/II software by simulating a microalgae photo-bio-reactor and thermolysis with fixed conversion isothermal reactors adding a heat exchanger for thermolysis. We model a cooling tower and gas floatation with zero-duty flash drums adding solids removal for floatation. Properties data are from PRO/II's thermodynamic data manager. Hydrotreating is analyzed within PRO/II's case study option, made subject to Jet B fuel constraints, and we determine an optimal 6.8% bioleum bypass ratio, 230°C hydrotreater temperature, and 20:1 bottoms to overhead distillation ratio. Process economic feasibility occurs if cheap CO2, H2O and nutrient resources are available, along with solar energy and energy from byproduct combustion, and hydrotreater H2 from product reforming.

  15. The role of simulation in the design of a neural network chip

    NASA Technical Reports Server (NTRS)

    Desai, Utpal; Roppel, Thaddeus A.; Padgett, Mary L.

    1993-01-01

    An iterative, simulation-based design procedure for a neural network chip is introduced. For this design procedure, the goal is to produce a chip layout for a neural network in which the weights are determined by transistor gate width-to-length ratios. In a given iteration, the current layout is simulated using the circuit simulator SPICE, and layout adjustments are made based on conventional gradient-decent methods. After the iteration converges, the chip is fabricated. Monte Carlo analysis is used to predict the effect of statistical fabrication process variations on the overall performance of the neural network chip.

  16. Design, simulation, fabrication, and characterization of MEMS vibration energy harvesters

    NASA Astrophysics Data System (ADS)

    Oxaal, John

    Energy harvesting from ambient sources has been a longtime goal for microsystem engineers. The energy available from ambient sources is substantial and could be used to power wireless micro devices, making them fully autonomous. Self-powered wireless sensors could have many applications in for autonomous monitoring of residential, commercial, industrial, geological, or biological environments. Ambient vibrations are of particular interest for energy harvesting as they are ubiquitous and have ample kinetic energy. In this work a MEMS device for vibration energy harvesting using a variable capacitor structure is presented. The nonlinear electromechanical dynamics of a gap-closing type structure is experimentally studied. Important experimental considerations such as the importance of reducing off-axis vibration during testing, characterization methods, dust contamination, and the effect of grounding on parasitic capacitance are discussed. A comprehensive physics based model is developed and validated with two different microfabricated devices. To achieve maximal power, devices with high aspect ratio electrodes and a novel two-level stopper system are designed and fabricated. The maximum achieved power from the MEMS device when driven by sinusoidal vibrations was 3.38 muW. Vibrations from HVAC air ducts, which have a primary frequency of 65 Hz and amplitude of 155 mgrms, are targeted as the vibration source and devices are designed for maximal power harvesting potential at those conditions. Harvesting from the air ducts, the devices reached 118 nW of power. When normalized to the operating conditions, the best figure of merit of the devices tested was an order of magnitude above state-of-the-art of the devices (1.24E-6).

  17. The Tumor Suppressor DiRas3 Forms a Complex with H-Ras and C-RAF Proteins and Regulates Localization, Dimerization, and Kinase Activity of C-RAF*

    PubMed Central

    Baljuls, Angela; Beck, Matthias; Oenel, Ayla; Robubi, Armin; Kroschewski, Ruth; Hekman, Mirko; Rudel, Thomas; Rapp, Ulf R.

    2012-01-01

    The maternally imprinted Ras-related tumor suppressor gene DiRas3 is lost or down-regulated in more than 60% of ovarian and breast cancers. The anti-tumorigenic effect of DiRas3 is achieved through several mechanisms, including inhibition of cell proliferation, motility, and invasion, as well as induction of apoptosis and autophagy. Re-expression of DiRas3 in cancer cells interferes with the signaling through Ras/MAPK and PI3K. Despite intensive research, the mode of interference of DiRas3 with the Ras/RAF/MEK/ERK signal transduction is still a matter of speculation. In this study, we show that DiRas3 associates with the H-Ras oncogene and that activation of H-Ras enforces this interaction. Furthermore, while associated with DiRas3, H-Ras is able to bind to its effector protein C-RAF. The resulting multimeric complex consisting of DiRas3, C-RAF, and active H-Ras is more stable than the two protein complexes H-Ras·C-RAF or H-Ras·DiRas3, respectively. The consequence of this complex formation is a DiRas3-mediated recruitment and anchorage of C-RAF to components of the membrane skeleton, suppression of C-RAF/B-RAF heterodimerization, and inhibition of C-RAF kinase activity. PMID:22605333

  18. DSC: software tool for simulation-based design of control strategies applied to wastewater treatment plants.

    PubMed

    Ruano, M V; Ribes, J; Seco, A; Ferrer, J

    2011-01-01

    This paper presents a computer tool called DSC (Simulation based Controllers Design) that enables an easy design of control systems and strategies applied to wastewater treatment plants. Although the control systems are developed and evaluated by simulation, this tool aims to facilitate the direct implementation of the designed control system to the PC of the full-scale WWTP (wastewater treatment plants). The designed control system can be programmed in a dedicated control application and can be connected to either the simulation software or the SCADA of the plant. To this end, the developed DSC incorporates an OPC server (OLE for process control) which facilitates an open-standard communication protocol for different industrial process applications. The potential capabilities of the DSC tool are illustrated through the example of a full-scale application. An aeration control system applied to a nutrient removing WWTP was designed, tuned and evaluated with the DSC tool before its implementation in the full scale plant. The control parameters obtained by simulation were suitable for the full scale plant with only few modifications to improve the control performance. With the DSC tool, the control systems performance can be easily evaluated by simulation. Once developed and tuned by simulation, the control systems can be directly applied to the full-scale WWTP. PMID:21330730

  19. DSC: software tool for simulation-based design of control strategies applied to wastewater treatment plants.

    PubMed

    Ruano, M V; Ribes, J; Seco, A; Ferrer, J

    2011-01-01

    This paper presents a computer tool called DSC (Simulation based Controllers Design) that enables an easy design of control systems and strategies applied to wastewater treatment plants. Although the control systems are developed and evaluated by simulation, this tool aims to facilitate the direct implementation of the designed control system to the PC of the full-scale WWTP (wastewater treatment plants). The designed control system can be programmed in a dedicated control application and can be connected to either the simulation software or the SCADA of the plant. To this end, the developed DSC incorporates an OPC server (OLE for process control) which facilitates an open-standard communication protocol for different industrial process applications. The potential capabilities of the DSC tool are illustrated through the example of a full-scale application. An aeration control system applied to a nutrient removing WWTP was designed, tuned and evaluated with the DSC tool before its implementation in the full scale plant. The control parameters obtained by simulation were suitable for the full scale plant with only few modifications to improve the control performance. With the DSC tool, the control systems performance can be easily evaluated by simulation. Once developed and tuned by simulation, the control systems can be directly applied to the full-scale WWTP.

  20. Design data package and operating procedures for MSFC solar simulator test facility

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Design and operational data for the solar simulator test facility are reviewed. The primary goal of the facility is to evaluate the performance capacibility and worst case failure modes of collectors, which utilize either air or liquid transport media. The facility simulates environmental parameters such as solar radiation intensity, solar spectrum, collimation, uniformity, and solar attitude. The facility also simulates wind conditions of velocity and direction, solar system conditions imposed on the collector, collector fluid inlet temperature, and geometric factors of collector tilt and azimuth angles. Testing the simulator provides collector efficiency data, collector time constant, incident angle modifier data, and stagnation temperature values.

  1. The simulative calculation and optimum design for FOA, the purge gas sweeping system

    NASA Astrophysics Data System (ADS)

    Wang, Liquan; Jing, Yukun; Feng, Bing; Li, Fuquan; Xiang, Yong; Han, Wei; Wang, Fang

    2016-01-01

    This paper first studies the structure effect law in order to design a reasonable option in theory for the Final Optics Assembly(FOA)' harmonic converter module, involved in the design of the fluid theory, including the basic equations of fluid motion, the form of fluid motion and fluid movement in the small hole. Optimizing the structure need to be applied to the simulation software, which requires the Fluent simulation principle. Then, combined with theoretical knowledge to design the overall structure of the multiplier module, It will apply the simulation software to optimize structural parameters of the board and use control system to realize it for verifying the law obtained by simulation under various conditions whether consistent with the law in actual work of the sweeping system.

  2. Interim Service ISDN Satellite (ISIS) simulator development for advanced satellite designs and experiments

    NASA Technical Reports Server (NTRS)

    Pepin, Gerard R.

    1992-01-01

    The simulation development associated with the network models of both the Interim Service Integrated Services Digital Network (ISDN) Satellite (ISIS) and the Full Service ISDN Satellite (FSIS) architectures is documented. The ISIS Network Model design represents satellite systems like the Advanced Communications Technology Satellite (ACTS) orbiting switch. The FSIS architecture, the ultimate aim of this element of the Satellite Communications Applications Research (SCAR) Program, moves all control and switching functions on-board the next generation ISDN communications satellite. The technical and operational parameters for the advanced ISDN communications satellite design will be obtained from the simulation of ISIS and FSIS engineering software models for their major subsystems. Discrete event simulation experiments will be performed with these models using various traffic scenarios, design parameters, and operational procedures. The data from these simulations will be used to determine the engineering parameters for the advanced ISDN communications satellite.

  3. A Simulation-Based LED Design Project in Photonics Instruction Based on Industry-University Collaboration

    ERIC Educational Resources Information Center

    Chang, S. -H.; Chen, M. -L.; Kuo, Y. -K.; Shen, Y. -C.

    2011-01-01

    In response to the growing industrial demand for light-emitting diode (LED) design professionals, based on industry-university collaboration in Taiwan, this paper develops a novel instructional approach: a simulation-based learning course with peer assessment to develop students' professional skills in LED design as required by industry as well as…

  4. Using R to Simulate Permutation Distributions for Some Elementary Experimental Designs

    ERIC Educational Resources Information Center

    Eudey, T. Lynn; Kerr, Joshua D.; Trumbo, Bruce E.

    2010-01-01

    Null distributions of permutation tests for two-sample, paired, and block designs are simulated using the R statistical programming language. For each design and type of data, permutation tests are compared with standard normal-theory and nonparametric tests. These examples (often using real data) provide for classroom discussion use of metrics…

  5. Assessing the Effectiveness of a Computer Simulation for Teaching Ecological Experimental Design

    ERIC Educational Resources Information Center

    Stafford, Richard; Goodenough, Anne E.; Davies, Mark S.

    2010-01-01

    Designing manipulative ecological experiments is a complex and time-consuming process that is problematic to teach in traditional undergraduate classes. This study investigates the effectiveness of using a computer simulation--the Virtual Rocky Shore (VRS)--to facilitate rapid, student-centred learning of experimental design. We gave a series of…

  6. The Interior Design Simulator. Courseware Evaluation for Vocational and Technical Education.

    ERIC Educational Resources Information Center

    Worts, Nancy; And Others

    This courseware evaluation rates the Interior Design Simulator program developed by Orange Juice Software Systems. (This program--not contained in this document--allows the user to design a room of any shape with maximum dimensions of 14 x 26 feet.) Part A describes the program in terms of subject area (furniture arrangement) and hardware…

  7. Fractal Simulations of African Design in Pre-College Computing Education

    ERIC Educational Resources Information Center

    Eglash, Ron; Krishnamoorthy, Mukkai; Sanchez, Jason; Woodbridge, Andrew

    2011-01-01

    This article describes the use of fractal simulations of African design in a high school computing class. Fractal patterns--repetitions of shape at multiple scales--are a common feature in many aspects of African design. In African architecture we often see circular houses grouped in circular complexes, or rectangular houses in rectangular…

  8. CLARREO shortwave observing system simulation experiments of the twenty-first century: Simulator design and implementation

    SciTech Connect

    Feldman, D.R.; Algieri, C.A.; Ong, J.R.; Collins, W.D.

    2011-04-01

    Projected changes in the Earth system will likely be manifested in changes in reflected solar radiation. This paper introduces an operational Observational System Simulation Experiment (OSSE) to calculate the signals of future climate forcings and feedbacks in top-of-atmosphere reflectance spectra. The OSSE combines simulations from the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report for the NCAR Community Climate System Model (CCSM) with the MODTRAN radiative transfer code to calculate reflectance spectra for simulations of current and future climatic conditions over the 21st century. The OSSE produces narrowband reflectances and broadband fluxes, the latter of which have been extensively validated against archived CCSM results. The shortwave reflectance spectra contain atmospheric features including signals from water vapor, liquid and ice clouds, and aerosols. The spectra are also strongly influenced by the surface bidirectional reflectance properties of predicted snow and sea ice and the climatological seasonal cycles of vegetation. By comparing and contrasting simulated reflectance spectra based on emissions scenarios with increasing projected and fixed present-day greenhouse gas and aerosol concentrations, we find that prescribed forcings from increases in anthropogenic sulfate and carbonaceous aerosols are detectable and are spatially confined to lower latitudes. Also, changes in the intertropical convergence zone and poleward shifts in the subsidence zones and the storm tracks are all detectable along with large changes in snow cover and sea ice fraction. These findings suggest that the proposed NASA Climate Absolute Radiance and Refractivity Observatory (CLARREO) mission to measure shortwave reflectance spectra may help elucidate climate forcings, responses, and feedbacks.

  9. Modeling, simulation, and concept design for hybrid-electric medium-size military trucks

    NASA Astrophysics Data System (ADS)

    Rizzoni, Giorgio; Josephson, John R.; Soliman, Ahmed; Hubert, Christopher; Cantemir, Codrin-Gruie; Dembski, Nicholas; Pisu, Pierluigi; Mikesell, David; Serrao, Lorenzo; Russell, James; Carroll, Mark

    2005-05-01

    A large scale design space exploration can provide valuable insight into vehicle design tradeoffs being considered for the U.S. Army"s FMTV (Family of Medium Tactical Vehicles). Through a grant from TACOM (Tank-automotive and Armaments Command), researchers have generated detailed road, surface, and grade conditions representative of the performance criteria of this medium-sized truck and constructed a virtual powertrain simulator for both conventional and hybrid variants. The simulator incorporates the latest technology among vehicle design options, including scalable ultracapacitor and NiMH battery packs as well as a variety of generator and traction motor configurations. An energy management control strategy has also been developed to provide efficiency and performance. A design space exploration for the family of vehicles involves running a large number of simulations with systematically varied vehicle design parameters, where each variant is paced through several different mission profiles and multiple attributes of performance are measured. The resulting designs are filtered to remove dominated designs, exposing the multi-criterial surface of optimality (Pareto optimal designs), and revealing the design tradeoffs as they impact vehicle performance and economy. The results are not yet definitive because ride and drivability measures were not included, and work is not finished on fine-tuning the modeled dynamics of some powertrain components. However, the work so far completed demonstrates the effectiveness of the approach to design space exploration, and the results to date suggest the powertrain configuration best suited to the FMTV mission.

  10. The Template of Events for Applied and Critical Healthcare Simulation (TEACH Sim): a tool for systematic simulation scenario design.

    PubMed

    Benishek, Lauren E; Lazzara, Elizabeth H; Gaught, William L; Arcaro, Lygia L; Okuda, Yasuharu; Salas, Eduardo

    2015-02-01

    Simulation-based training (SBT) affords practice opportunities for improving the quality of clinicians' technical and nontechnical skills. However, the development of practice scenarios is a process plagued by a set of challenges that must be addressed for the full learning potential of SBT to be realized. Scenario templates are useful tools for assisting with SBT and navigating its inherent challenges. This article describes existing SBT templates, explores considerations in choosing an appropriate template, and introduces the Template of Events for Applied and Critical Healthcare Simulation (TEACH Sim) as a tool for facilitating the formation of practice scenarios in accordance with an established evidence-based simulation design methodology. TEACH Sim's unique contributions are situated within the landscape of previously existing templates, and each of its component sections is explained in detail.

  11. Notch-1 expression levels in 3T3-L1 cells influence ras signaling and transformation by oncogenic ras.

    PubMed

    Ruiz-Hidalgo, M J; Garcés, C; Laborda, J

    1999-04-01

    Notch proteins participate in interactions between several cell types involved on the specification of numerous cell fates during development. We previously showed that enforced downregulation of Notch-1 expression prevented adipogenesis of 3T3-L1 cells. Since adipogenesis of 3T3-L1 cells can be induced by oncogenic ras, we studied whether this was also the case in 3T3-L1 cells with decreased levels of Notch-1 expression. We found that oncogenic ras induces transformation and not differentiation of 3T3-L1 cells with diminished levels of Notch-1. This result suggests that Notch-1 is implicated in the interpretation of signals leading to activation of p21 Ras.

  12. Computer Simulator for OTEC System Design : Pump Control of Flow Rate

    NASA Astrophysics Data System (ADS)

    Nakamura, Masatoshi; Ikegami, Yasuyuki; Uehara, Haruo

    The purpose of ocean thermal energy conversion (OTEC) is to extract power from temperature differences existing in the oceans. The OTEC system design mainly comprises an OTEC plant design and an OTEC control design. The main purpose of this paper is to demonstrate the importance of a computer simulator for the OTEC system design. The computer simulator, constructed by a computer with A/D and D/A converters, produces analogue input and output signals which are equivalent to those of an actual OTEC plant. By using the computer simulator of an OTEC plant, we can estimate properties of any OTEC plant easily, economically and safely. The computer simulator also plays an important role in detecting difficulties in designing the OTEC controller. We furthermore described the procedure for designing the OTEC controller as follows: (i) statement of the control objective, (ii) modeling of the controlled object, (iii) application of control theory to the model, (iv) characterization of the detector and the input signal part, and (v) construction of the controller. We constructed the computer simulator and the controller for pump flow rate as part of the OTEC plant. We then obtained satisfactory control performance for flow rate control of experiments.

  13. MEMS 3-DoF gyroscope design, modeling and simulation through equivalent circuit lumped parameter model

    SciTech Connect

    Mian, Muhammad Umer Khir, M. H. Md.; Tang, T. B.; Dennis, John Ojur; Riaz, Kashif; Iqbal, Abid; Bazaz, Shafaat A.

    2015-07-22

    Pre-fabrication, behavioural and performance analysis with computer aided design (CAD) tools is a common and fabrication cost effective practice. In light of this we present a simulation methodology for a dual-mass oscillator based 3 Degree of Freedom (3-DoF) MEMS gyroscope. 3-DoF Gyroscope is modeled through lumped parameter models using equivalent circuit elements. These equivalent circuits consist of elementary components which are counterpart of their respective mechanical components, used to design and fabricate 3-DoF MEMS gyroscope. Complete designing of equivalent circuit model, mathematical modeling and simulation are being presented in this paper. Behaviors of the equivalent lumped models derived for the proposed device design are simulated in MEMSPRO T-SPICE software. Simulations are carried out with the design specifications following design rules of the MetalMUMPS fabrication process. Drive mass resonant frequencies simulated by this technique are 1.59 kHz and 2.05 kHz respectively, which are close to the resonant frequencies found by the analytical formulation of the gyroscope. The lumped equivalent circuit modeling technique proved to be a time efficient modeling technique for the analysis of complex MEMS devices like 3-DoF gyroscopes. The technique proves to be an alternative approach to the complex and time consuming couple field analysis Finite Element Analysis (FEA) previously used.

  14. MEMS 3-DoF gyroscope design, modeling and simulation through equivalent circuit lumped parameter model

    NASA Astrophysics Data System (ADS)

    Mian, Muhammad Umer; Dennis, John Ojur; Khir, M. H. Md.; Riaz, Kashif; Iqbal, Abid; Bazaz, Shafaat A.; Tang, T. B.

    2015-07-01

    Pre-fabrication, behavioural and performance analysis with computer aided design (CAD) tools is a common and fabrication cost effective practice. In light of this we present a simulation methodology for a dual-mass oscillator based 3 Degree of Freedom (3-DoF) MEMS gyroscope. 3-DoF Gyroscope is modeled through lumped parameter models using equivalent circuit elements. These equivalent circuits consist of elementary components which are counterpart of their respective mechanical components, used to design and fabricate 3-DoF MEMS gyroscope. Complete designing of equivalent circuit model, mathematical modeling and simulation are being presented in this paper. Behaviors of the equivalent lumped models derived for the proposed device design are simulated in MEMSPRO T-SPICE software. Simulations are carried out with the design specifications following design rules of the MetalMUMPS fabrication process. Drive mass resonant frequencies simulated by this technique are 1.59 kHz and 2.05 kHz respectively, which are close to the resonant frequencies found by the analytical formulation of the gyroscope. The lumped equivalent circuit modeling technique proved to be a time efficient modeling technique for the analysis of complex MEMS devices like 3-DoF gyroscopes. The technique proves to be an alternative approach to the complex and time consuming couple field analysis Finite Element Analysis (FEA) previously used.

  15. Application of the ProtoWare simulation testbed to the design and evaluation of advanced avionics

    NASA Astrophysics Data System (ADS)

    Bubb, Daniel M.; Wilson, Leo T.; Stoltz, John R.

    1991-07-01

    The authors describe ProtoWare, a system design methodology and a supporting toolset, that is used to develop robust tactical simulation systems. An example is provided of the use of ProtoWare in the development, testing, and evaluation of an avionics requirements simulation system. Comparisons are made to show the improvements achieved by considering various tracking, fusion, and sensor manager algorithm designs. Risk reduction figures of merit are generated to assist the tactical system designer in controlling the risk of inserting a new unproven technology.

  16. Simulation Results for the New NSTX HHFW Antenna Straps Design by Using Microwave Studio

    SciTech Connect

    Kung, C C; Brunkhorst, C; Greenough, N; Fredd, E; Castano, A; Miller, D; D'Amico, G; Yager, R; Hosea, J; Wilson, J R; Ryan, P

    2009-05-26

    Experimental results have shown that the high harmonic fast wave (HHFW) at 30 MHz can provide substantial plasma heating and current drive for the NSTX spherical tokamak operation. However, the present antenna strap design rarely achieves the design goal of delivering the full transmitter capability of 6 MW to the plasma. In order to deliver more power to the plasma, a new antenna strap design and the associated coaxial line feeds are being constructed. This new antenna strap design features two feedthroughs to replace the old single feed-through design. In the design process, CST Microwave Studio has been used to simulate the entire new antenna strap structure including the enclosure and the Faraday shield. In this paper, the antenna strap model and the simulation results will be discussed in detail. The test results from the new antenna straps with their associated resonant loops will be presented as well.

  17. Design and simulation of a cable-pulley-based transmission for artificial ankle joints

    NASA Astrophysics Data System (ADS)

    Liu, Huaxin; Ceccarelli, Marco; Huang, Qiang

    2016-06-01

    In this paper, a mechanical transmission based on cable pulley is proposed for human-like actuation in the artificial ankle joints of human-scale. The anatomy articular characteristics of the human ankle is discussed for proper biomimetic inspiration in designing an accurate, efficient, and robust motion control of artificial ankle joint devices. The design procedure is presented through the inclusion of conceptual considerations and design details for an interactive solution of the transmission system. A mechanical design is elaborated for the ankle joint angular with pitch motion. A multi-body dynamic simulation model is elaborated accordingly and evaluated numerically in the ADAMS environment. Results of the numerical simulations are discussed to evaluate the dynamic performance of the proposed design solution and to investigate the feasibility of the proposed design in future applications for humanoid robots.

  18. Integrated layout based Monte-Carlo simulation for design arc optimization

    NASA Astrophysics Data System (ADS)

    Shao, Dongbing; Clevenger, Larry; Zhuang, Lei; Liebmann, Lars; Wong, Robert; Culp, James

    2016-03-01

    Design rules are created considering a wafer fail mechanism with the relevant design levels under various design cases, and the values are set to cover the worst scenario. Because of the simplification and generalization, design rule hinders, rather than helps, dense device scaling. As an example, SRAM designs always need extensive ground rule waivers. Furthermore, dense design also often involves "design arc", a collection of design rules, the sum of which equals critical pitch defined by technology. In design arc, a single rule change can lead to chain reaction of other rule violations. In this talk we present a methodology using Layout Based Monte-Carlo Simulation (LBMCS) with integrated multiple ground rule checks. We apply this methodology on SRAM word line contact, and the result is a layout that has balanced wafer fail risks based on Process Assumptions (PAs). This work was performed at the IBM Microelectronics Div, Semiconductor Research and Development Center, Hopewell Junction, NY 12533

  19. Developing a workstation-based, real-time simulation for rapid handling qualities evaluations during design

    NASA Technical Reports Server (NTRS)

    Anderson, Frederick; Biezad, Daniel J.

    1994-01-01

    This paper describes the Rapid Aircraft DynamIcs AssessmeNt (RADIAN) project - an integration of the Aircraft SYNThesis (ACSTNT) design code with the USAD DATCOM code that estimates stability derivatives. Both of these codes are available to universities. These programs are then linked to flight simulation and flight controller synthesis tools and resulting design is evaluated on a graphics workstation. The entire process reduces the preliminary design time by an order of magnitude and provides an initial handling qualities evaluation of the design coupled to a control law. The integrated design process is applicable to both conventional aircraft taken from current textbooks and to unconventional designs emphasizing agility and propulsive control of attitude. The interactive and concurrent nature of the design process has been well received by industry and by design engineers at NASA. The process is being implemented into the design curriculum and is being used by students who view it as a significant advance over prior methods.

  20. A simulation of fishway design: An example of simulation in environmental problem solving

    SciTech Connect

    Karisch, S.E.; Power, M.

    1994-05-01

    This paper agrees that modelling provides a convenient and cost-effective means of characterizing and predicting the behaviour of environmental systems disturbed by man. A series of modeling criteria are suggested that aim at compelling modelling work with current data, explicitly represent the current understanding of a system, include considerations of variability, and address predictive uncertainty. Models which do so provide a rigorous framework for the comparison of alternative courses of action. As an example of the methodology, the problems associated with the fishway design, highlighting the required statistical analysis and insights, are discussed. Comparison of the modelling results to those gained from operational experience with real fishways were used to validate model results and ensure model credibility. The models were then used to examine the effect of design on interactions between pools in fishways as a means of selecting the designs which minimized migration stress. 15 refs., 2 figs., 2 tabs.

  1. Enhancing the energy-efficient design of office buildings using a based-simulation design support system

    NASA Astrophysics Data System (ADS)

    Kassab, Mohamed Samy Moawad

    This thesis presents a comprehensive study for enhancing the energy efficiency of office buildings in Canada. Two models were used: the thermal model to develop the thermal-related alternatives, and the daylighting model to explore means for more effectively exploiting daylight in buildings through extending periods of illumination free from glare problems. The key concept is to quantify and examine the impact of developed design parameters on the buildings' performance. The University of Calgary's Information and Communication Technology (ICT) office building is used as a base model for which the innovative techniques are developed and presented in this study. Although simulation programs can evaluate the illuminance levels and energy consumption of buildings, they are predicting programs rather than optimizing tools. Moreover, the concept of energy efficiency includes more than the total energy consumption; therefore, the Simulation-Based Design Support System (SBDSS) was developed to decide on the optimum design solutions for office buildings. The SBDSS was established using the C++ program and based on the simulation results of the EnergyPlus and Desktop Radiance software programs. The thermal and daylighting models were developed first; then, the SBDSS automatically modified the design parameters of models according to information provided by users. A database was created that includes the entire simulation results, comprising a large number of design solutions. The alternatives include the variations of individual parameters and the available combinations among such parameters composing multi-dimensional groups. The evaluation of the design alternatives was based on the life-cycle approach. Three objective functions were used in this analysis, including the total energy consumption; life-cycle cost; and environmental impacts, evaluated in terms of the equivalent CO2 emissions. A selection tool, developed by Excel, was used to derive the optimum alternatives

  2. Rasputin, the Drosophila homologue of the RasGAP SH3 binding protein, functions in ras- and Rho-mediated signaling.

    PubMed

    Pazman, C; Mayes, C A; Fanto, M; Haynes, S R; Mlodzik, M

    2000-04-01

    The small GTPase Ras plays an important role in many cellular signaling processes. Ras activity is negatively regulated by GTPase activating proteins (GAPs). It has been proposed that RasGAP may also function as an effector of Ras activity. We have identified and characterized the Drosophila homologue of the RasGAP-binding protein G3BP encoded by rasputin (rin). rin mutants are viable and display defects in photoreceptor recruitment and ommatidial polarity in the eye. Mutations in rin/G3BP genetically interact with components of the Ras signaling pathway that function at the level of Ras and above, but not with Raf/MAPK pathway components. These interactions suggest that Rin is required as an effector in Ras signaling during eye development, supporting an effector role for RasGAP. The ommatidial polarity phenotypes of rin are similar to those of RhoA and the polarity genes, e.g. fz and dsh. Although rin/G3BP interacts genetically with RhoA, affecting both photoreceptor differentiation and polarity, it does not interact with the gain-of-function genotypes of fz and dsh. These data suggest that Rin is not a general component of polarity generation, but serves a function specific to Ras and RhoA signaling pathways.

  3. Experimental design: computer simulation for improving the precision of an experiment.

    PubMed

    van Wilgenburg, Henk; Zillesen, Piet G van Schaick; Krulichova, Iva

    2004-06-01

    An interactive computer-assisted learning program, ExpDesign, that has been developed for simulating animal experiments, is introduced. The program guides students through the steps for designing animal experiments and estimating optimal sample sizes. Principles are introduced for controlling variation, establishing the experimental unit, selecting randomised block and factorial experimental designs, and applying the appropriate statistical analysis. Sample Power is a supporting tool that visualises the process of estimating the sample size. The aim of developing the ExpDesign program has been to make biomedical research workers more familiar with some basic principles of experimental design and statistics and to facilitate discussions with statisticians.

  4. Design study to simulate the development of a commercial transportation system

    NASA Technical Reports Server (NTRS)

    1991-01-01

    Seven teams of senior-level Aerospace Engineering undergraduates were given a Request for Proposals (RFP) for a design concept of a remotely piloted vehicle (RPV). The RPV designs were intended to simulate commercial transport aircraft within the model of 'Aeroworld.' The Aeroworld model was developed so that the RPV designs would be subject to many of the engineering problems and tradeoffs that dominate real-world commercial air transport designs, such as profitability, fuel efficiency, range vs. payload capabilities, and ease of production and maintenance. As part of the proposal, each team was required to construct a prototype and validate its design with a flight demonstration.

  5. Evaluation of agile designs in first-in-human (FIH) trials--a simulation study.

    PubMed

    Perlstein, Itay; Bolognese, James A; Krishna, Rajesh; Wagner, John A

    2009-12-01

    The aim of the investigation was to evaluate alternatives to standard first-in-human (FIH) designs in order to optimize the information gained from such studies by employing novel agile trial designs. Agile designs combine adaptive and flexible elements to enable optimized use of prior information either before and/or during conduct of the study to seamlessly update the study design. A comparison of the traditional 6 + 2 (active + placebo) subjects per cohort design with alternative, reduced sample size, agile designs was performed by using discrete event simulation. Agile designs were evaluated for specific adverse event models and rates as well as dose-proportional, saturated, and steep-accumulation pharmacokinetic profiles. Alternative, reduced sample size (hereafter referred to as agile) designs are proposed for cases where prior knowledge about pharmacokinetics and/or adverse event relationships are available or appropriately assumed. Additionally, preferred alternatives are proposed for a general case when prior knowledge is limited or unavailable. Within the tested conditions and stated assumptions, some agile designs were found to be as efficient as traditional designs. Thus, simulations demonstrated that the agile design is a robust and feasible approach to FIH clinical trials, with no meaningful loss of relevant information, as it relates to PK and AE assumptions. In some circumstances, applying agile designs may decrease the duration and resources required for Phase I studies, increasing the efficiency of early clinical development. We highlight the value and importance of useful prior information when specifying key assumptions related to safety, tolerability, and PK.

  6. International conference on quantum simulators and design, hiroshima, Japan, 3-6 december 2006.

    PubMed

    Akai, Hisazumi; Oguchi, Tamio

    2007-09-12

    This special issue of Journal of Physics: Condensed Matter comprises selected papers from the 1st International Conference on Quantum Simulators and Design (QSD2006) held in Hiroshima, Japan, 3-6 December 2006. This conference was organized under the auspices of the Development of New Quantum Simulators and Quantum Design Grant-in-Aid for Scientific Research on Priority Areas, Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and Hiroshima University Quantum design is a computational approach to the development of new materials with specified properties and functionalities. The basic ingredient is the use of quantum simulations to design a material that meets a given specification of properties and functionalities. For this to be successful, the quantum simulation should be highly reliable and be applicable to systems of realistic size. A central interest is, therefore, the development of new methods of quantum simulation and quantum design. This includes methods beyond the local density approximation of density functional theory (LDA), order-N methods, methods dealing with excitations and reactions, and so on, as well as the application of these methods to the design of new materials and devices. The field of quantum design has developed rapidly in the past few years and this conference provides an international forum for experimental and theoretical researchers to exchange ideas. A total of 183 delegates from 8 countries participated in the conference. There were 18 invited talks, 16 oral presentations and 100 posters. There were many new ideas and we foresee dramatic progress in the coming years. The 2nd International Conference on Quantum Simulators and Design will be held in Tokyo, Japan, 31 May-3 June 2008. PMID:21694146

  7. International conference on quantum simulators and design, hiroshima, Japan, 3-6 december 2006.

    PubMed

    Akai, Hisazumi; Oguchi, Tamio

    2007-09-12

    This special issue of Journal of Physics: Condensed Matter comprises selected papers from the 1st International Conference on Quantum Simulators and Design (QSD2006) held in Hiroshima, Japan, 3-6 December 2006. This conference was organized under the auspices of the Development of New Quantum Simulators and Quantum Design Grant-in-Aid for Scientific Research on Priority Areas, Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), and Hiroshima University Quantum design is a computational approach to the development of new materials with specified properties and functionalities. The basic ingredient is the use of quantum simulations to design a material that meets a given specification of properties and functionalities. For this to be successful, the quantum simulation should be highly reliable and be applicable to systems of realistic size. A central interest is, therefore, the development of new methods of quantum simulation and quantum design. This includes methods beyond the local density approximation of density functional theory (LDA), order-N methods, methods dealing with excitations and reactions, and so on, as well as the application of these methods to the design of new materials and devices. The field of quantum design has developed rapidly in the past few years and this conference provides an international forum for experimental and theoretical researchers to exchange ideas. A total of 183 delegates from 8 countries participated in the conference. There were 18 invited talks, 16 oral presentations and 100 posters. There were many new ideas and we foresee dramatic progress in the coming years. The 2nd International Conference on Quantum Simulators and Design will be held in Tokyo, Japan, 31 May-3 June 2008.

  8. Optimal design and uncertainty quantification in blood flow simulations for congenital heart disease

    NASA Astrophysics Data System (ADS)

    Marsden, Alison

    2009-11-01

    Recent work has demonstrated substantial progress in capabilities for patient-specific cardiovascular flow simulations. Recent advances include increasingly complex geometries, physiological flow conditions, and fluid structure interaction. However inputs to these simulations, including medical image data, catheter-derived pressures and material properties, can have significant uncertainties associated with them. For simulations to predict clinically useful and reliable output information, it is necessary to quantify the effects of input uncertainties on outputs of interest. In addition, blood flow simulation tools can now be efficiently coupled to shape optimization algorithms for surgery design applications, and these tools should incorporate uncertainty information. We present a unified framework to systematically and efficient account for uncertainties in simulations using adaptive stochastic collocation. In addition, we present a framework for derivative-free optimization of cardiovascular geometries, and layer these tools to perform optimization under uncertainty. These methods are demonstrated using simulations and surgery optimization to improve hemodynamics in pediatric cardiology applications.

  9. Regulation of Raf-1 and Raf-1 mutants by Ras-dependent and Ras-independent mechanisms in vitro.

    PubMed

    Dent, P; Reardon, D B; Morrison, D K; Sturgill, T W

    1995-08-01

    The serine/threonine kinase Raf-1 functions downstream from Ras to activate mitogen-activated protein kinase kinase, but the mechanisms of Raf-1 activation are incompletely understood. To dissect these mechanisms, wild-type and mutant Raf-1 proteins were studied in an in vitro system with purified plasma membranes from v-Ras- and v-Src-transformed cells (transformed membranes). Wild-type (His)6- and FLAG-Raf-1 were activated in a Ras- and ATP-dependent manner by transformed membranes; however, Raf-1 proteins that are kinase defective (K375M), that lack an in vivo site(s) of regulatory tyrosine (YY340/341FF) or constitutive serine (S621A) phosphorylation, that do not bind Ras (R89L), or that lack an intact zinc finger (CC165/168SS) were not. Raf-1 proteins lacking putative regulatory sites for an unidentified kinase (S259A) or protein kinase C (S499A) were activated but with apparently reduced efficiency. The kinase(s) responsible for activation by Ras or Src may reside in the plasma membrane, since GTP loading of plasma membranes from quiescent NIH 3T3 cells (parental membranes) induced de novo capacity to activate Raf-1. Wild-type Raf-1, possessing only basal activity, was not activated by parental membranes in the absence of GTP loading. In contrast, Raf-1 Y340D, possessing significant activity, was, surprisingly, stimulated by parental membranes in a Ras-independent manner. The results suggest that activation of Raf-1 by phosphorylation may be permissive for further modulation by another membrane factor, such as a lipid. A factor(s) extracted with methanol-chloroform from transformed membranes or membranes from Sf9 cells coexpressing Ras and SrcY527F significantly enhanced the activity of Raf-1 Y340D or active Raf-1 but not that of inactive Raf-1. Our findings suggest a model for activation of Raf-1, wherein (i) Raf-1 associates with Ras-GTP, (ii) Raf-1 is activated by tyrosine and/or serine phosphorylation, and (iii) Raf-1 activity is further increased by a

  10. FEM design and simulation of a short, 10 MV, S-band Linac with Monte Carlo dose simulations

    SciTech Connect

    Baillie, Devin; Aubin, J. St.; Steciw, S.; Fallone, B. G.

    2015-04-15

    Purpose: Current commercial 10 MV Linac waveguides are 1.5 m. The authors’ current 6 MV linear accelerator–magnetic resonance imager (Linac–MR) system fits in typical radiotherapy vaults. To allow 10 MV treatments with the Linac–MR and still fit within typical vaults, the authors design a 10 MV Linac with an accelerator waveguide of the same length (27.5 cm) as current 6 MV Linacs. Methods: The first design stage is to design a cavity such that a specific experimental measurement for breakdown is applicable to the cavity. This is accomplished through the use of finite element method (FEM) simulations to match published shunt impedance, Q factor, and ratio of peak to mean-axial electric field strength from an electric breakdown study. A full waveguide is then designed and tuned in FEM simulations based on this cavity design. Electron trajectories are computed through the resulting radio frequency fields, and the waveguide geometry is modified by shifting the first coupling cavity in order to optimize the electron beam properties until the energy spread and mean energy closely match values published for an emulated 10 MV Linac. Finally, Monte Carlo dose simulations are used to compare the resulting photon beam depth dose profile and penumbra with that produced by the emulated 10 MV Linac. Results: The shunt impedance, Q factor, and ratio of peak to mean-axial electric field strength are all matched to within 0.1%. A first coupling cavity shift of 1.45 mm produces an energy spectrum width of 0.347 MeV, very close to the published value for the emulated 10 MV of 0.315 MeV, and a mean energy of 10.53 MeV, nearly identical to the published 10.5 MeV for the emulated 10 MV Linac. The depth dose profile produced by their new Linac is within 1% of that produced by the emulated 10 MV spectrum for all depths greater than 1.5 cm. The penumbra produced is 11% narrower, as measured from 80% to 20% of the central axis dose. Conclusions: The authors have successfully

  11. Domain contributions to signaling specificity differences between Ras-guanine nucleotide releasing factor (Ras-GRF) 1 and Ras-GRF2.

    PubMed

    Jin, Shan-Xue; Bartolome, Christopher; Arai, Junko A; Hoffman, Laurel; Uzturk, B Gizem; Kumar-Singh, Rajendra; Waxham, M Neal; Feig, Larry A

    2014-06-01

    Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of similar calcium sensors that regulate synaptic plasticity. They are both guanine exchange factors that contain a very similar set of functional domains, including N-terminal pleckstrin homology, coiled-coil, and calmodulin-binding IQ domains and C-terminal Dbl homology Rac-activating domains, Ras-exchange motifs, and CDC25 Ras-activating domains. Nevertheless, they regulate different forms of synaptic plasticity. Although both GRF proteins transduce calcium signals emanating from NMDA-type glutamate receptors in the CA1 region of the hippocampus, GRF1 promotes LTD, whereas GRF2 promotes θ-burst stimulation-induced LTP (TBS-LTP). GRF1 can also mediate high frequency stimulation-induced LTP (HFS-LTP) in mice over 2-months of age, which involves calcium-permeable AMPA-type glutamate receptors. To add to our understanding of how proteins with similar domains can have different functions, WT and various chimeras between GRF1 and GRF2 proteins were tested for their abilities to reconstitute defective LTP and/or LTD in the CA1 hippocampus of Grf1/Grf2 double knock-out mice. These studies revealed a critical role for the GRF2 CDC25 domain in the induction of TBS-LTP by GRF proteins. In contrast, the N-terminal pleckstrin homology and/or coiled-coil domains of GRF1 are key to the induction of HFS-LTP by GRF proteins. Finally, the IQ motif of GRF1 determines whether a GRF protein can induce LTD. Overall, these findings show that for the three forms of synaptic plasticity that are regulated by GRF proteins in the CA1 hippocampus, specificity is encoded in only one or two domains, and a different set of domains for each form of synaptic plasticity.

  12. Design, Test, Redesign: Simulation in Technology, Engineering, and Design Education Classrooms

    ERIC Educational Resources Information Center

    Swinson, Ronnie; Clark, Aaron C.; Ernst, Jeremy V.; Sutton, Kevin

    2016-01-01

    Today's engineers, designers, and technologists are often thrust into the role of problem solver, from the initial design phase of a product or process all the way to final development. Many engineers in manufacturing environments are tasked with solving problems and continuously improving processes to enhance company profitability, efficiency,…

  13. Design for dependability: A simulation-based approach. Ph.D. Thesis, 1993

    NASA Technical Reports Server (NTRS)

    Goswami, Kumar K.

    1994-01-01

    This research addresses issues in simulation-based system level dependability analysis of fault-tolerant computer systems. The issues and difficulties of providing a general simulation-based approach for system level analysis are discussed and a methodology that address and tackle these issues is presented. The proposed methodology is designed to permit the study of a wide variety of architectures under various fault conditions. It permits detailed functional modeling of architectural features such as sparing policies, repair schemes, routing algorithms as well as other fault-tolerant mechanisms, and it allows the execution of actual application software. One key benefit of this approach is that the behavior of a system under faults does not have to be pre-defined as it is normally done. Instead, a system can be simulated in detail and injected with faults to determine its failure modes. The thesis describes how object-oriented design is used to incorporate this methodology into a general purpose design and fault injection package called DEPEND. A software model is presented that uses abstractions of application programs to study the behavior and effect of software on hardware faults in the early design stage when actual code is not available. Finally, an acceleration technique that combines hierarchical simulation, time acceleration algorithms and hybrid simulation to reduce simulation time is introduced.

  14. Simulating an Actomyosin in Vitro Motility Assay: Toward the Rational Design of Actomyosin-Based Microtransporters.

    PubMed

    Ishigure, Yuki; Nitta, Takahiro

    2015-09-01

    We present a simulation study of an actomyosin in vitro motility assay. In vitro motility assays have served as an essential element facilitating the application of actomyosin in nanotechnology; such applications include biosensors and biocomputation. Although actomyosin in vitro motility assays have been extensively investigated, some ambiguities remain, as a result of the limited spatio-temporal resolution and unavoidable uncertainties associated with the experimental process. These ambiguities hamper the rational design of nanodevices for practical applications. Here, with the aim of moving toward a rational design process, we developed a 3D computer simulation method of an actomyosin in vitro motility assay, based on a Brownian dynamics simulation. The simulation explicitly included the ATP hydrolysis cycle of myosin. The simulation was validated by the reproduction of previous experimental results. More importantly, the simulation provided new insights that are difficult to obtain experimentally, including data on the number of myosin motors actually binding to actin filaments, the mechanism responsible for the guiding of actin filaments by chemical edges, and the effect of the processivity of motor proteins on the guiding probabilities. The simulations presented here will be useful in interpreting experimental results, and also in designing future nanodevices integrated with myosin motors.

  15. Nucleophosmin and Nucleolin Regulate K-Ras Plasma Membrane Interactions and MAPK Signal Transduction*

    PubMed Central

    Inder, Kerry L.; Lau, Chiyan; Loo, Dorothy; Chaudhary, Natasha; Goodall, Andrew; Martin, Sally; Jones, Alun; van der Hoeven, Dharini; Parton, Robert G.; Hill, Michelle M.; Hancock, John F.

    2009-01-01

    The spatial organization of Ras proteins into nanoclusters on the inner leaflet of the plasma membrane is essential for high fidelity signaling through the MAPK pathway. Here we identify two selective regulators of K-Ras nanoclustering from a proteomic screen for K-Ras interacting proteins. Nucleophosmin (NPM) and nucleolin are predominantly localized to the nucleolus but also have extranuclear functions. We show that a subset of NPM and nucleolin localizes to the inner leaflet of plasma membrane and forms specific complexes with K-Ras but not other Ras isoforms. Active GTP-loaded and inactive GDP-loaded K-Ras both interact with NPM, although NPM-K-Ras binding is increased by growth factor receptor activation. NPM and nucleolin both stabilize K-Ras levels on the plasma membrane, but NPM concurrently increases the clustered fraction of GTP-K-Ras. The increase in nanoclustered GTP-K-Ras in turn enhances signal gain in the MAPK pathway. In summary these results reveal novel extranucleolar functions for NPM and nucleolin as regulators of K-Ras nanocluster formation and activation of the MAPK pathway. The study also identifies a new class of K-Ras nanocluster regulator that operates independently of the structural scaffold galectin-3. PMID:19661056

  16. Performance of McRAS-AC in the GEOS-5 AGCM: Part 1, Aerosol-Activated Cloud Microphysics, Precipitation, Radiative Effects, and Circulation

    NASA Technical Reports Server (NTRS)

    Sud, Y. C.; Lee, D.; Oreopoulos, L.; Barahona, D.; Nenes, A.; Suarez, M. J.

    2012-01-01

    A revised version of the Microphysics of clouds with Relaxed Arakawa-Schubert and Aerosol-Cloud interaction (McRAS-AC), including, among others, the Barahona and Nenes ice nucleation parameterization, is implemented in the GEOS-5 AGCM. Various fields from a 10-year long integration of the AGCM with McRAS-AC were compared with their counterparts from an integration of the baseline GEOS-5 AGCM, and with satellite data as observations. Generally using McRAS-AC reduced biases in cloud fields and cloud radiative effects are much better over most of the regions of the Earth. Two weaknesses are identified in the McRAS-AC runs, namely, too few cloud particles around 40S-60S, and too high cloud water path during northern hemisphere summer over the Gulf Stream and North Pacific. Sensitivity analyses showed that these biases potentially originated from biases in the aerosol input. The first bias is largely eliminated in a sensitivity test using 50% smaller aerosol particles, while the second bias is much reduced when interactive aerosol chemistry was turned on. The main drawback of McRAS-AC is dearth of low-level marine stratus clouds, probably due to lack of dry-convection, not yet implemented into the cloud scheme. Despite these biases, McRAS-AC does simulate realistic clouds and their optical properties that can improve with better aerosol-input and thereby has the potential to be a valuable tool for climate modeling research because of its aerosol indirect effect simulation capabilities involving prediction of cloud particle number concentration and effective particle size for both convective and stratiform clouds is quite realistic.

  17. Targeting Bcl-2 stability to sensitize cells harboring oncogenic ras.

    PubMed

    Peng, Bo; Ganapathy, Suthakar; Shen, Ling; Huang, Junchi; Yi, Bo; Zhou, Xiaodong; Dai, Wei; Chen, Changyan

    2015-09-01

    The pro-survival factor Bcl-2 and its family members are critical determinants of the threshold of the susceptibility of cells to apoptosis. Studies are shown that cells harboring an oncogenic ras were extremely sensitive to the inhibition of protein kinase C (PKC) and Bcl-2 could antagonize this apoptotic process. However, it remains unrevealed how Bcl-2 is being regulated in this apoptotic process. In this study, we investigate the role of Bcl-2 stability in sensitizing the cells harboring oncogenic K-ras to apoptosis triggered by PKC inhibitor GO6976. We demonstrated that Bcl-2 in Swiss3T3 cells ectopically expressing or murine lung cancer LKR cells harboring K-ras rapidly underwent ubiquitin-dependent proteasome pathway after the treatment of GO6976, accompanied with induction of apoptosis. In this process, Bcl-2 formed the complex with Keap-1 and Cul3. The mutation of serine-17 and deletion of BH-2 or 4 was required for Bcl-2 ubiquitination and degradation, which elevate the signal threshold for the induction of apoptosis in the cells following PKC inhibition. Thus, Bcl-2 appears an attractive target for the induction of apoptosis by PKC inhibition in cancer cells expressing oncogenic K-ras. PMID:26041886

  18. Minireview: physiological and pathological actions of RAS in the ovary.

    PubMed

    Fan, Heng-Yu; Richards, Joanne S

    2010-02-01

    The small G proteins of the RAS superfamily act as molecular switches in the transduction of cellular signals critical for a wide range of normal developmental events as well as pathological processes. However, the functions of Ras genes in ovarian cells have only started to be unveiled. RAS, most likely KRAS that is highly expressed in granulosa cells of growing follicles, appears crucial for mediating the gonadotropin-induced events associated with the unique physiological process of ovulation. By contrast, conditional expression of a constitutively active Kras(G12D) mutant in granulosa cells results in ovulation defects due to the complete disruption of normal follicular growth, cessation of granulosa cell proliferation, and blockage of granulosa cell apoptosis and differentiation. When the tumor suppressor Pten is disrupted conditionally in the Kras(G12D)-expressing granulosa cells, granulosa cell tumors fail to develop. However, ovarian surface epithelial cells expressing the same Pten;Kras(G12D) mutations rapidly become ovarian surface epithelial serous cystadenocarcinomas. In this minireview, we summarize some of the physiological as well as pathological functions of RAS in the rodent ovary, discuss the implications of the Kras(G12D) mutant mouse models for understanding human diseases such as premature ovarian failure and ovarian cancers, and highlight new questions raised by the results of recent studies.

  19. RAS and BRAF in metastatic colorectal cancer management

    PubMed Central

    Gong, Jun; Cho, May

    2016-01-01

    The treatment of metastatic colorectal cancer (mCRC) has been further refined with the development of monoclonal antibodies, cetuximab and panitumumab, towards the epidermal growth factor receptor (EGFR). Anti-EGFR therapy has afforded improved survival in those with wild-type RAS mCRC but provides no benefit and even harm in those with RAS-mutant tumors. BRAF mutations have also been shown to predict lack of clinically meaningful benefit to anti-EGFR therapy in mCRC. Mechanisms of resistance to EGFR blockade in wild-type RAS or BRAF metastatic colorectal tumors appear to converge on the mitogen-activated protein kinase (MAPK) signaling pathway. Clinical trials involving combined BRAF, EGFR, and/or MAPK kinase (MEK) inhibition have shown promising activity in BRAF-mutant mCRC. Here, we review pivotal clinical trials that have redefined our treatment approach in mCRC with respect to anti-EGFR therapy based on RAS and BRAF mutation status. Future studies will likely focus on improving efficacy of anti-EGFR-based therapy in mCRC through sustained MAPK pathway inhibition. PMID:27747083

  20. Analyzing the influence of median cross-section design on highway safety using vehicle dynamics simulations.

    PubMed

    Stine, Jason S; Hamblin, Bridget C; Brennan, Sean N; Donnell, Eric T

    2010-11-01

    Although vehicle dynamics simulations have long been used in vehicle design and crash reconstruction, their use for highway design is rare. This paper investigates the safety of highway medians through iterative simulations of off-road median encroachments. The commercially available software CarSim was used to simulate over one hundred thousand encroachments, representing the entire passenger vehicle fleet and a wide range of encroachment angles, departure speeds, steering inputs, and braking inputs. Each individual simulation output was then weighted using data from previous studies to reflect the probability of each specific accident scenario occurring in a real-life median encroachment. Results of this analysis illustrate the relative influence of median cross-section geometry on the resulting accident outcomes. The simulations indicate that the overall safety of a highway median depends on the occurrence of both vehicle rollover and median crossover events, and the cross-section shape, slope, and width are all shown to greatly affect each of these incidents. An evaluation of the simulation results was conducted with vehicle trajectories from previous experimental crash tests. Further assessment of the aggregate simulation results to actual crash data was achieved through comparison with several databases of crash statistics. Both efforts showed a strong agreement between the simulations and the real-life crash data.

  1. Efforts in developing design and simulation tools for MEMS: DS/MEMS and CA/MEMS

    NASA Astrophysics Data System (ADS)

    Youn, Sung Kie; Kwak, Byung M.; Kwon, Jang-Hyuk; Chang, Su-Young; Huh, Jae S.; Kim, Eugene

    2002-04-01

    In this work, multi-physics simulation software (CA/MEMS) and design-optimization software (DS/MEMS) tailored for MEMS devices are introduced. The CA/MEMS, which is a simulation engine for DS/MEMS, is a 3-D multi-physics analysis code utilizing various numerical methods such as FEM, BEM and FVM to efficiently model MEMS application problems. The current CA/MEMS includes analysis- modules for structural, thermal, electric, electromagnetic and fluidic fields and is capable of the analyses of various coupled- field problems for MEMS applications. DS/MEMS is design optimization engine for MEMS devices. With integrating CA/MEMS and pre/post processor into CAD environment, DS/MEMS is organized to work in parametric CAD platform. DS/MEMS consists of optimal design module and robust design module. The optimal design module provides users three methods nonlinear programming, Taguchi parameter design and the response surface method. The robust design module, which is specially developed for MEMS application, can be used to minimize the perturbation of performances of MEMS devices under uncertainties of MEMS devices, such as process tolerance and the change of operating environments. To verify the efficiency and accuracy of CA/MEMS and the practical usefulness of DS/MEMS, we have been comparing the simulated results of CA/MEMS with those of other commercial codes and experimental data of manufactured MEMS devices, and investigating the performances of the optimized designs through DS/MEMS.

  2. NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition

    PubMed Central

    Garcia-Rendueles, Maria E.R.; Ricarte-Filho, Julio C.; Untch, Brian R.; Landa, Iňigo; Knauf, Jeffrey A.; Voza, Francesca; Smith, Vicki E.; Ganly, Ian; Taylor, Barry S.; Persaud, Yogindra; Oler, Gisele; Fang, Yuqiang; Jhanwar, Suresh C.; Viale, Agnes; Heguy, Adriana; Huberman, Kety H.; Giancotti, Filippo; Ghossein, Ronald; Fagin, James A.

    2015-01-01

    Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation are insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP-TEAD transcriptional program. We find that the three RAS genes are themselves YAP-TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacological disruption of YAP-TEAD with verteporfin blocks RAS transcription and signaling, and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability. PMID:26359368

  3. Multidisciplinary Simulation of Graphite-Composite and Cermet Fuel Elements for NTP Point of Departure Designs

    NASA Technical Reports Server (NTRS)

    Stewart, Mark E.; Schnitzler, Bruce G.

    2015-01-01

    This paper compares the expected performance of two Nuclear Thermal Propulsion fuel types. High fidelity, fluid/thermal/structural + neutronic simulations help predict the performance of graphite-composite and cermet fuel types from point of departure engine designs from the Nuclear Thermal Propulsion project. Materials and nuclear reactivity issues are reviewed for each fuel type. Thermal/structural simulations predict thermal stresses in the fuel and thermal expansion mis-match stresses in the coatings. Fluid/thermal/structural/neutronic simulations provide predictions for full fuel elements. Although NTP engines will utilize many existing chemical engine components and technologies, nuclear fuel elements are a less developed engine component and introduce design uncertainty. Consequently, these fuel element simulations provide important insights into NTP engine performance.

  4. Quasi-optimum design of a six degree of freedom moving base simulator control system

    NASA Technical Reports Server (NTRS)

    Friedland, B.; Ling, C.; Hutton, M. F.

    1973-01-01

    The design of a washout control system for a moving base simulator is treated by a quasi-optimum control technique. The broad objective of the design is to reproduce the sensed motion of a six degree of freedom simulator as accurately as possible without causing the simulator excursions to exceed specified limits. A performance criterion is established that weights magnitude and direction errors in specific force and in angular velocity and attempts to maintain the excursion within set limits by penalizing excessive excursions. A FORTRAN routine for relizing the washout law was developed and typical time histories using the washout routine were simulated for a range of parameters in the penalty- and weighting-functions. These time histories and the listing of the routine are included in the report.

  5. Design optimization of pixel sensors using device simulations for the phase-II CMS tracker upgrade

    NASA Astrophysics Data System (ADS)

    Jain, G.; Bhardwaj, A.; Dalal, R.; Eber, R.; Eichorn, T.; Fernandez, M.; Lalwani, K.; Messineo, A.; Palomo, F. R.; Peltola, T.; Printz, M.; Ranjan, K.; Villa, I.; Hidalgo, S.

    2016-07-01

    In order to address the problems caused by the harsh radiation environment during the high luminosity phase of the LHC (HL-LHC), all silicon tracking detectors (pixels and strips) in the CMS experiment will undergo an upgrade. And so to develop radiation hard pixel sensors, simulations have been performed using the 2D TCAD device simulator, SILVACO, to obtain design parameters. The effect of various design parameters like pixel size, pixel depth, implant width, metal overhang, p-stop concentration, p-stop depth and bulk doping density on the leakage current and critical electric field are studied for both non-irradiated as well as irradiated pixel sensors. These 2D simulation results of planar pixels are useful for providing insight into the behaviour of non-irradiated and irradiated silicon pixel sensors and further work on 3D simulation is underway.

  6. Designing Scenarios for Controller-in-the-Loop Air Traffic Simulations

    NASA Technical Reports Server (NTRS)

    Kupfer, Michael; Mercer, Joey S.; Cabrall, Christopher; Callantine, Todd

    2013-01-01

    Well prepared traffic scenarios contribute greatly to the success of controller-in-the-loop simulations. This paper describes each stage in the design process of realistic scenarios based on real-world traffic, to be used in the Airspace Operations Laboratory for simulations within the Air Traffic Management Technology Demonstration 1 effort. The steps from the initial analysis of real-world traffic, to the editing of individual aircraft records in the scenario file, until the final testing of the scenarios before the simulation conduct, are all described. The iterative nature of the design process and the various efforts necessary to reach the required fidelity, as well as the applied design strategies, challenges, and tools used during this process are also discussed.

  7. Design and CFD Simulation of the Drift Eliminators in Comparison with PIV Results

    NASA Astrophysics Data System (ADS)

    Stodůlka, Jiří; Vitkovičová, Rut

    2015-05-01

    Drift eliminators are the essential part of all modern cooling towers preventing significant losses of liquid water escaping to the enviroment. These eliminators need to be effective in terms of water capture but on the other hand causing only minimal pressure loss as well. A new type of such eliminator was designed and numerically simulated using CFD tools. Results of the simulation are compared with PIV visulisation on the prototype model.

  8. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    PubMed

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types. PMID:26568031

  9. Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane.

    PubMed

    Cho, Kwang-Jin; van der Hoeven, Dharini; Zhou, Yong; Maekawa, Masashi; Ma, Xiaoping; Chen, Wei; Fairn, Gregory D; Hancock, John F

    2015-01-01

    K-Ras must localize to the plasma membrane for biological activity; thus, preventing plasma membrane interaction blocks K-Ras signal output. Here we show that inhibition of acid sphingomyelinase (ASM) mislocalizes both the K-Ras isoforms K-Ras4A and K-Ras4B from the plasma membrane to the endomembrane and inhibits their nanoclustering. We found that fendiline, a potent ASM inhibitor, reduces the phosphatidylserine (PtdSer) and cholesterol content of the inner plasma membrane. These lipid changes are causative because supplementation of fendiline-treated cells with exogenous PtdSer rapidly restores K-Ras4A and K-Ras4B plasma membrane binding, nanoclustering, and signal output. Conversely, supplementation with exogenous cholesterol restores K-Ras4A but not K-Ras4B nanoclustering. These experiments reveal different operational pools of PtdSer on the plasma membrane. Inhibition of ASM elevates cellular sphingomyelin and reduces cellular ceramide levels. Concordantly, delivery of recombinant ASM or exogenous ceramide to fendiline-treated cells rapidly relocalizes K-Ras4B and PtdSer to the plasma membrane. K-Ras4B mislocalization is also recapitulated in ASM-deficient Neimann-Pick type A and B fibroblasts. This study identifies sphingomyelin metabolism as an indirect regulator of K-Ras4A and K-Ras4B signaling through the control of PtdSer plasma membrane content. It also demonstrates the critical and selective importance of PtdSer to K-Ras4A and K-Ras4B plasma membrane binding and nanoscale spatial organization. PMID:26572827

  10. Oncogenicity of human N-ras oncogene and proto-oncogene introduced into retroviral vectors

    SciTech Connect

    Souyri, M.; Vigon, I.; Charon, M.; Tambourin, P. )

    1989-09-01

    The N-ras gene is the only member of the ras family which has never been naturally transduced into a retrovirus. In order to study the in vitro and in vivo oncogenicity of N-ras and to compare its pathogenicity to that of H-ras, the authors have inserted an activated or a normal form of human N-ras cDNA into a slightly modified Harvey murine sarcoma virus-derived vector in which the H-ras p21 coding region had been deleted. The resulting constructions were transfected into NIH 3T3 cells. The activated N-ras-containing construct (HSN) induced 10{sup 4} foci per {mu}g of DNA and was found to be as transforming as H-ras was. After infection of the transfected cells by either the ecotropic Moloney murine leukemia virus or the amphotropic 4070A helper viruses, rescued transforming viruses were injected into newborn mice. Both pseudotypes of HSN virus containing activated N-ras induced the typical Harvey disease with similar latency. However, they found that the virus which contained normal N-ras p21 (HSn) was also pathogenic and induced splenomegaly, lymphadenopathies, and sarcoma in mice after a latency of 3 to 7 weeks. In addition, Moloney murine leukemia virus pseudotypes of N-ras caused neurological disorders in 30% of the infected animals. These results differed markedly from those of previous experiments in which the authors had inserted the activated form of N-ras in the pSV(X) vector: the resulting SVN-ras virus was transforming on NIH 3T3 cells but was poorly oncogenic in vivo. Altogether, these data demonstrated unequivocally that N-ras is potentially as oncogenic as H-ras and that such oncogenic effect could depend on the vector environment.

  11. Phenotypic Screening Identifies Protein Synthesis Inhibitors as H-Ras-Nanocluster-Increasing Tumor Growth Inducers.

    PubMed

    Najumudeen, Arafath K; Posada, Itziar M D; Lectez, Benoit; Zhou, Yong; Landor, Sebastian K-J; Fallarero, Adyary; Vuorela, Pia; Hancock, John; Abankwa, Daniel

    2015-12-15

    Ras isoforms H-, N-, and K-ras are each mutated in specific cancer types at varying frequencies and have different activities in cell fate control. On the plasma membrane, Ras proteins are laterally segregated into isoform-specific nanoscale signaling hubs, termed nanoclusters. As Ras nanoclusters are required for Ras signaling, chemical modulators of nanoclusters represent ideal candidates for the specific modulation of Ras activity in cancer drug development. We therefore conducted a chemical screen with commercial and in-house natural product libraries using a cell-based H-ras-nanoclustering FRET assay. Next to established Ras inhibitors, such as a statin and farnesyl-transferase inhibitor, we surprisingly identified five protein synthesis inhibitors as positive regulators. Using commonly employed cycloheximide as a representative compound, we show that protein synthesis inhibition increased nanoclustering and effector recruitment specifically of active H-ras but not of K-ras. Consistent with these data, cycloheximide treatment activated both Erk and Akt kinases and specifically promoted H-rasG12V-induced, but not K-rasG12V-induced, PC12 cell differentiation. Intriguingly, cycloheximide increased the number of mammospheres, which are enriched for cancer stem cells. Depletion of H-ras in combination with cycloheximide significantly reduced mammosphere formation, suggesting an exquisite synthetic lethality. The potential of cycloheximide to promote tumor cell growth was also reflected in its ability to increase breast cancer cell tumors grown in ovo. These results illustrate the possibility of identifying Ras-isoform-specific modulators using nanocluster-directed screening. They also suggest an unexpected feedback from protein synthesis inhibition to Ras signaling, which might present a vulnerability in certain tumor cell types.

  12. Hybrid airfoil design methods for full-scale ice accretion simulation

    NASA Astrophysics Data System (ADS)

    Saeed, Farooq

    The objective of this thesis is to develop a design method together with a design philosophy that allows the design of "subscale" or "hybrid" airfoils that simulate fullscale ice accretions. These subscale or hybrid airfoils have full-scale leading edges and redesigned aft-sections. A preliminary study to help develop a design philosophy for the design of hybrid airfoils showed that hybrid airfoils could be designed to simulate full-scale airfoil droplet-impingement characteristics and, therefore, ice accretion. The study showed that the primary objective in such a design should be to determine the aft section profile that provides the circulation necessary for simulating full-scale airfoil droplet-impingement characteristics. The outcome of the study, therefore, reveals circulation control as the main design variable. To best utilize this fact, this thesis describes two innovative airfoil design methods for the design of hybrid airfoils. Of the two design methods, one uses a conventional flap system while the other only suggests the use of boundary-layer control through slot-suction on the airfoil upper surface as a possible alternative for circulation control. The formulation of each of the two design methods is described in detail, and the results from each method are validated using wind-tunnel test data. The thesis demonstrates the capabilities of each method with the help of specific design examples highlighting their application potential. In particular, the flap-system based hybrid airfoil design method is used to demonstrate the design of a half-scale hybrid model of a full-scale airfoil that simulates full-scale ice accretion at both the design and off-design conditions. The full-scale airfoil used is representative of a scaled modern business-jet main wing section. The study suggests some useful advantages of using hybrid airfoils as opposed to full-scale airfoils for a better understanding of the ice accretion process and the related issues. Results

  13. Targeting the K-Ras/PDEδ protein-protein interaction: the solution for Ras-driven cancers or just another therapeutic mirage?

    PubMed

    Frett, Brendan; Wang, Yuanxiang; Li, Hong-Yu

    2013-10-01

    The holy grail, finally? After years of unsuccessful attempts at drugging the Ras oncogene, a recent paper by Zimmerman et al. has revealed the possibility of inhibiting Ras signaling on a clinically relevant level by blocking the K-Ras/PDEδ protein-protein interaction. The results, reported in Nature, are highlighted herein with future implications and directions to evaluate the full clinical potential of this research. PMID:23939923

  14. The farnesyltransferase inhibitor, LB42708, inhibits growth and induces apoptosis irreversibly in H-ras and K-ras-transformed rat intestinal epithelial cells

    SciTech Connect

    Kim, Han-Soo; Kim, Ju Won; Gang, Jingu; Wen, Jing; Koh, Sang Seok; Koh, Jong Sung; Chung, Hyun-Ho; Song, Si Young . E-mail: gisong@yumc.yonsei.ac.kr

    2006-09-15

    LB42708 (LB7) and LB42908 (LB9) are pyrrole-based orally active farnesyltransferase inhibitors (FTIs) that have similar structures. The in vitro potencies of these compounds against FTase and GGTase I are remarkably similar, and yet they display different activity in apoptosis induction and morphological reversion of ras-transformed rat intestinal epithelial (RIE) cells. Both FTIs induced cell death despite K-ras prenylation, implying the participation of Ras-independent mechanism(s). Growth inhibition by these two FTIs was accompanied by G1 and G2/M cell cycle arrests in H-ras and K-ras-transformed RIE cells, respectively. We identified three key markers, p21{sup CIP1/WAF1}, RhoB and EGFR, that can explain the differences in the molecular mechanism of action between two FTIs. Only LB7 induced the upregulation of p21{sup CIP1/WAF1} and RhoB above the basal level that led to the cell cycle arrest and to distinct morphological alterations of ras-transformed RIE cells. Both FTIs successfully inhibited the ERK and activated JNK in RIE/K-ras cells. While the addition of conditioned medium from RIE/K-ras reversed the growth inhibition of ras-transformed RIE cells by LB9, it failed to overcome the growth inhibitory effect of LB7 in both H-ras- and K-ras-transformed RIE cells. We found that LB7, but not LB9, decreased the expression of EGFRs that confers the cellular unresponsiveness to EGFR ligands. These results suggest that LB7 causes the induction of p21{sup CIP1/WAF1} and RhoB and downregulation of EGFR that may serve as critical steps in the mechanism by which FTIs trigger irreversible inhibitions on the cell growth and apoptosis in ras-transformed cells.

  15. A large scale software system for simulation and design optimization of mechanical systems

    NASA Technical Reports Server (NTRS)

    Dopker, Bernhard; Haug, Edward J.

    1989-01-01

    The concept of an advanced integrated, networked simulation and design system is outlined. Such an advanced system can be developed utilizing existing codes without compromising the integrity and functionality of the system. An example has been used to demonstrate the applicability of the concept of the integrated system outlined here. The development of an integrated system can be done incrementally. Initial capabilities can be developed and implemented without having a detailed design of the global system. Only a conceptual global system must exist. For a fully integrated, user friendly design system, further research is needed in the areas of engineering data bases, distributed data bases, and advanced user interface design.

  16. Use of agent-based simulations to design and interpret HIV clinical trials.

    PubMed

    Cuadros, Diego F; Abu-Raddad, Laith J; Awad, Susanne F; García-Ramos, Gisela

    2014-07-01

    In this study, we illustrate the utility of an agent-based simulation to inform a trial design and how this supports outcome interpretation of randomized controlled trials (RCTs). We developed agent-based Monte Carlo models to simulate existing landmark HIV RCTs, such as the Partners in Prevention HSV/HIV Transmission Study. We simulated a variation of this study using valacyclovir therapy as the intervention, and we used a male circumcision RCT based on the Rakai Male Circumcision Trial. Our results indicate that a small fraction (20%) of the simulated Partners in Prevention HSV/HIV Transmission Study realizations rejected the null hypothesis, which was no effect from the intervention. Our results also suggest that an RCT designed to evaluate the effectiveness of a more potent drug regimen for HSV-2 suppression (valacyclovir therapy) is more likely to identify the efficacy of the intervention. For the male circumcision RCT simulation, the greater biological effect of the male circumcision yielded a major fraction (81%) of RCT realizations' that rejects the null hypothesis, which was no effect from the intervention. Our study highlights how agent-based simulations synthesize individual variation in the epidemiological context of the RCT. This methodology will be particularly useful for designing RCTs aimed at evaluating combination prevention interventions in community-based RCTs, wherein an intervention׳s effectiveness is challenging to predict. PMID:24792492

  17. Design of flexible manufacturing systems with reuse in a KB simulation environment

    SciTech Connect

    Kovacs, G.L.; Kopacsi, S.; Kmecs, I.

    1996-12-31

    In this paper object-oriented design and the reuse of FMS components in new applications using a hybrid simulation and scheduling system (SSS) will be introduced. The goal of this research is to provide methods and tools to build up FMS simulation models easily, fast and reliable. Simulation is one of the most effective tools for assisting in the design of FMS. SSS has been implemented as a combination of a traditional simulation language (SIMAN/Cinema) and an intelligent expert environment (G2). The application of the real-time, intelligent G2 environment points to one of our recent R&D goal, to intelligent, real-time control of FMS. Reuse in SIMAN/Cinema and in G2 will be analyzed separately and together in general, and in the context of FMS to get acceptable solutions, to build up new simulation models fast and reliable reusing elements of previous, different other models. The design methodology used for model development is based on the object-oriented Rational Rose CASE tool and on use-case design of the OOSE methodology.

  18. Simulation study to determine the impact of different design features on design efficiency in discrete choice experiments

    PubMed Central

    Vanniyasingam, Thuva; Cunningham, Charles E; Foster, Gary; Thabane, Lehana

    2016-01-01

    Objectives Discrete choice experiments (DCEs) are routinely used to elicit patient preferences to improve health outcomes and healthcare services. While many fractional factorial designs can be created, some are more statistically optimal than others. The objective of this simulation study was to investigate how varying the number of (1) attributes, (2) levels within attributes, (3) alternatives and (4) choice tasks per survey will improve or compromise the statistical efficiency of an experimental design. Design and methods A total of 3204 DCE designs were created to assess how relative design efficiency (d-efficiency) is influenced by varying the number of choice tasks (2–20), alternatives (2–5), attributes (2–20) and attribute levels (2–5) of a design. Choice tasks were created by randomly allocating attribute and attribute level combinations into alternatives. Outcome Relative d-efficiency was used to measure the optimality of each DCE design. Results DCE design complexity influenced statistical efficiency. Across all designs, relative d-efficiency decreased as the number of attributes and attribute levels increased. It increased for designs with more alternatives. Lastly, relative d-efficiency converges as the number of choice tasks increases, where convergence may not be at 100% statistical optimality. Conclusions Achieving 100% d-efficiency is heavily dependent on the number of attributes, attribute levels, choice tasks and alternatives. Further exploration of overlaps and block sizes are needed. This study's results are widely applicable for researchers interested in creating optimal DCE designs to elicit individual preferences on health services, programmes, policies and products. PMID:27436671

  19. Design and beam dynamics simulations of an S-band photocathode rf gun

    NASA Astrophysics Data System (ADS)

    Kumar, Arvind; Pant, K. K.; Krishnagopal, S.

    2002-10-01

    We are building an S-band photocathode rf gun as an injector to a 30MeV electron linac for FEL applications. Here we discuss details of design simulations performed using superfish and gdfidl and compare with results of cold tests performed on prototype cells of the photocathode rf gun. We also discuss beam dynamics simulations performed using parmela and report results from simulations to achieve a normalized transverse rms emittance of about 1π mm mrad for a 10ps pulse with 1nC charge in the presence of a solenoid magnetic field used for emittance compensation.

  20. The design and implementation of a multi-waveform radar echo simulator.

    PubMed

    Quan, Yinghui; Gao, Xiaoxiao; Li, Yachao; Xing, Mengdao

    2015-10-01

    Radar simulator is an effective tool for performance assessment of radar systems by accurately reproducing echo signals from complicated environment. This paper presents a design of fast multi-waveform radar echo generation based on deconvolution method. First, scene information is retrieved from outfield data based on improved conjugate gradient algorithm. Then, the new radar echoes are generated through convolution of new transmitted signal and restored scene information. A fast and area-efficient field programmable gate array realization is provided to meet the real-time requirement of radar echo simulation. Finally, a series of experiments are performed to evaluate the effectiveness of proposed radar simulation instrument.

  1. Consensus Standardization of Slurry Simulant Development Process to Reduce Design Risk Within the DOE Complex

    SciTech Connect

    Smith, Gary L.; Enderlin, Carl W.; Wells, Beric E.; Kurath, Dean E.; Denslow, Kayte M.

    2014-06-30

    A critical responsibility of DOE’s Office of Environmental Management is the design, construction, and operation of equipment and facilities to process legacy radioactive waste slurries for safe, long-term disposal. The accomplishment of this mission requires the extensive use of physical and chemical simulants to represent the hazardous radioactive waste. Development and characterization of simulants can often be difficult to compare or utilize as questions exist as to the basis, techniques, or consistency associated with reported parameters. In addition, controversy has existed in the interpretation and application of the characterization data for the wastes that the simulants are intended to represent.

  2. The design and implementation of a multi-waveform radar echo simulator

    NASA Astrophysics Data System (ADS)

    Quan, Yinghui; Gao, Xiaoxiao; Li, Yachao; Xing, Mengdao

    2015-10-01

    Radar simulator is an effective tool for performance assessment of radar systems by accurately reproducing echo signals from complicated environment. This paper presents a design of fast multi-waveform radar echo generation based on deconvolution method. First, scene information is retrieved from outfield data based on improved conjugate gradient algorithm. Then, the new radar echoes are generated through convolution of new transmitted signal and restored scene information. A fast and area-efficient field programmable gate array realization is provided to meet the real-time requirement of radar echo simulation. Finally, a series of experiments are performed to evaluate the effectiveness of proposed radar simulation instrument.

  3. Targeting the RAS pathway by mitogen-activated protein kinase inhibitors.

    PubMed

    Kiessling, Michael K; Rogler, Gerhard

    2015-01-01

    Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer. PMID:26691679

  4. Filtered Mass Density Function for Design Simulation of High Speed Airbreathing Propulsion Systems

    NASA Technical Reports Server (NTRS)

    Givi, P.; Madnia, C. K.; Gicquel, L. Y. M.; Sheikhi, M. R. H.; Drozda, T. G.

    2002-01-01

    The objective of this research is to improve and implement the filtered mass density function (FDF) methodology for large eddy simulation (LES) of high speed reacting turbulent flows. NASA is interested in the design of various components involved in air breathing propulsion systems such as the scramjet. There is a demand for development of robust tools that can aid in the design procedure. The physics of high speed reactive flows is rich with many complexities. LES is regarded as one of the most promising means of simulating turbulent reacting flows.

  5. Current and emerging opportunities for molecular simulations in structure-based drug design

    PubMed Central

    Michel, Julien

    2014-01-01

    An overview of the current capabilities and limitations of molecular simulation of biomolecular complexes in the context of computer-aided drug design is provided. Steady improvements in computer hardware coupled with more refined representations of energetics are leading to a new appreciation of the driving forces of molecular recognition. Molecular simulations are poised to more frequently guide the interpretation of biophysical measurements of biomolecular complexes. Ligand design strategies emerge from detailed analyses of computed structural ensembles. The feasibility of routine applications to ligand optimization problems hinges upon successful extensive large scale validation studies and the development of protocols to intelligently automate computations. PMID:24469595

  6. Three axis electronic flight motion simulator real time control system design and implementation

    SciTech Connect

    Gao, Zhiyuan; Miao, Zhonghua Wang, Xiaohua; Wang, Xuyong

    2014-12-15

    A three axis electronic flight motion simulator is reported in this paper including the modelling, the controller design as well as the hardware implementation. This flight motion simulator could be used for inertial navigation test and high precision inertial navigation system with good dynamic and static performances. A real time control system is designed, several control system implementation problems were solved including time unification with parallel port interrupt, high speed finding-zero method of rotary inductosyn, zero-crossing management with continuous rotary, etc. Tests were carried out to show the effectiveness of the proposed real time control system.

  7. Note: The design of thin gap chamber simulation signal source based on field programmable gate array

    SciTech Connect

    Hu, Kun; Wang, Xu; Li, Feng; Jin, Ge; Lu, Houbing; Liang, Futian

    2015-01-15

    The Thin Gap Chamber (TGC) is an important part of ATLAS detector and LHC accelerator. Targeting the feature of the output signal of TGC detector, we have designed a simulation signal source. The core of the design is based on field programmable gate array, randomly outputting 256-channel simulation signals. The signal is generated by true random number generator. The source of randomness originates from the timing jitter in ring oscillators. The experimental results show that the random number is uniform in histogram, and the whole system has high reliability.

  8. Three axis electronic flight motion simulator real time control system design and implementation.

    PubMed

    Gao, Zhiyuan; Miao, Zhonghua; Wang, Xuyong; Wang, Xiaohua

    2014-12-01

    A three axis electronic flight motion simulator is reported in this paper including the modelling, the controller design as well as the hardware implementation. This flight motion simulator could be used for inertial navigation test and high precision inertial navigation system with good dynamic and static performances. A real time control system is designed, several control system implementation problems were solved including time unification with parallel port interrupt, high speed finding-zero method of rotary inductosyn, zero-crossing management with continuous rotary, etc. Tests were carried out to show the effectiveness of the proposed real time control system. PMID:25554333

  9. Satellite Systems Design/Simulation Environment: A Systems Approach to Pre-Phase A Design

    NASA Technical Reports Server (NTRS)

    Ferebee, Melvin J., Jr.; Troutman, Patrick A.; Monell, Donald W.

    1997-01-01

    A toolset for the rapid development of small satellite systems has been created. The objective of this tool is to support the definition of spacecraft mission concepts to satisfy a given set of mission and instrument requirements. The objective of this report is to provide an introduction to understanding and using the SMALLSAT Model. SMALLSAT is a computer-aided Phase A design and technology evaluation tool for small satellites. SMALLSAT enables satellite designers, mission planners, and technology program managers to observe the likely consequences of their decisions in terms of satellite configuration, non-recurring and recurring cost, and mission life cycle costs and availability statistics. It was developed by Princeton Synergetic, Inc. and User Systems, Inc. as a revision of the previous TECHSAT Phase A design tool, which modeled medium-sized Earth observation satellites. Both TECHSAT and SMALLSAT were developed for NASA.

  10. Space station Simulation Computer System (SCS) study for NASA/MSFC. Volume 4: Conceptual design report

    NASA Technical Reports Server (NTRS)

    1989-01-01

    The Simulation Computer System (SCS) is the computer hardware, software, and workstations that will support the Payload Training Complex (PTC) at Marshall Space Flight Center (MSFC). The PTC will train the space station payload scientists, station scientists, and ground controllers to operate the wide variety of experiments that will be onboard the Space Station Freedom. In the first step of this task, a methodology was developed to ensure that all relevant design dimensions were addressed, and that all feasible designs could be considered. The development effort yielded the following method for generating and comparing designs in task 4: (1) Extract SCS system requirements (functions) from the system specification; (2) Develop design evaluation criteria; (3) Identify system architectural dimensions relevant to SCS system designs; (4) Develop conceptual designs based on the system requirements and architectural dimensions identified in step 1 and step 3 above; (5) Evaluate the designs with respect to the design evaluation criteria developed in step 2 above. The results of the method detailed in the above 5 steps are discussed. The results of the task 4 work provide the set of designs which two or three candidate designs are to be selected by MSFC as input to task 5-refine SCS conceptual designs. The designs selected for refinement will be developed to a lower level of detail, and further analyses will be done to begin to determine the size and speed of the components required to implement these designs.

  11. POLLUTION PREVENTION IN THE DESIGN OF CHEMICAL PROCESSES USING HIERARCHICAL DESIGN AND SIMULATION

    EPA Science Inventory

    The design of chemical processes is normally an interactive process of synthesis and analysis. When one also desires or needs to limit the amount of pollution generated by the process the difficulty of the task can increase substantially. In this work, we show how combining hier...

  12. Using Virtual Simulations in the Design of 21st Century Space Science Environments

    NASA Technical Reports Server (NTRS)

    Hutchinson, Sonya L.; Alves, Jeffery R.

    1996-01-01

    Space Technology has been rapidly increasing in the past decade. This can be attributed to the future construction of the International Space Station (ISS). New innovations must constantly be engineered to make ISS the safest, quality, research facility in space. Since space science must often be gathered by crew members, more attention must be geared to the human's safety and comfort. Virtual simulations are now being used to design environments that crew members can live in for long periods of time without harmful effects to their bodies. This paper gives a few examples of the ergonomic design problems that arise on manned space flights, and design solutions that follow NASA's strategic commitment to customer satisfaction. The conclusions show that virtual simulations are a great asset to 21st century design.

  13. Non-singular terminal dynamic surface control based integrated guidance and control design and simulation.

    PubMed

    Cong, Zhang; Yun-Jie, Wu

    2016-07-01

    In this paper, a novel cascade type design model is transformed from the simulation model, which has a broader scope of application, for integrated guidance and control (IGC). A novel non-singular terminal dynamic surface control based IGC method is proposed. It can guarantee the missile with multiple disturbances fast hits the target with high accuracy, while considering the terminal impact angular constraint commendably. And the stability of the closed-loop system is strictly proved. The essence of integrated guidance and control design philosophy is reached that establishing a direct relation between guidance and attitude equations by "intermediate states" and then designing an IGC law for the obtained integrated cascade design model. Finally, a series of simulations and comparisons with a 6-DOF nonlinear missile that includes all aerodynamic effects are demonstrated to illustrate the effectiveness and advantage of the proposed IGC method.

  14. Non-singular terminal dynamic surface control based integrated guidance and control design and simulation.

    PubMed

    Cong, Zhang; Yun-Jie, Wu

    2016-07-01

    In this paper, a novel cascade type design model is transformed from the simulation model, which has a broader scope of application, for integrated guidance and control (IGC). A novel non-singular terminal dynamic surface control based IGC method is proposed. It can guarantee the missile with multiple disturbances fast hits the target with high accuracy, while considering the terminal impact angular constraint commendably. And the stability of the closed-loop system is strictly proved. The essence of integrated guidance and control design philosophy is reached that establishing a direct relation between guidance and attitude equations by "intermediate states" and then designing an IGC law for the obtained integrated cascade design model. Finally, a series of simulations and comparisons with a 6-DOF nonlinear missile that includes all aerodynamic effects are demonstrated to illustrate the effectiveness and advantage of the proposed IGC method. PMID:27049772

  15. K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling.

    PubMed

    Wang, Man-Tzu; Holderfield, Matthew; Galeas, Jacqueline; Delrosario, Reyno; To, Minh D; Balmain, Allan; McCormick, Frank

    2015-11-19

    K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-Ras(V12)-transformed cells enhances their tumor initiating capacity. Interrupting K-Ras-calmodulin binding using genetic means or by treatment with an orally active protein kinase C (PKC)-activator, prostratin, represses tumorigenesis in K-Ras mutant pancreatic cancer cells. These findings provide an alternative way to selectively target this "undruggable" protein.

  16. N-terminally myristoylated Ras proteins require palmitoylation or a polybasic domain for plasma membrane localization.

    PubMed

    Cadwallader, K A; Paterson, H; Macdonald, S G; Hancock, J F

    1994-07-01

    Plasma membrane targeting of Ras requires CAAX motif modifications together with a second signal from an adjacent polybasic domain or nearby cysteine palmitoylation sites. N-terminal myristoylation is known to restore membrane binding to H-ras C186S (C-186 is changed to S), a mutant protein in which all CAAX processing is abolished. We show here that myristoylated H-ras C186S is a substrate for palmitoyltransferase, despite the absence of C-terminal farnesylation, and that palmitoylation is absolutely required for plasma membrane targeting of myristoylated H-ras. Similarly, the polybasic domain is required for specific plasma membrane targeting of myristoylated K-ras. In contrast, the combination of myristoylation plus farnesylation results in the mislocalization of Ras to numerous intracellular membranes. Ras that is only myristoylated does not bind with a high affinity to any membrane. The specific targeting of Ras to the plasma membrane is therefore critically dependent on signals that are contained in the hypervariable domain but can be supported by N-terminal myristoylation or C-terminal prenylation. Interestingly, oncogenic Ras G12V that is localized correctly to the plasma membrane leads to mitogen-activated protein kinase activation irrespective of the combination of targeting signals used for localization, whereas Ras G12V that is mislocalized to the cytosol or to other membranes activates mitogen-activated protein kinase only if the Ras protein is farnesylated.

  17. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.

    PubMed

    Burns, Michael C; Sun, Qi; Daniels, R Nathan; Camper, DeMarco; Kennedy, J Phillip; Phan, Jason; Olejniczak, Edward T; Lee, Taekyu; Waterson, Alex G; Rossanese, Olivia W; Fesik, Stephen W

    2014-03-01

    Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras:Son of Sevenless (SOS):Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras:SOS:Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling.

  18. RasGRP1 Transgenic Mice Develop Cutaneous Squamous Cell Carcinomas in Response to Skin Wounding

    PubMed Central

    Diez, Federico R.; Garrido, Ann A.; Sharma, Amrish; Luke, Courtney T.; Stone, James C.; Dower, Nancy A.; Cline, J. Mark; Lorenzo, Patricia S.

    2009-01-01

    Models of epidermal carcinogenesis have demonstrated that Ras is a critical molecule involved in tumor initiation and progression. Previously, we have shown that RasGRP1 increases the susceptibility of mice to skin tumorigenesis when overexpressed in the epidermis by a transgenic approach, related to its ability to activate Ras. Moreover, RasGRP1 transgenic mice develop spontaneous papillomas and cutaneous squamous cell carcinomas, some of which appear to originate in sites of injury, suggesting that RasGRP1 may be responding to signals generated during the wound-healing process. In this study, we examined the response of the RasGRP1 transgenic animals to full-thickness incision wounding of the skin, and demonstrated that they respond by developing tumors along the wounded site. The tumors did not present mutations in the H-ras gene, but Rasgrp1 transgene dosage correlated with tumor susceptibility and size. Analysis of serum cytokines showed increased levels of granulocyte colony-stimulating factor in transgenic animals after wounding. Furthermore, in vitro experiments with primary keratinocytes showed that granulocyte colony-stimulating factor stimulated Ras activation, although RasGRP1 was dispensable for this effect. Since granulocyte colony-stimulating factor has been recently associated with proliferation of skin cancer cells, our results may help in the elucidation of pathways that activate Ras in the epidermis during tumorigenesis in the absence of oncogenic ras mutations. PMID:19497993

  19. Absence of K-Ras Reduces Proliferation and Migration But Increases Extracellular Matrix Synthesis in Fibroblasts.

    PubMed

    Muñoz-Félix, José M; Fuentes-Calvo, Isabel; Cuesta, Cristina; Eleno, Nélida; Crespo, Piero; López-Novoa, José M; Martínez-Salgado, Carlos

    2016-10-01

    The involvement of Ras-GTPases in the development of renal fibrosis has been addressed in the last decade. We have previously shown that H- and N-Ras isoforms participate in the regulation of fibrosis. Herein, we assessed the role of K-Ras in cellular processes involved in the development of fibrosis: proliferation, migration, and extracellular matrix (ECM) proteins synthesis. K-Ras knockout (KO) mouse embryonic fibroblasts (K-ras(-/-) ) stimulated with transforming growth factor-β1 (TGF-β1) exhibited reduced proliferation and impaired mobility than wild-type fibroblasts. Moreover, an increase on ECM production was observed in K-Ras KO fibroblasts in basal conditions. The absence of K-Ras was accompanied by reduced Ras activation and ERK phosphorylation, and increased AKT phosphorylation, but no differences were observed in TGF-β1-induced Smad signaling. The MEK inhibitor U0126 decreased cell proliferation independently of the presence of K-ras but reduced migration and ECM proteins expression only in wild-type fibroblasts, while the PI3K-AKT inhibitor LY294002 decreased cell proliferation, migration, and ECM synthesis in both types of fibroblasts. Thus, our data unveil that K-Ras and its downstream effector pathways distinctively regulate key biological processes in the development of fibrosis. Moreover, we show that K-Ras may be a crucial mediator in TGF-β1-mediated effects in this cell type. J. Cell. Physiol. 231: 2224-2235, 2016. © 2016 Wiley Periodicals, Inc.

  20. A high precision dual feedback discrete control system designed for satellite trajectory simulator

    NASA Astrophysics Data System (ADS)

    Liu, Ximin; Liu, Liren; Sun, Jianfeng; Xu, Nan

    2005-08-01

    Cooperating with the free-space laser communication terminals, the satellite trajectory simulator is used to test the acquisition, pointing, tracking and communicating performances of the terminals. So the satellite trajectory simulator plays an important role in terminal ground test and verification. Using the double-prism, Sun etc in our group designed a satellite trajectory simulator. In this paper, a high precision dual feedback discrete control system designed for the simulator is given and a digital fabrication of the simulator is made correspondingly. In the dual feedback discrete control system, Proportional- Integral controller is used in velocity feedback loop and Proportional- Integral- Derivative controller is used in position feedback loop. In the controller design, simplex method is introduced and an improvement to the method is made. According to the transfer function of the control system in Z domain, the digital fabrication of the simulator is given when it is exposed to mechanism error and moment disturbance. Typically, when the mechanism error is 100urad, the residual standard error of pitching angle, azimuth angle, x-coordinate position and y-coordinate position are 0.49urad, 6.12urad, 4.56urad, 4.09urad respectively. When the moment disturbance is 0.1rad, the residual standard error of pitching angle, azimuth angle, x-coordinate position and y-coordinate position are 0.26urad, 0.22urad, 0.16urad, 0.15urad respectively. The digital fabrication results demonstrate that the dual feedback discrete control system designed for the simulator can achieve the anticipated high precision performance.